University College London

UKRI Gateway to Research · FY 2025 · 2025-07

Quantum computers could be useful for simulating biological and chemical reactions beyond the reach of traditional computers. Among many other advances, this will revolutionise medicine and materials discovery. Various technologies are explored for quantum computing. For example, superconductors used by Google and IBM rely on qubits, two-level quantum systems with distinct energy spacing. To solve real-world problems, arrays of millions of qubits are needed. This current implementation, operating at microwave frequencies (a few GHz), demands colder temperatures than even outer space - and the only refrigerators that can support this have limited cooling power. Higher frequencies would allow an increased working temperature, although different superconducting materials would also be needed. Furthermore, copper cables for controlling the qubit arrays electrically introduces unwanted heat, limiting the refrigerator’s capacity to support around 1000 qubits. I aim to develop the enabling technology needed to realise a scalable quantum computer operating at THz frequencies. I propose two solutions: replacing electrical cables with optical fibres for control-signal distribution, and elevating working frequencies to the THz range. Generating high frequencies is challenging; however, I have devised a light-based system to achieve this leap, enabling operation at higher temperatures. These shifts allow the use of cooling technologies with greater power, potentially scaling the quantum technology to hundreds of millions of qubits.

UKRI Gateway to Research · FY 2025 · 2025-07

The Early Life Cohort (ELC) will collect rich, longitudinal data on a 30,000-strong cohort of infants born across the UK in the mid-2020s. The ELC will be the first nationwide birth cohort in a quarter of a century, providing urgently needed data for science, practice and policy on a new generation of children and families. The study will paint a nationally representative picture of the early environments shaping the developmental, social, and health trajectories of children in a period of unprecedented social, technological, and environmental change. Using a stratified sampling strategy based on birth records, boosted recruitment in devolved UK nations, disadvantaged areas and for minoritised ethnic groups, and an inclusive approach to cohort engagement, the ELC will ensure that traditionally under-represented and 'seldom-heard' populations are well represented from the outset and retained in sufficient numbers over time. Ongoing input from the public, expert advisory groups and regular open consultations will ensure the continuing relevance and timeliness of the ELC's data collection strategy over its lifetime. In this first phase of the study, infants and their families will be recruited from across the UK. It will include face-to-face data collection at 9-10 months and 3 years of age. These intensive sweeps will collect high-quality behavioural, cognitive, and health assessments, alongside biological samples and key contextual data. Between these two waves, families will be invited to complete questionnaires on a bespoke smartphone app, enabling low-burden data collection at higher frequency and on a wider range of topics than is possible from the two major waves. Record linkage will also substantially enhance the analytical scope of the data collected, incorporating information from parent and child education, health and social care records, including retrospectively from pregnancy and early infancy, providing additional indicators of outcomes, contextual stressors and vulnerabilities. Together, the approach we propose combines inclusivity, positive cohort engagement, measurement depth and breadth alongside scale and cost-efficiency. To deliver this, Co-Directors Professors Goodman, Calderwood and Fearon, lead a scientific and delivery leadership team (SDLT) with senior collaborators from universities in Wales, Scotland and Northern Ireland and the Fatherhood Institute and a wider project team. Together with specific expertise from National Children's Bureau, the Anna Freud Centre, the Institute for Health Visiting and Bryson-Purdon Social Research, we collectively offer unrivalled scientific and operational expertise alongside exceptional policy and societal reach, to deliver the objectives of the project. A robust management and governance structure, with ESRC and study advisory groups, as well as wider open consultations, provides assurance on both delivery and scientific quality.

UKRI Gateway to Research · FY 2025 · 2025-07

In the UK, approximately 150,000 people are living with Parkinson's disease (PD) and this is estimated to rise to around 175,000 people by 2030. Therefore, PD is a common and debilitating cause of morbidity and mortality in the UK, representing significant economic cost to the National Health Service. In current clinical practice, the diagnosis of PD is made by a physician-led clinical examination as there are no objective tests that reliably diagnose the condition. However, achieving an early and accurate clinical diagnosis of PD is challenging because at that stage there is significant clinical overlap with Parkinson-plus disorders, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which also lack objective diagnostic tests. Being able to accurately diagnose Parkinsonian disorders at an early disease stage is important because it removes diagnostic uncertainty for patients. It also enables patients to be recruited to clinical trials at a stage in their disease when minimal irreversible damage has occurred, therefore representing a window of opportunity for effective drugs to stop or slow disease progression. The primary neuropathology of PD and MSA is characterised by a build-up of pathological forms of alpha-synuclein protein (Lewy bodies) in brain cells which leads to progressive brain cell loss and associated symptoms of PD. Of note, secondary Lewy body co-pathology can be found in other neurodegenerative disorders. In contrast, brain cell loss in PSP is associated with a build-up of pathological 4-repeat tau (4RT) protein in brain cells, and this never occurs as a co-pathology in other neurodegenerative disorders. Recently, an alpha-synuclein seed amplification assay (SAA) test has been developed. When applied to patient CSF samples, it reliably detects the presence of alpha-synuclein related PD pathology at the earliest stages of disease, and may even enable differentiation between PD- and MSA-type alpha-synuclein pathology. However, our own recent work has shown that the CSF alpha-synuclein SAA is also positive in a subset of PSP patient samples, likely due to alpha-synuclein co-pathology which may impact on disease trajectory. Therefore, using alpha-synuclein SAA in isolation as a diagnostic biomarker cannot reliably differentiate between PD and PSP. As such, there is a need to develop a 4RT tau SAA (which we expect to only be positive in PSP CSF samples) to use in combination with alpha-synuclein SAA for accurate diagnostic differentiation between PD, MSA and PSP. Accordingly, we have developed a novel 4RT SAA and are currently optimising its application to CSF samples. In this project we aim to: 1) apply alpha-synuclein and 4RT SAAs in combination to CSF samples from patients with: a) clinically established PD and PSP; b) early symptoms of an underlying Parkinsonian disorder that is clinically indeterminate. 2) assess whether quantitative kinetic measures that are derived from the alpha-synuclein and 4RT SAA tests (in combination with other biomarkers of interest) can predict and/or track clinical disease progression in PD and PSP. 3) use SAA kinetic measures as quantitative traits in separate genome-wide association studies of PD and PSP. This ambitious project has the potential to address major unmet needs for patients with parkinsonian disorders. Primarily, our results will provide evidence for combining alpha-synuclein and 4RT SAA testing for early and accurate diagnosis and prognosis of PD and PSP. Furthermore, our approach of integrating SAA kinetic measures and genetic data has the potential to identify novel treatment targets.

