Newcastle University

UKRI Gateway to Research · FY 2025 · 2025-02

Hepatocellular carcinoma (HCC) is a cancer arising from the liver and the third commonest cause of death from cancer globally, with 906,000 new cases and 830,000 deaths in 2020 alone. Non-alcohol-related steatohepatitis ('NASH', fat within the liver causing dysfunction) is also becoming increasingly common, and HCC commonly occurs in patients with NASH. One requirement for the development of cancer (and HCC) is for tumour cells to gain the ability to 'hide' from the immune system. There is evidence that the immune system promotes survival and evolution of cancer by creating an ideal environment for tumour cells to grow (known as the tumour microenvironment). New treatments have been developed that 'switch on' the tumour immune system, resulting in immune-mediated killing of tumour cells. This is broadly known as 'immunotherapy' and has been particularly successful in treating patients with melanoma. However there is evidence that it may be less effective in patients with NASH for unknown reasons. The best treatment for patients with HCC is surgery to either remove the HCC from the liver (liver resection) or a liver transplant (which removes the tumour and the whole diseased liver, replacing it with a liver usually from a deceased donor). However, in most patients, the HCC is too advanced for resection or transplantation, therefore the majority are treated with chemotherapy. Immunotherapies may help reduce the size and number of tumours in patients with advanced HCC, and allow more patients to undergo liver resection or transplantation. I aim to experimentally recapitulate features of the human HCC tumour microenvironment using HCC cells obtained from patients (with permission) and grown on 'slices' of human liver tissue that have been treated with fat to cause NASH. Our research group has developed this model, which allows us to observe the impact different conditions have on the liver and tumour tissue, and model novel HCC treatments. I will use this model to observe how immune cells in the liver tissue interact with the tumour, and why these conditions make immunotherapy less effective. I also plan to find out what impact the presence of fat in the liver tissue has on immune cell functions and immunotherapy. I will investigate what effect liver resection has on tumour growth in the liver tissue left behind using a mouse model of HCC. Although liver resection removes the tumour, there may be more 'hidden' tumours in the liver tissue left behind that were not known about. Liver resection switches on growth signals, which may drive HCC growth as an unwanted side effect. Determining whether this happens may help us understand why some patients develop disease recurrence very early after resection. Finally I will determine what effect immunotherapy has on the ability of the liver to heal after liver resection, and how it impacts the behaviour of immune cells in tumour tissue left behind in the remnant liver. This PhD project will establish a strong foundation for my future career as an academic liver surgeon focussed on HCC research, and provide insights that will help cancer researchers design improved HCC immunotherapies that reduce the risk of tumour recurrence. The research will have wider applications, as surgery is used for other types of cancer (in the liver and other organs), and will develop our understanding of how the immune system affects cancer behaviour/growth in general.