UKRI Gateway to Research · FY 2025 · 2025-07

Mass spectrometry (MS)-based proteomics has revolutionised cell biology by enabling the identification of tens of thousands of proteins per cell, and the detailed characterisation of post-translational modifications (PTMs). Traditionally, these analyses needed large quantities of protein, which led to bulk and average readouts that obscured important differences between individual cells. Single-cell technologies on the contrary now allow for the study of cellular heterogeneity and protein dynamics at an unprecedented resolution. Recent advancements in sample preparation and mass spectrometry instrumentation have made single-cell proteomics feasible. It is now possible to reproducibly identify over 4,000 proteins from single-cells, and significantly improve the depth of coverage for crosslinking experiments, enhancing our understanding of protein-protein interactions (PPIs) and cellular functions. These capabilities are crucial for studying complex biological systems, as proteins carry out essential cellular functions and their interactions influence cellular behaviour. We request funds to purchase the latest and most sensitive mass spectrometer, capable of such single-cell measurements. The new mass spectrometer will be placed in the UCL Mass Spectrometry Science Technology Platform (MS-STP), ensuring broad community access and supporting diverse research initiatives. The MS-STP has a growing demand for single-cell proteomics, which will provide deeper insights into cellular heterogeneity and function. Since its establishment in 2019, UCL has heavily invested in the MS-STP, including ancillary instrumentation for isolating and processing single-cells for downstream MS analyses, as well as the latest deep-learning-enabled bioinformatics tools for processing MS data. The only missing component for a complete single-cell proteomics workflow is a single-cell capable mass spectrometer. The proposed equipment will advance research aligned with BBSRC's strategic goals in areas such as industrial biotechnology, adaptive immunity, DNA repair mechanisms, proteostasis and cell competition, to name a few. Given the limited availability of such advanced instruments in the UK, UCL is positioned to lead in this field, driving innovation and impact in biosciences. The MS-STP facility is accessible not only to researchers at UCL but also to those from institutions outside UCL and even outside the UK. This broad accessibility has attracted a diverse range of users, including those from industry. The facility offers comprehensive training programs for users, enabling them to operate mass spectrometers and stay updated with the latest advancements in MS technology. This training ensures that users can effectively utilise the equipment for their research, fostering a collaborative and innovative environment and providing highly skilled personnel in this exciting new technology for the benefit of the UK economy.

UKRI Gateway to Research · FY 2025 · 2025-07

We seek to acquire a state-of-the-art light-sheet fluorescence microscope that combines multi-view and multi-position imaging. This new microscope will address a major gap in our imaging capability by allowing imaging of organs and tissues at low phototoxicity and with high temporal and spatial resolution over long periods -up to several days- of development. Recognising the critical importance of this equipment, UCL is contributing 50% of the total economic cost. Our proposal delivers exceptional value for money and will have an immediate, far-reaching impact on many world-leading research laboratories funded by UKRI and other agencies, at UCL. A major research focus at UCL is the investigation of developmental, morphogenetic and homeostatic processes across scales, from molecular to organ level. These studies utilise various model organisms and examine both normal and pathological conditions. Recent efforts have expanded to include the use of organoids, facilitating research into tissue and organ development and the cell biology underlying these processes. Morphogenesis is a dynamic process that involves patterns of cell movement and shape remodelling alongside cell fate acquisition. These processes can be promoted through remodelling of cell adhesion or polarity; both apical-basal and planar, cytoplasmic re-organisation, intracellular transport, and membrane trafficking. Investigating these pathways and collective cell behaviours requires live-imaging technologies capable of bridging the molecular to organ scales, while also allowing long-term live imaging; tens of hours to days. The Viventis Deep Dual View Light-Sheet Fluorescent microscope provides such capabilities. It is uniquely suited for long-term culture of living samples including embryos and organoids (up to 90 hours for embryoids: https://www.nature.com/articles/s41592-024-02213-w and 40 hours for mouse embryos: https://www.biorxiv.org/content/10.1101/2023.12.19.572445v2). This is due to its open-top configuration, which supports media exchange even during acquisition. It was recently used for live imaging of human embryos generated through in vitro fertilization (IVF) treatments (https://www.biorxiv.org/content/10.1101/2024.09.26.614906v1). Moreover, this microscope enables high-throughput imaging through its multilocation capability, which allows for the study of both normal and perturbed conditions in a single experiment. This new equipment will be integrated into the Faculty of Life Science (FLS) Science Technology Platform, specifically in the Centre for Cell and Molecular Dynamics’ Light Microscopy Platform (CCMD), where it will be managed by a team of five expert research technical professionals. This setup will ensure optimum maintenance and user training. The microscope is user-friendly and will serve numerous laboratories (>15) across various UCL departments.

UKRI Gateway to Research · FY 2025 · 2025-07

Approximately 74% of proteins in the human proteome are not targeted by any known drugs. With a BBSRC funded LIDo PhD studentship we have produced a new technology platform that degrades and removes cellular targets by initiating the natural autophagy process at the site of the target. We term our novel degradation technology platform, AUTOCURE. A key advantage of this platform is the ability to produce clinically relevant degradation of conventionally undruggable targets, such as the cancer super-controller MYC and faulty mitochondria. This proposal aims to develop this technology into a commercial platform for wide use across many targets and indications. Our inability to drug many promising therapeutic targets prevents us from turning key molecular insights into effective healthcare interventions. PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new exciting degradation technologies which utilise the cells’ 26S proteasome to degrade target proteins. However, PROTACs and molecular glues are mostly limited to the degradation of small soluble proteins. Autophagy: a universally conserved cellular recycling mechanism, is required for the degradation of damaged or long-lived proteins, cytoplasmic contents, and organelles like mitochondria - a significantly wider substrate profile versus the 26S proteasome. We have generated bi-functional molecules to co-localise the autophagy initiator kinase ULK1 with our target of interest, enabling degradation by the de novo creation of an autophagosome around the target. We termed these molecules ULK1-TArgeting Chimeras (ULKTACs) . Our data shows AUTOCURE is non-toxic, does not disrupt cell homeostasis, and leaves, for example healthy mitochondria untouched. AUTOCURE does not use existing autophagosomes for targeted degradation, but uniquely initiates autophagosomes at the targeted site. This represents a significant advance over existing autophagy-based technologies . Our technology also degrades multiple target types as shown by our strong proof of concept data. We have directly targeted the previously undruggable transcription factor MYC, which is amplified and aberrantly expressed in >70% of cancers. MYC is intrinsically disordered, lacking well-defined pockets for traditional drugs. Using our AUTOCURE platform we repurposed a weak (10 micromolar) c-MYC inhibitor into an ULKTAC to enable the direct autophagy-mediated degradation of the c-MYC/MAX complex at nanomolar concentrations. This impaired c-MYC controlled gene expression, rescued oncogenic c-MYC induced replication stress and importantly specifically kills MYC-addicted cancer cells . A second undruggable target are damaged mitochondria: in cells from patients with Parkinson’s disease, we showed effective clearance of damaged or fragmented mitochondria. Studies on cells from people with ALS (motor neurone disease) are ongoing. Together these examples illustrate the power of this approach. We will provide industry standard, in vitro and in vivo assessments that define the pharmacological and toxicological properties of our new prototype drugs. Project aims: 1) Establish what determines the potency and effectiveness of targeted degradation by ULKTACs 2) Optimise the ULK ligand agonist and the in vivo pharmacokinetics of ULKTACs. 3) Optimise and establish the anti-cancer efficacy of MYC-ULKTAC. 4) In collaboration we will expand our platform using in vitro models of neurodegenerative diseases (Parkinson’s disease, ALS), and infection models (HIV-1, Epstein – Barr virus). Our overall aim is to establish AUTOCURE as a platform technology to maximise its clinical and commercial impact and provide industry standard, in vitro and in vivo assessments that define the pharmacological and toxicological properties of new prototype drugs.

UKRI Gateway to Research · FY 2025 · 2025-07

Time-use diary evidence, representing national populations throughout the year, is exhaustive—no aspect of any activity undertaken by any member of the society is excluded. It covers the entire range of unpaid work and consumption. It provides information about paid work not available from any other source (when, during the day and the week, does it happen?).  It has a uniquely broad range of applications across economics. sociology, public health and environmental studies. The Centre for Time Use Research (CTUR) has a leading international role in collecting, harmonising and analysing time use diary data. It proposed the Harmonised European Time Use Study to Eurostat and initially chaired the HETUS design committee.  Its members have organised UK time-use data collections since the early 1980s, sometimes collaborating with, sometimes (eg 2014-15) substituting for, the Office of National Statistics. It provides consultancy services for academic researchers and government agencies (recently the Social Mobility Commission and the ILO) It compiles the Multinational Time Use Study (MTUS), currently including >100 surveys covering 30 countries from 1961 to 2020, the largest collection of fully anonymised, publicly downloadable time-diary microdata available anywhere, with 2.17 million days of data ready-prepared for comparative analysis, and >2000 users. It writes downloadable programmes simplifying access to, and increasing usability of, complex-structured diary datasets, It carries out research on diary design and performance, and investigations of gender, class and age variations in time use, household processes for providing care and money income, of the health and wellbeing effects of physical exercise, on work and recreational practices, and on innovations in National Accounts. The ESRC has been supporting CTUR, providing grants 2004-2013 and then Centre and Legacy funding (2014-2024).  UCL has now agreed to appoint a new permanent Professorial member of staff to lead the CTUR program from September 2025 (replacing Gershuny as Director).  The current grant proposal is intended to cover this transitional period (legacy funding ends September 2024; Gershuny will remain in an advisory role after the new appointment). CTUR is actively collaborating with the ONS and the Economic Statistics Centre of Excellence based at Kings College London, contributing to the design of the UK’s new national time-use survey.  This “Online Time Use Survey” OTUS) is currently underfunded, needing more respondents, and—rather than the currently proposed reduction from two to one monthly samples-per-year—a more continuous spread of sampling across the year.  ESCoE/CTUR is also concerned about the design of the current OTUS instrument.  Our aim is to arrive at a shared design, meeting both the ONS’ immediate needs, and those of the wider research community that can be supported by the ESRC. This proposal includes five work packages: Contributing to the development of new time dairy samples for a variety of research purposes. Supporting the collection of new UK time-use survey data by the Economic Statistics Centre of Excellence in collaboration with the ONS Extending the coverage of the MTUS—lengthening existing national data series with the latest surveys, and enlarging it to include new countries. Developing new methods for extending the scope of National Accounts, and producing other time-based social indicators of individual and collective wellbeing. Advising new and continuing users on the design, collection and analysis of time diary data; preparing and delivering online course materials. Training via short courses, a doctoral studentship, secondments and hosting visitors.

UKRI Gateway to Research · FY 2025 · 2025-06

Bowel cancer afflicts >900,000 people worldwide and is a major source of cancer-related mortality. While surgical resection of primary bowel tumours is occasionally curative, metastases in other organs such as the liver are responsible for residual disease and ultimately patient death. Existing bowel cancer chemotherapies target fast-growing cancer cells while sparing slow-growing cells. Unfortunately, new research has revealed that bowel cancer cells can rapidly change from fast-growing into slow-growing cells to escape chemotherapy. Such cellular 'plasticity' is now considered to be a fundamental feature of bowel cancer. Unfortunately we currently have no way to target plasticity to treat either primary or metastatic bowel cancer. This MRC Research Grant will explore the inter- and intra-cellular signalling mechanisms controlling cellular plasticity in both primary and metastatic bowel cancer. Using a combination of patient-derived mini-tumour models (known as organoids) from primary and metastatic bowel cancer, novel high-throughput single-cell analysis technologies, and advanced computational methods, we will chart the cell-extrinsic and cell-intrinsic processes that regulate bowel cancer plasticity. Specifically, we will address the following research questions: Question 1: What are the cell-extrinsic cues that regulate cellular plasticity and drug responses in primary and metastatic CRC and how do these vary across patients? Question 2: How do cell-extrinsic cues signal via post-translational modifications (PTMs) to regulate gene expression programmes required for plasticity? Question 3: How can we control patient-specific stem cell plasticity to improve therapeutic responses? We will investigate these questions by integrating three novel technology platforms: 1) A cohort of x20 primary and x20 metastatic CRC patient-derived organoids (PDOs) from Memorial Sloan Kettering Cancer Centre (MSKCC) (Moorman et al., Nature, in press) and University College London Hospital (UCLH). 2) Thiol-organoid barcoding in situ mass cytometry (TOBis MC) (from Qin et al Nature Methods, 2020 and Sufi et al Nature Protocols, 2021). 3) Split-pool Indexing siGNalling AnaLysis by sequencing (SIGNAL-seq) (from Opzoomer et al, bioRxiv, 2024). By combining a unique cohort of primary and metastatic CRC patient organoids with novel single-cell analysis technologies we will chart cell-extrinsic and cell-intrinsic regulation of cancer cell states. We will measure how plasticity responses vary between primary and metastatic cancer cells and map how patient-specific plasticity relates to therapy response. These mechanistic insights will be used to rationally overcome plasticity-induced chemoresistance to provide novel therapeutic options for advanced CRC.  

UKRI Gateway to Research · FY 2025 · 2025-06

Antibiotic combination treatment is an essential strategy to combat complex, antimicrobial resistant (AMR) infections. To date, antibiotic combination treatments have been derived empirically and may be suboptimal.  Defining the optimal drug combination of antibiotics and the associated dosing schedules to maximise efficacy and minimise the risk for AMR selection is complex and requires extensive preclinical development. To advance development and optimisation of antibiotic combination treatments, and exploit their underused potential, there is an urgent need for standardised, regulatory-endorsed experimental and computational pharmacokinetic/pharmacodynamic (PK/PD) methodologies. The COMBAT-AMR project aims to develop a standardised toolbox of connected experimental and computational approaches tailored to the pre-clinical design of antibiotic combination treatments. The unique integrative approach proposed will enable the efficient, rational translational development of antibacterial combinations, which are optimised towards treatment of AMR-associated bacterial infections and preventing AMR emergence. The workflows established in COMBAT-AMR will be applied to several exemplar antibiotic combination treatments to further evaluate and optimise their potential, and to demonstrate the application of the toolbox. The project will result in experimental protocols and open-source computational modelling resources for which we will seek regulatory qualification and support for clinical combination breakpoint determination to optimise clinical and investigational application.