UKRI Gateway to Research · FY 2025 · 2025-02

The most straightforward reason for asking a question is to gather information, as in Do you have a bike? Yet questions can also request confirmation of a belief, as in Don't you have a bike? The latter question is a so-called biased question because the speaker expresses a bias toward, i.e., is leaning toward, the possibility that the interlocutor owns a bike whilst asking whether this is true. The meaning layers expressed by different biased questions have been the issue of intense research in the past two decades. Yet, their exact conditions of use in various communicative situations, the interplay of diverse linguistic cues signalling different types of biases, and the issue of how we acquire as children the intricate form-meaning relations of such multi-layered functionality are poorly understood. In the proposed project, we seek to fill this gap in order to arrive at a more nuanced account of biased questions. Biased questions are an ideal way to study how people negotiate complex layers of meaning through word order, intonation and gestures, which will further our understanding of communication in general. While previous research has focused on the word order and meaning of 'classic' biased questions, which are essentially negative yes-no questions (e.g., Don't you have a bike? Do you not have a bike?), the goal of our project is to unravel the nuanced meanings such questions can express in comparison to constructions which also express a bias but have not been treated under this term, like tag questions (You have a bike, don't you?) and formulaic suggestions (Why don't you get a bike?). We aim to tease apart the roles of sentence structure, meaning, the immediate context, sentence melody and gesture (head, hands, body movements and facial gesture) in all these biased questions (broadly defined) in conversation. With new tools and frameworks for multimodal research emerging, we have now the means to study these linguistic cues and their interaction in detail. Indeed, there is initial evidence that speakers use different gestural means in different question types in English, and crosslinguistic research shows that gesture is used to mark many different meaning aspects in conversation, highlighting the need for gesture research when studying subtle meaning differences. We will conduct our research on English and German. These two languages use similar morphosyntactic means to mark different types of bias, but there is evidence that the interplay of prosody and morphosyntax differs between them. We will also investigate how biased questions can be learned in the early years (children aged 4 to 6) in our cross-linguistic comparison. Complementing our empirical and analytical contributions on the expression and learnability of biased questions, we will contribute a theoretical account of the division of labour across linguistic modules in identifying different types of bias. This will feed our understanding of how different kinds of linguistic means contribute to interpretation in human language more generally. If these theories are to reflect cognitive reality, the assumed structures must be learnable and their development traceable in the course of first language acquisition. These theoretical considerations make biased questions an ideal springboard for interdisciplinary engagement with researchers, for instance in psychology for investigating the development of Theory of Mind, language pathology for exploiting developmental disorders manifesting in social and linguistic behaviour, or computer scientists who seek to improve machine-to-human-interaction.

UKRI Gateway to Research · FY 2025 · 2025-02

At 07:30 on the 15th September 2024 a shallow, vegetated landslide above the A83 'Rest and Be Thankful' in Scotland transitioned into 500 tonne debris flow, forcing a precautionary closure of the road. The failure occurred in 'dry' conditions (<20 mm rainfall in the 24 hours before failure) with low soil saturation. It is a paradigm shift to consider landslides being triggered in dry conditions with no other external driver (e.g. an earthquake) that has rarely been documented. Landslides in the U.K., especially debris flows, are often linked to the closest rainfall event when the triggering time is unknown. The 'Phase 7' landslide mentioned above, named after the phase of mitigation nets and catch-pit construction, offers a rare and transient opportunity to analyse a 'DrySlide'. Existing landslide warning systems rely on the well-established link between rainfall and landslide triggering. Warnings are issues when rainfall exceeds predefined intensity-duration thresholds. 'DrySlides' thus pose risks that are not usually assessed and for which there are no current warning or management systems. We fundamentally do not understand the processes of dry failure and how we can use an improved process understanding to allow failure prediction - the ultimate aim of much landslide work. We hypothesise DrySlides are due to a combination of plant root reinforcement resisting soil deformations prior to failure, and deformation-induced alterations to subsurface water flow. If this is true then green engineering / bioengineering / 'nature-based solutions' need an improved understanding of the role of plant root strength in failures and how/when (or IF in the case of 'arrested' landslides) this strength is overcome. This is especially topical given current revegetation efforts on this slope by Transport Scotland and Forestry and Land Scotland. We believe DrySlides are likely forecastable with precursors linked to failure mechanics and that precursors are recorded in the landscape.