UKRI Gateway to Research · FY 2025 · 2025-06

Overview:       For the past two decades, the PIs have studied the structure of fault damage zones with the intent of understanding how damage zone architecture develops over long term fault evolution and provides feedbacks with the earthquake rupture in the principal slip zone, resulting – along with work of others – in a deep literature regarding damage zone structure, the impact of fault zone damage on effective constitutive behavior and permeability, and scaling laws between slip, fault damage intensity, and fault zone thickness. Much like the debate on the genesis/significance of pseudotachylyte toward the end of the 20th century, leading to insights into earthquake source characteristics from pseudotachylyte-bearing faults, the next step in advancing the state of the art in damage zone science is to make direct connections between outcrop observables and earthquake source characteristics. A fundamental question in our research is whether fault damage zones contain information about Mmax (the maximum earthquake size a fault can host) in terms of type, style, extent, width and degree of damage. We propose to developing criteria to distinguish damage related to earthquake rupture from quasi-static damage accrued over the longer-term fault evolution, and to use these criteria to test the hypothesis that the style and intensity of damage on faults that experience earthquake magnitudes greater than ~Mw6.6 to 6.8 can be clearly distinguished from that on faults experiencing smaller magnitude events.  We suggest the difference in damage state can be explained by increased energy dissipation by off fault deformation above a critical moment magnitude threshold, and understanding this relation yields the potential for estimating Mmax for active faults with incomplete historical and paleoseismological records. We propose to conduct a collaborative study utilizing field-based structural geology, cutting edge rock mechanics experiments, and theoretical rock and fracture mechanics to provide a roadmap for identifying uniquely seismic features preserved in damage zones, and to test the overarching hypothesis that Mmax can be estimated by examining the damage zone structure of active strike slip faults. Intellectual Merit: Mmax is a critical component of probabilistic seismic hazard assessment (PSHA) as it limits the maximum size of earthquakes considered in a seismic hazard model. The slip rates of faults are the main driver of hazard, but Mmaxcontrols the upper end of moment release. If Mmax is large, then a significant proportion of the long-term seismic moment release is accommodated by rare large earthquakes.  In PSHA, this actually decreases hazard because it results in fewer moderate earthquakes, which also generate strong shaking but have higher recurrence rates. Hence, quantitative information on Mmax is a significant aspect of quantifying hazard to critical facilities. Current approaches for determining Mmax can be strengthened by developing independent criteria that allow for Mmax determination without knowing the full paleoseismic history. This project has the potential for developing an independent, deterministic criterion for Mmax on individual active faults by examining the damage zone structure. Broader Impacts:      The Broader Impacts lie in large part in the development of an independent check on Mmax determined for individual faults. If successful, this will have transformative impact on PSHA. This effort is synergistic with the aims of NSF-supported centers like SCEC and dovetails with the recent push to build a near fault observatory in California.Furthermore, this proposal is being submitted between US PIs Ashley Griffith (Ohio State) and Thomas Rockwell (SDSU) and UK PI Thomas Mitchell (UCL) under the NSF/GEO-NERC Dear Colleague letter; therefore, the project will benefit from significant investment from the NERC if selected for funding by the NSF. This project will support multidisciplinary education of two graduate students in the US, all of whom will participate in field work and experiments in both laboratories, as well as bi-weekly Zoom meetings of all project participants. Undergraduate students at OSU, where a thesis forms the capstone requirement of all B.S. degree seekers in Earth Sciences, will participate in experiments and microstructural analysis.

UKRI Gateway to Research · FY 2025 · 2025-06

The Sun’s corona is composed of charged particles, or plasma, which escape into the interplanetary medium as the solar wind and fill the heliosphere. The solar wind drives potentially hazardous ‘Space Weather’ conditions in near-Earth space and is a natural, almost unbounded, laboratory for study of astrophysical plasmas. The understanding of the solar corona and its extension into the solar wind is thus vital to predicting when hazardous conditions may arise and for revealing which fundamental plasma processes lead, for example, to the heating and acceleration (to 100’s km/s) of the solar wind itself. A unique advantage of this natural plasma system is its accessibility to spacecraft, such as ESA’s current Solar Orbiter mission, carrying scientific instruments that directly sample, in situ, its electromagnetic fields and particles. Despite their small mass, electrons play a disproportionate role in processes driving and controlling the solar wind, since they dominate certain contributions to the solar wind thermal energy budget, such as the pressure and heat flux. Understanding processes that influence the nature of the electron populations in the solar wind is thus a major milestone on the road to addressing unanswered questions on the formation, heating and acceleration of the solar wind itself. Our proposed work involves novel analysis of measurements of electrons and electromagnetic fields made in the solar wind by Solar Orbiter as it transits close to the Sun, at increasing latitudes and during different phases of the solar cycle. We lead the Solar Wind Analyser sensor suite on the mission and we built the Electron Analyser System (EAS) to detect and characterize the solar wind electrons. EAS resolves details of the electron populations with higher resolution in energy, arrival direction and time than previously achieved. This enables better understanding of processes that determine the electron properties such as temperature, speed, and density and create, for example, anisotropies and beams in the electron population which mitigate energy exchange of with electromagnetic fields and waves.  These processes operate on fast timescales compared to most previous measurements, so EAS measurements open new windows on these processes and their impacts on the solar wind. Combined with a novel analysis technique developed by us and proven in a recent pilot study, we will make important breakthroughs in open science questions relating to how processes such as wave-particle interactions and collisions shape the solar wind electron populations and what implications these have on the global heliosphere.

UKRI Gateway to Research · FY 2025 · 2025-06

We aim at carrying the first ever systematic numerical investigation of neutron stars (NSs) atmospheres embedded in quantising magnetic fields (B = 4 x1013 G), by developing MAUS (Magnetised Atmosphere Universal Simulator) a fast and robust numerical algorithm using state-of-the art knowledge of opacities and QED effects.  The proposal is needed: the few existing codes dealing with this regime, including one by our team, rely on different microphysical inputs and are often built on outdated architectures which make them unsuitable for a systematic, fast modelling of NSs atmospheres exploring wide range of parameters. Despite these limitations, available atmospheric models have been used for the last two decades to interpret NSs spectral and timing data. However, the advent of X-ray polarimetry and the recent IXPE magnetar observations, have shown that previously unfathomable physical effects are now accessible to observations, including QED vacuum polarisation, particle back bombardment and magnetic condensation. These effects are also expected to modify the spectral properties (in particular regarding detectability of line emission, which will be accessible with future X-ray observatories such as Athena). Combining polarimetry with spectral and timing information can therefore reveal exquisite details on the physics of the atmospheric plasma around these compact objects, pushing our knowledge of quantising electron dynamics to a higher gear. The need for a novel atmospheric code is urgent: MAUS will allow us for the systematic investigation and re-analysis of all existing  spectral/timing (XMM-Newton, Nustar, Chandra, etc..) and polarimetric (IXPE, and future XpoSat) data of currently observed thernally emitting NSs, available from different observatories. This has the potential to revolutionise our physical  understanding of NS atmospheres. It will make it possible to perform systematic simulations and also generate simulated training data  for future AI/ML applications,  for the spectral, timing  and polarimetric signal. This will inform the scientific development of future X-ray observatories (Athena, GoSoX, Colibri, eXTP, and potentially many others). We are in a unique position to carry out this challenging project, thanks to our long standing expertise in the field of radiative transfer in strong fields. The team of proposers is deeply involved in the design  and scientific development of several of the above-mentioned missions, which will ensure maximum dissemination of the results within the relevant teams. We plan to make MAUS public in a user-friendly interface, and therefore to build a long standing legacy  for the entire X-ray community.

UKRI Gateway to Research · FY 2025 · 2025-06

The discovery of electromagnetic (EM) counterparts of the gravitational wave (GW) source GW170817 has opened up new opportunities for exploring the energetic Universe with multi-messenger astronomy. This project aims to provide a reliable theoretical toolset for exploitation of the rich information in high-precision EM/particle observational data of GW sources. The objective is to advance our understanding of fundamental physics phenomena that are not replicable in laboratories, such as, dynamics and spin-curvature coupling in extreme-mass-ratio binaries (EMRB), and  black-hole (BH) formation and QCD phase transition in binary neutron-star (NS) mergers. We will construct a new general relativistic radiative transport (GRRT) formulation and derive solution schemes for solving the GRRT equations to accurately determine the EM/particle signals from GW sources. We anticipate (i) a generalised covariant formulation, in Hamilton-Jacobi (HJ) form, for EM/particle transport in non-stationary gravitational fields, (ii) a new adaptive ray-tracing code and a new level-set code, that take advantage of excellent numerical accuracy in the symplectic scheme for solving the HJ-form GRRT equations, and (iii) a GRRT code for computing high-precision pulsed radiation from  EMRB containing a millisecond pulsar, and (iv) a GRRT code for computing the EM/particle signals from the core region of binary NS mergers in the final stage. The impacts of this work include: make possible (1) to compute EM/particle signals with accuracy sufficient for fully utilisimg the high-precision multi-messenger data of GW sources, (2) to conduct proper GRRT of EM/particle in modulating gravitational fields, (3) to use EM information in GW template construction for EMRB in the presence of GW self-force, and (4) to determine the EM/particle signatures when a binary NS merger is collapsing into a BH. This work will take us to the next level of precision GRRT calculations in strong gravity and to a new paradigm of precision quantitative multi-messenger theoretical astrophysics. Wu/Younsi/Zane are world leading RT researchers, with proven track records on producing high-calibre, ground-breaking works in high-energy and relativistic astrophysics of NS and BH systems. The UCL-MSSL team is perhaps the strongest internationally for undertaking this project, as all necessary technical skills and expertises are in-house, from laying-down of mathematical foundation, construction of GRRT formulation, derivation of GRRT equations, development of numerical algorithms and solution schemes, and applications in real astrophysical systems, in addition to solid in-field knowledge and vast hand-on experience in high-energy and relativistic astrophysics, GW astrophysics, and particle/nuclear astrophysics. All codes will be made public.

UKRI Gateway to Research · FY 2025 · 2025-06

The overall objective of the AQUAPACK project is the development and evaluation of the effect of novel biodegradable packaging systems on the quality and safety of perishable food and cosmetics in the supply chain of the EU region and worldwide, through the introduction of economically and environmentally sustainable packaging materials based on marine biomass (micro and macroalgae, fish processing side streams and by-catch). AQUAPACK faces the challenge of reducing plastic pollution through transnationally designed innovations for development of novel biodegradable packaging systems. Well-designed secondments between academic and industrial partners with complimentary capacities, will deliver the project objectives: (i) to introduce economically and environmentally sustainable, low carbon packaging materials based on aquatic biomass and side-streams, that can appropriately preserve the quality and safety of food and cosmetics products, from production all the way to consumption. (ii) design and test at least 2 biodegradable packaging materials appropriate for fish fillets and cosmetics, by developing: (i) biodegradable, active films appropriate for food and cosmetics by utilizing aquatic biomass, (ii) biodegradable films appropriate for secondary packaging of cosmetics. (b) An innovative direct freshness monitoring system (biosensor) applicable across the supply chain of perishable products. (iii) to improve the sustainability of the food and cosmetics sectors by preserving their quality, extending their shelf life and thus reducing waste. (iv) reduce waste of packaging materials by applying non-plastic, biodegradable packaging solutions for food and cosmeceutical products. (v) assess the sustainability and safety of the new packaging solutions in comparison to commonly used packaging for food and cosmetics. (vi) to provide cross-cutting interdisciplinary knowledge exchange, technology transfer and training to improve employability and career prospects.

UKRI Gateway to Research · FY 2025 · 2025-06

The discovery of thousands of exoplanets orbiting stars other than our Sun has revealed a wide range of planetary properties, both like and unlike planets in our own solar system. One unexplored parameter to understand exoplanet characteristics is their age: the solar system is roughly 4.6 billion years old, whereas some exoplanets are of similar age, while others are as old as the universe, or were born very recently. While it is likely that the properties of planetary systems are related to their age, both due to the evolution of the galaxy shaping the formation of planetary systems, and the evolution of planetary systems and their host stars over time, the potential to understand exoplanets in this context has remained largely unexplored. This is because stellar ages are notoriously difficult to determine. Here, we will overcome this challenge by using state-of-the-art Bayesian techniques to derive reliable ages combining stellar observations from high-resolution spectroscopic observations and Gaia measurements, as well as asteroseismology from current missions such as TESS and future missions like PLATO. This will allow us to derive accurate and precise stellar ages for a large sample of small extrasolar Earth and Neptune planets. We will pair the stellar characterisation with a detailed study of planet properties, including their occurrence. By doing so, we will determine how the occurrence of Earth and Neptune planets depends on the characteristics and age of their host stars over billions of years. In doing so, we will test how planet formation can be linked to galactic evolution, and how planets evolve over time. This work will also deliver important knowledge build-up in the context of the upcoming PLATO mission, whose main focus is understanding small planets and linking their properties to precise host star ages.

UKRI Gateway to Research · FY 2025 · 2025-06

This grant's vision is to develop the novel technologies that reduce the incidence and severity of mental ill-health in young people who have experienced complex trauma. Childhood trauma such as sexual, physical or mental abuse and neglect represents the most potent predictor of poor mental health across the life span. The world appears This can be explained in part by changes in their neurological processing. The abuse fundamentally changed the way the brain functions in areas that process threat and reward responses, as well as the executive function ability. The changes at a brain level may not yet express as mental illness, but they are similar in nature to the brain functioning of people with severe mental illness. They can are waiting to be activated into ill health, and as the world is confusing and threatening to these children, there are increases stressors present to activate the ill-health pathways. Children who experienced trauma are therefore much more at risk of later life diagnosis of a range of mental health conditions (e.g.depression, anxiety, borderline personality disorder ADHD and Autism). Current treatment for overcoming trauma is psychological therapy, where children, often through play, get to explore situations at distance from reality. Play is central for child development, it allows children to experience emotions and behaviours and role play coping strategies. However, current healthcare services are struggling to scale therapeutic care. Furthermore, digital interventions could support the therapeutic relationship. For example wearable technology could help a young person learn about their body responses which happen just before an episode of anger, it could also help in simulating rupture and repair  - moments where things break down but needed to be mended. Expressing emotion and repairing ruptures - small breakdowns in play or communication are incredibly difficult for children who have experienced trauma, and their inability to master these essential life skills is linked to later life physical and mental illness. Therefore, by co-designing playful technologies which support emotional expression and help build capacity to repair and build relationships we aim to increase the quality of life of these children who have had the most difficult of starts whilst simultaneously reducing the strain on NHS and social services.  