UKRI Gateway to Research · FY 2025 · 2025-02

Bacteria can be divided into two types. Gram-positive bacteria have a thick cell wall on the cell surface and a single, cytoplasmic membrane. By contrast, Gram-negative bacteria such as E. coli have two membranes: a cytoplasmic (inner) membrane (IM) and an outer membrane (OM). Both membranes are separated by the periplasmic space that contains a thin cell wall. The OM is a unique lipid bilayer that is essential for most Gram-negative bacteria for two reasons. First, the OM is important for the mechanical stability of the cell. Second, the OM creates a physical barrier that prevents entry of harmful small molecules such as antibiotics, and therefore forms a protective layer on the outside of the cell. However, for the bacterium to grow, OM channels and other OM proteins ("OMPs") are needed, for example for the uptake of nutrients. Like all proteins, OMPs are made in the cytoplasmic space in an unfolded form. Therefore, in Gram-negative bacteria, the newly-made, unfolded OMPs have to cross the IM and the periplasmic space before they arrive at their OM destination. There, they are folded into their active form and inserted into the OM. Both processes are carried out by an OMP complex named BAM, which stands for barrel assembly machine due to the fact that many OMPs form barrel-like structures. Due to its important functions, BAM is essential for the viability of all Gram-negative bacteria, and much research has been devoted in the past 20 years to determine how BAM works. However, most of this research has been done in model bacteria such as E. coli, and it is not clear whether BAM from very different bacteria, such as those from the human gut, has the same structure and functions in the same way as BAM from, for example, E. coli. From preliminary experiments that form the basis of this proposal, we have good evidence that the BAM complex from an abundant group of human gut bacteria is in fact very different from E. coli BAM, both in structure but likely also regarding its functions. This proposal will characterise the functions of this novel BAM complex (named BtBAM) via three research aims. In the first aim, we will determine the structure of BtBAM to a level that will allow building of complete atomic models for all the seven proteins that form the complex. This will be done via cryogenic electron microscopy (cryo-EM), in which individual, frozen protein molecules can be visualised and imaged at high magnifications. Knowing the detailed structure of BtBAM is important because it will allow us to hypothesise how all the individual components of this protein machine work together, much like it is only possible to understand how a car engine works if one can see what it looks like. In the second aim, we will do experiments to get more information on the function of the different protein components of BtBAM. We will remove one or more components, followed by experiments to understand how that affects BAM function. For example, we can culture "mutant" bacteria with the modified BAM complex and compare growth with bacteria that still have the original complex. Due to its importance, bacteria with a defective BAM will likely grow slower, or not at all. For making more subtle changes in BtBAM, the structural information from aim 1 is also important, because it suggests where changes should be made. Besides growth experiments, we will also analyse which OMPs are present in the bacteria and their quantities in the OM, something that is likely to be affected if BAM doesn't function properly. The final, third aim will be to study the function(s) of BtBAM in the test tube, rather than in live bacteria, to visualise more directly what BAM does. Together, these experiments will clarify the structure and function of a BAM complex that is likely to be very different from that of model bacteria like E. coli. The project will show that even fundamental processes like OMP biogenesis can differ substantially in bacteria.

UKRI Gateway to Research · FY 2025 · 2025-02

Every human carries genetic variants that increase their risk of developing serious health conditions. Although some diseases have simple genetic causes that are straightforward to identify, for complex conditions such as autoimmune diseases, cancers or psychiatric disorders locating associations is more challenging. Over the past 20 years, research consortia have analysed thousands of datasets that describe genetic variation in millions of individuals with different diseases. Each of these genome-wide association studies (GWAS) produces information on hundreds of thousands or millions of locations on the genome; comparisons with healthy individuals allow genetic associations to be identified. While the quantity of data available on human disease genetics is vast, statisticians working with these datasets are required to be highly conservative. False positive associations waste limited and expensive laboratory time and could potentially lead to ineffective treatments being developed. The standard method for analysing GWAS data is simplistic: separate logistic regressions are fitted for each variable, ignoring the correlation structure between them; a stringent correction is applied for multiple testing, and then meta-analyses are carried out using data from independent studies. This controls for false positives in a way that is acceptable to the genetics community but is known to have high type II error. An improved method that maintained the same strict control over type I error but that reduced the number of false negatives would be of great benefit to geneticists and would eventually lead to important new medical treatments. Bayesian non-parametric methods are a promising solution as they allow flexible and realistic statistical modelling and have already been applied successfully to large genetic datasets for various purposes. However, there has been only limited work on adapting the models to find genetic associations. This project will act as a proof of concept, applying Bayesian non-parametric methods to find known variants in simulated and real data of varying complexity. This is intended to be the start of a long-term research programme that will bring together theoretical and applied statisticians and geneticists. The initial work using genomic data is challenging and it is likely to take some time to develop methods that can be used routinely in genetic studies. However, once this challenge is met, further work could add time- and location-varying data on proteomics and transcriptomics, for example, and then environmental data.