UKRI Gateway to Research · FY 2025 · 2025-06

The ExoMol project provides spectroscopic and other data on molecules which are used world-wide for studies of exoplanets as well as other astronomical objects such as brown dwarfs and cool stars.  It is proposed to expand the database to cover process stimulated by ultraviolet (UV) radiation. Both photoadsorption and photodissociation will be studied as a function temperature of the absorbing molecule: initial studies have already shown that the rate of photodissociation, a key parameter in the atmospheric chemistry of exoplanets, can show strong dependence on the underlying temperature of the molecule in question. The proposed project will focus on the effects of UV light on water, important in many atmospheres and, given the widespread interest in sulphur chemistry, sulphur-containing molecules such as H2S, SO2, HS, SO and S2. Studies will start from first principle electronic structure calculations which provide potential energy surfaces and transition dipole moment surfaces; these surfaces will be adjusted so that nuclear-motion calculations using them reproduce the low temperature cross sections such as those available in the Leiden database and elsewhere. Calculations will then be repeated as a function of molecular temperature. All the results will be made available via the ExoMol database, www.exomol.com.

UKRI Gateway to Research · FY 2025 · 2025-06

UKRI has recently invested in a Photoinduced Force Microscope (PiFM) which is used by The UK Catalysis Hub applied to local catalyst chemistry. This powerful tool – one of the few currently available worldwide – is ideally placed to provide a previously unobtainable detailed understanding of the edge chemistries of 2D nanomaterial edges. In this collaborative project, we will combine the nanomaterials expertise at UCL with the characterisation strengths of the UK Catalysis Hub to measure the IR spectra of nanosheet and nanoribbon edges with near atomic precision for the first time. These insights open bountiful opportunities across nanomaterial science from understanding and controlling nanoribbon synthesis mechanisms, to dictating edge-patterned functionalisaiton. Beyond the unparalleled insight into 2D nanomaterial chemistries, the work will further cement the UK and the UK Catalysis Hub as a world-leading centre for PiFM and advanced microscopy research.

UKRI Gateway to Research · FY 2025 · 2025-05

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern, causing around 1.3 million deaths in 2022. The World Health Organization's 'End TB Strategy' sets out to reduce TB deaths significantly by 2035 and ultimately eliminate the disease worldwide. Unfortunately, many countries are falling behind global targets for elimination, with efforts also hampered in recent years due to disruptions in diagnosis and treatment during the COVID-19 pandemic. A central pillar of the 'End TB Strategy' is to identify high-risk groups and individuals to ensure early diagnosis of the disease to direct targeted, cost-effective treatment strategies and prioritise contacts for preventative therapy. We can understand factors that contribute to the spread of pathogens to guide control efforts by reconstructing the transmission history of past outbreaks using whole genome sequence (WGS) data. By linking cases with few genomic differences, likely chains of transmission and highly transmissible infections can be identified. WGS can also be used to detect complex disease states such as mixed infection. However, this is not a trivial exercise in clonal organisms like TB where low population-level diversity leads to many seemingly identical sequences, confounding efforts to identify who-infected-whom or fully characterise within-host variation. Long-read, deep sequencing can improve whole genome assemblies by accurately reconstructing genomic features that are routinely ignored in Mtb, such as highly variable genes linked to virulence (PE/PPE genes), repetitive elements, and insertions and deletions. It can be difficult to assemble these features with short-read sequence data as reads are far shorter in length than the target gene. In contrast, long-read sequencing produces reads that span the length of multiple genes to allow for high confidence sequence reconstruction in these complex regions. Previously under-characterised regions comprise almost 20% of the Mtb genome and can be a rich source of added variation between closely related strains. We can use this information to better infer the timing and direction of transmission events between individuals with TB. I will build on our exciting preliminary results in which we can now produce high-quality Mtb whole genome assemblies using long read sequencing to improve TB transmission analysis and better characterise mixed-strain TB infections. I will leverage a comprehensive dataset of ~15,000 Mtb samples with long-read sequencing, along with >6,000 matched, short-read sequences, from Peru and Moldova. The population wide diversity and evolution in under-characterised genomic regions will be explored in high-confidence assemblies, including minor variants and mutations in complex regions. I will use well-validated assembly approaches with long and short-read data and assess assembly quality to guide recommendations for sequencing strategies and analysis pipelines for pathogen transmission investigation. I will produce a novel dataset of long-read sequences from in vitro mixed TB samples to build and validate highly-sensitive tools to detect mixed infection and assemble the underlying constituent strains, addressing previous limitations of these approaches when using short-read sequencing data. These will be applied to our real-world datasets to better understand the transmission of mixed infections. Finally, I will use the added resolution from these high-quality assemblies and include mixed constituent strains to produce high-resolution phylogenetic trees and fully reconstruct transmission networks. These will be used to build predictive models of TB transmission risk and cluster growth. Phylodynamic approaches will identify highly-transmissible TB strains and I will explore genomic associations with transmissibility.

UKRI Gateway to Research · FY 2025 · 2025-05

Context Cortical visual impairment caused by dementia (‘brainsight’, rather than eyesight loss) is associated with devastating consequences for independence, even more so than memory impairment. In Alzheimer’s disease (AD), the most common form of dementia, such visual impairment has been documented in more than half of patients, and can be the first sign of AD in posterior cortical atrophy (PCA; the most common atypical form of AD, which is visual-, not memory-led). Challenges the project addresses Dementia-related visual impairments fall between medical specialties particularly given patients often present initially to eyecare professionals. Correspondingly, such impairments are frequently overlooked or misdiagnosed, delaying diagnosis and treatment for years. Diagnostic challenges faced by people with dementia and their carers include unsuccessfully changing glasses or having surgery before realising issues do not relate to eyesight, but cortical visual loss. Challenges posed to detection of dementia-related visual impairment range from difficult-to-access specialist neurologic services and the current lack of tests suitable to detect higher-order cortical visual impairments in the eye services where patients typically first present. There is a need to distinguish higher-order cortical vision loss from eyesight-related loss in aging populations (e.g. differentiating PCA from glaucoma). Aims and Objectives We have developed a novel test to detect and distinguish cortical visual from ocular deficits (Graded Incomplete Letters Test; GILT) implemented within UK BioBank (UKB). GILT is currently lab-based, requires specialist software and its use has so far been restricted to research cohorts (UKB and UCL). Advancing Detection of dementia-related Cortical Visual Impairment (AD-CVI) will produce GILT versions suitable across research and clinical settings (WP1). We will validate GILT in UK (Moorfields Eye Hospital) and international eye clinics (Bergman Eye Clinics; Hospices Civil de Lyon) (WP2). We will evaluate GILT useability and feasibility through engaging eye professionals and inform refinements maximising GILT clinical utility. Key objectives Develop GILT versions available via iOS and Android devices Conduct GILT version testing and calibration for consistency across devices Validate the GILT in ophthalmic clinical and research settings Conduct user testing with professionals working across ophthalmic services Develop a UKCA Class 1 Licensed GILT available via iPad with prototyped web-based version Applications and benefits This work will benefit: Patients through accurate diagnosis enabling early treatment, symptom understanding and putting in place support tailored to visual loss. Staff through improved sight assessment for people with dementia. Services through reducing diagnostic delays and misdiagnoses: in particular, avoiding repeated visits with eye professionals, unsuccessful surgery and psychiatric referrals. Core team: Project lead: Dr Keir Yong (UCL) Project co-lead (international): Prof Aaron Seitz (Northeastern University), Prof Caroline Froment Tilikete (Hospices Civil de Lyon) Specialists: Prof John Greenwood (UCL), Dr Hari Jayaram & Dr Ahmed Toosy (Moorfields Eye Hospital), Dr Peter Jones (Irida Health Ltd) Partner organisations: College of Optometrists, Glaucoma UK, UK & Ireland Society of Cataract Surgeons

UKRI Gateway to Research · FY 2025 · 2025-05

My laboratory studies the biology of an important cell of the immune system - the T cell. These cells are made throughout life and circulate around the body via the blood stream. When they encounter an invading infection they recognise, they react to that infection by orchestrating an immune response against the invader, organising a host of different immune cell types to eliminate the infection. They are therefore a central component of the immune system. TNF is a protein made by many types of cells during immune responses and plays an important role in stimulating immune cells to fight invading organisms. Because TNF promotes immune activity, it  also makes it a potent inducer of inflammation, that can also result in serious damage to tissues and organs. Consequently,  excessive TNF activity has been linked with causing damage in various diseases including arthritis, inflammatory bowel disease and psoriasis to name some. There are several clinical therapies that work by specifically blocking TNF and these have proved highly effective in a number of different diseases. However, we do not fully understand how this therapy works. While some individuals with arthritis respond well to TNF inhibition, about 30% of sufferers gain no benefit. In other diseases, attempted TNF treatment has been unsuccessful or exacerbated symptoms. Because many of these diseases involve an over-active immune system, T cells are also thought to be involved.   T cells both synthesise and react to TNF, but our knowledge of how TNF might be influencing these critical immune cells is greatly lacking. New results from my lab have revealed that both generation and function of T cells in normal healthy people requires TNF. However, TNF is a double edged sword. On one hand, it can keep cells alive, but in other circumstance, it can give instructions for cells to kill themselves. In the last few years, my lab has explored how TNF controls life/death decision in T cells. TNF can regulate the genetic code in T cells to control how the cells behave, and for a long time, it was thought that the T cells were kept alive by activating a genetic survival programme. We showed that survival of T cells does not depend on TNF controlled genetic programme. Rather, TNF can directly inhibit death inducing proteins inside T cells, keep cells alive. This raises fundamental questions about how TNF controls what T cells do during immune responses. How does TNF block cell death ? What is the TNF induced genetic programme for, if it is not needed to keep cells alive ? Our work uses sophisticated mouse genetics to address these questions, but also raises the crucial question, do human T cells also work in the same way ? Our proposed research therefore aims to : 1. To understand the functions of TNF and related factors in controling T cells during influenza viral infection and inflammatory bowl disease in mice 2. To determine the molecular mechanisms by which TNF controls their behaviour. 3. Investigate the genetic mechanisms by which TNF controls human T cells.

UKRI Gateway to Research · FY 2025 · 2025-05

Glial cells are known to be crucial support cells for neurons in the central nervous system (CNS). The loss of molecular integrity in aged neurons results in neurodegeneration and loss of function; however, the potential role of glial cells in this process has been largely overlooked. Here, we will explore the kinetics glial dysregulation relative to neurodegeneration and manipulate glial homeostasis pathways in a vertebrate CNS tissue, the retina, to determine whether genetic dysregulation in glia drives age-related neuronal decline. If correct, this will revolutionise our understanding of how altered glial integrity can influence the long-term health of neurons. Ageing is a gradual and irreversible process whereby cell and tissue function declines. The CNS is particularly prone to age-related impairment and neurodegenerative disease. The precise mechanisms driving this age-related decline remain unclear. One of the many mechanisms documented in the ageing CNS is genetic dysregulation, whereby gene expression is altered leading to mis-expression of transcripts. However, the cause and consequence of this dysregulation remains poorly studied. Glial cells directly contact neurons and express key molecules to provide supportive functions, including maintaining homeostasis, sharing trophic factors, and recycling neurotransmitters. Like other cell types, ageing can cause a loss of normal function in glia which reduces their ability to properly maintain a healthy CNS environment, negatively altering their interactions with neighbouring cells, and potentially contributing to neuronal dysfunction and degeneration. We have recently identified several genetic pathways that are progressively dysregulated in glial cells in the ageing retina. Further, we have identified sex-specific differences in retinal degeneration, similar to what occurs in humans, leading to the intriguing potential that genetic dysregulation in the retina may be distinct between the sexes. These observations raise several intriguing questions regarding the basis of age-related neurodegeneration, most importantly: Does glial dysregulation precede neurodegeneration in the retina and does glial dysregulation drive neurodegeneration in the ageing CNS? Unfortunately, studies aiming to address these critical questions are hampered by a lack of a suitable model. The killifish is an eminently suitable model system to study ageing due to rapid ageing, sexual dimorphism, conserved CNS structure, cellular labels and amenability to genetic manipulation. We will take advantage of a well-characterised CNS tissue, the retina, and the rapidly ageing killifish to explore the kinetics of cell-specific degeneration, identify conserved cell-type specific molecular pathways underlying age-related neuronal degeneration and determine whether glial genetic dysregulation can drive neurodegeneration in the ageing retina. These studies would be challenging, if not impossible, in any other model system. As such we are eminently positioned to address these key pressing questions in the field of glial biology and ageing. This project aims to: 1) characterise the kinetics of retinal neurodegeneration throughout the life course; 2) Determine sex-specific cellular and genetic changes in the ageing retina; 3) Identify the epigenetic modifications underlying glial genetic dysregulation in ageing; 4) Determine the consequence of glial genetic dysregulation on neurodegeneration in the context of ageing. We will utilise a multi-disciplinary approach to achieve our goals, including cutting-edge multiplex cellular labelling developed in our laboratory, our expertise in semi-super resolution imaging, transcriptomics and epigenomics, robust computational morphometric analyses and genetics. Overall, this proposal will establish the killifish as the preeminent preclinical model to study the ageing retina and support the innovative study of fundamental mechanisms of CNS ageing.