UKRI Gateway to Research · FY 2025 · 2025-01

The project will explore how transregional artistic exchanges between countries of the former Eastern Bloc and Northern Africa shaped modern art during the Global Cold War, 1940s-1980s. Transregional encounters of artists ensured the transfer of ideas and inspired debates on what it meant to be modern in the aftermath of the Second World War and during decolonisation struggles. During the Global Cold War, fine art students from Northern Africa arrived in the Eastern Bloc as part of university exchanges and to attend International Youth and Student Festivals designed to cement anti-western, anti-colonial, and socialist alliances. Northern African artists exhibited in the Eastern Bloc, while their European counterparts participated in art festivals and took up teaching roles in fine art departments across Northern Africa. Through archival research, oral history and postcolonial art historical methods, this project aims to understand how the socialist ideas of the Eastern Bloc and the anti-colonial discourses in Northern Africa shaped the practices of modern artists working across these geographies. Eastern Bloc-Northern Africa responds to rising xenophobic nationalism in many countries of the former Eastern Bloc and a tendency to marginalise transregional exchanges in histories of cultural decolonisation across Northern Africa. It proposes to counteract these tendencies by centring cross-cultural mobilities and transfers that destabilise ideas of national homogeneity and cultural authenticity. Focusing on transfers, contact zones and reciprocal exchanges, the project responds to the 'mobilities turn' in the humanities and social sciences, building on recent developments in global art history (DaCosta Kaufmann 2015; Flood 2009, 2011; Fremont 2022). Attending to questions of cultural hybridity, translation and mistranslation, the project is committed to unravelling the cosmopolitan and hybrid nature of modern art in two regions whose cultural production, contrary to that of the 'West' (Mercer 1994, 2005, 2008; Sonn 2022), is rarely analysed through a transregional lens. How did the Polish artist Anna Draus-Hafid, who opened a weaving studio at the fine art academy in Casablanca in 1972, help shape Moroccan discussions about craft and postcolonial identity? How did the experimental pedagogies of the art school in Prague condition the work of Tunisian artist and later museum director Zoubeir Turki? What led Moroccan painter Ahmed Cherkaoui to declare that his internship at the art academy in Warsaw taught him everything there was to know about modern art? The project's focus on multiple communities, audiences and exposure to ideas and practices is matched by the international dissemination of research through a confirmed partnership and exhibition with the Centre d'Études Maghrébines à Tunis (CEMAT), an edited volume (with translations of selected chapters into English), articles in peer-reviewed journals, a workshop in Newcastle and a series of nine podcasts that can be accessed by people worldwide. The Core Team will also make selected material pertaining to the study and teaching of modern art from both regions available on a digital platform supported by the American Institute for Maghrib Studies (AIMS), of which CEMAT is a member. A vast majority of relevant archives are not well-known and do not have digital databases, slowing down art historical research. This project is as much about an inquiry into transregional histories of art as it is about sharing research methods and resources that can facilitate future research and curatorial work in this field.