UKRI Gateway to Research · FY 2025 · 2025-05

The Growing Up in Digital Europe (GUIDE) age 8 pilot study will test the feasibility of a future large-scale UK child cohort study on child development and well-being to fill a crucial gap in the UK’s data infrastructure and contribute to a major European comparative data infrastructure enabling both national and international research on this important topic. GUIDE is an input harmonised comparative longitudinal survey with a focus on child wellbeing. It has been recognised as an important European research infrastructure having been included on the European Strategy Forum on Research Infrastructure Roadmap (ESFRI 2021). It will collect multi-disciplinary policy-relevant data that will enable research in a variety of fields including children’s well-being and mental health, parenting and childcare, school experiences and performance, cognitive, social and emotional development, out-of-school activities, and wider family, social and environmental contexts. GUIDE will provide long term public benefits by informing evidence-based policy and interventions, aimed at improving children’s lives, and offer unique insights into child wellbeing in the UK and across Europe. In the aftermath of the COVID-19 pandemic and in an era where understanding and supporting child wellbeing is increasingly recognised as a cornerstone for societal progress (OECD, 2021; UNICEF, 2021), there is a clear scientific and policy need for high-quality longitudinal data to understand child development and wellbeing. The UK has a rich, existing data infrastructure including a planned new UK-wide birth cohort study of children born in the mid-2020s (the Early-Life Cohort or ELC) funded by ESRC, a recent ESRC-funded adolescent cohort study in England (the Covid Social Mobility and Opportunities Study or COSMO) and MRC’s planned adolescent mental health study. These studies will provide robust data on the crucial periods of early childhood and adolescence. However, there is a critical gap in the UK’s data infrastructure on child development and well-being in middle to late childhood and an urgent need for timely and robust UK wide data for research and policy. Although the Department for Education is funding a series of new cohorts (Education and Outcomes Panel Studies or EOPS), these studies are only in England and have a narrower focus on education. This project will conduct a large UK-wide pilot study with a representative sample of 250 families with data collected via an in-person interviewer home visit from 8-year-old children and their main carer. The pilot will utilise the established questionnaires, technical infrastructure and fieldwork processes already developed and successful implemented in pilots in five countries during 2023. The pilot will draw a representative sample in each UK country, with fieldwork undertaken by a specialist agency experienced in longitudinal survey data collection selected via open procurement. This pilot will prepare the UK to join the main GUIDE study which is planned to start in 2027. The age 8 survey is planned as the baseline wave for a longitudinal cohort study which collects data every 3 years until age 24 years. The project will produce a report for prospective UK funders, including UKRI, on the specific value that GUIDE will bring to the UK data infrastructure landscape in terms of science and policy, and a report on the adequacy of the instruments and processes, providing recommendations to the central GUIDE team for the main study. The pilot data will be deposited for research use at the UK Data Service.

UKRI Gateway to Research · FY 2025 · 2025-05

A fundamental aspect of mammalian behaviour is the ability to learn how the world works from experience to predict what will happen and plan what to do. Recent interdisciplinary advances from neuroscience, psychology and machine learning suggest that mammals, from mice to humans, abstract a “world-model” or “cognitive map” from experience, enabling appropriate behaviour in new situations via prediction and planning. The neural mechanisms that enable learning of such a world model are becoming clear through experiments in which rodents learn about their spatial environment while the activity of large populations of neurons are being recorded. We hypothesise that neurons in the hippocampus (a brain region required for learning and memory) encode states within a task and the sequence in which they are experienced, replaying these sequences to train nearby neocortical areas to capture the common transition structures of similar tasks to support prediction in new situations. In spatial foraging tasks, where “states” correspond to places, the hippocampal neurons will resemble “place cells”, while neurons in entorhinal cortex that capture the structure of transitions between places will resemble “grid cells”, and analogous patterns of neural responses can be predicted for non-spatial tasks. We aim to test the key predictions of this model, taking advantage of our virtual reality (VR) system for mice. VR allows us to manipulate a task’s transition structure in ways not previously possible, while also performing large-scale neuronal recordings and immediate inhibition of specific sequences of neural activity. A series of experiments will directly assess how hippocampal neurons encode the sequences of states experienced within a task, and how the overall structure of the transitions between states within a task is learned across multiple experiences. We will test predictions for how the task transition structure is represented by entorhinal neurons, and whether and how the replay of specific sequences of hippocampal neural activity causes these representations to be learned. The use of VR allows us to observe mice learning any transition structures that we want, including those that are impossible in real spatial environments. The outcome of this work will be a fundamental advance in cognitive neuroscience towards a mechanistic understanding of the rules of life governing complex behaviour in mammals.

UKRI Gateway to Research · FY 2025 · 2025-05

There is a clear unmet clinical need for a blood test to identify and quantify peripheral nerve degeneration. Nerve damage is estimated to affect more than 4.2 million people annually and can be caused by traumatic injury (e.g. road traffic accidents), surgical procedures (e.g. tumour removal), and birth complications (e.g. obstetric brachial plexus palsy) but often nerve damage is initially undiagnosed. Furthermore, even when a loss of nerve function is identified, there is no diagnostic test to identify whether this is the mild form of nerve injury - neurapraxia (temporary conduction block which will resolve with time), or is more severe (permanent degeneration of axons) and therefore may require surgical intervention. Due to the complexity of this clinical differential diagnosis, there is often a significant delay in identifying those patients with nerve degeneration that require specialist referral and microsurgical repair. Such delays are seriously detrimental to functional recovery because nerves have a limited capacity for regeneration which fades with time; ideally injured nerves should be repaired immediately. The consequences for patients of poor functional recovery can be life changing and include permanent loss of sensation and movement, chronic pain, mental illness and significant personal, societal and economic impact. Therefore, there is an urgent need for a valid, accurate and reliable test that could be used to identify the presence of nerve degeneration at the time of injury. Currently there is no such test available and therefore management is often delayed causing significant additional morbidity. Recently our research team demonstrated that the serum concentration of neurofilament light chain (NfL), a protein that is released when axons degenerate, provides an accurate indication of the presence and severity of peripheral nerve damage in rats. The aim of this project is to progress this work along the translational pathway towards establishing a new diagnostic test, by assessing the feasibility of using NfL as a biomarker in human nerve injury. The approach will be informed by our previous animal study and will determine the correlation between serum NfL and the volume of axonal damage in patients undergoing elective nerve surgery. Serum NfL testing is already used widely in hospitals as a rapid, affordable and effective diagnostic tool in traumatic brain injury and acquired neuropathies. Therefore if this project shows that serum NfL is a suitable biomarker for identifying peripheral nerve damage it could easily be incorporated into clinical diagnostic pathways to address this unmet need. Furthermore, our team has already established the ethical approval and started to collect suitable nerve and blood samples. This project will (1) assess nerve tissue histologically in order to measure the volume of axonal degeneration, (2) measure serum NfL concentration in corresponding blood samples from the same patients, then (3) integrate these data to test feasibility and underpin the next stage of development.