UKRI Gateway to Research · FY 2025 · 2025-01

The Agrimensores and Roman Mathematics (AgRoMa) will transform our understanding of the intellectual world of Greco-Roman antiquity and mathematical accomplishments of the Romans by establishing a new textual basis and contextual framework for the study of the overlooked Roman mathematical tradition, producing the first complete critical edition, translation, and commentary of the collection of practical mathematical problems attributed to Epaphroditus and Vitruvius Rufus (EVR). Practical mathematics is a key area of ancient science, but the history of this tradition in the Latin-speaking Roman world has been largely ignored. The problem collection of EVR survives among the late-antique collections of Roman surveyors' manuals known as the Corpus Agrimensorum Romanorum (CAR). CAR is fundamental to our understanding of Roman civilization, from land-use and bureaucracy to law and colonisation, but the practical mathematical tradition of the Romans has been overlooked by classicists and historians of science because existing editions of CAR omit this material, thus obscuring the true character of CAR and its historical significance for the exact sciences. The problem collection of EVR demonstrates that the intellectual horizons of the Roman land surveyors (agrimensores) stretched beyond practical mensuration, encompassing a sophisticated, integrative concept of mathematics embracing geometry and arithmetic. The mathematical texts of CAR show how these agents of empire cultivated mathematical knowledge as an intellectual exercise and marker of professional status, engaging creatively with Greek mathematics to create an independent tradition grounded in their own socio-cultural reality. New work on ancient practical mathematics, currently dominated by Greek perspectives, makes a reassessment of the Roman tradition particularly pressing. EVR provides vital new evidence that illuminates the context and sources of some of the most important Greek-speaking engineers and mathematicians of the Roman empire, including Hero of Alexandria, a pioneer of robotics, and Diophantus of Alexandria, the father of modern algebra, both subjects of recent major scholarly reassessments. The study of CAR itself is experiencing a renewal, with new editions of many surveyors' manuals planned or in print. AgRoMa provides the necessary complement to these studies by making the full range of evidence for the surveyors' mathematical education and interests available for the first time. The commentary accompanying AgRoMa's critical edition will chart how a group of sub-elite practitioners creatively re-fashioned the literary and structural forms of their Greek mathematical sources to forge a specialised vocabulary, new modes of exposition, and new problems based on Roman units of measurement. AgRoMa will thus re-define the scientific significance of CAR and revolutionize our understanding of practical mathematics in the Greco-Roman world. AgRoMa is the first element of an ambitious plan to further the study of Roman mathematics and its medieval legacy, building scholarly capacity and public interest to support such work. AgRoMa will result in a major published edition, online database, new Unicode standards, seminars and workshops, and orient findings towards educational audiences by developing activities to support the National Curriculum. Using AgRoMa as a career catalyst, the team will employ the knowledge and experience generated to promote future study of the Roman mathematical tradition.

UKRI Gateway to Research · FY 2025 · 2025-01

    Unmanned Aerial Vehicles (UAVs) are emerging as powerful tools for sustainable environmental monitoring, playing a vital role in comprehending the diverse effects of climate change on ecosystems. The integration of state of the art techniques such as Artificial Intelligence (AI) with UAV technology has introduced innovative pathways for various environmental applications. However, their full potential remains to be explored. ACCELERATE proposes the development of a fertile inter-discipline and inter-sectoral ecosystem that aims to radically contribute towards enhancing UAV technology to enable the sustainable environmental management. The specific objectives of the project are to: a) Create a continuously updated ecosystem with UAV datasets suitable for environmental studies and climate change impact assessment, b) promote methodological advances in the field of UAVs technology, by exploiting the unique capabilities of those data with state-of-the-art techniques and c) establish clear guidelines and homogenized protocols for the characterization of the exploitation of UAVs in specific application domains. Experimental analysis will also be carried to showcase the practical use of the project outputs via four carefully selected and innovative Use Cases, that will serve as Key Performance Indicators of the project. ACCELERATE brings together enthusiastic staff from academia and industry via a series of carefully-designed secondments, establishing a unique fertile collaborative research and innovation environment to promote pioneering research in environmental and socioeconomic studies implementation within urban, natural and agricultural environments. A strong inter-sectoral experienced research team of 17 partners from 9 countries, of 9 academic and 8 industrial partners coming from Greece (2), Romania (3), Italy (2), Cyprus (1), United Kingdom (5), North Macedonia (1), France (1), Germany (1) and Portugal (1) constitute the project’s Consortium.

UKRI Gateway to Research · FY 2025 · 2025-01

Human and nonhuman animals rely on memories of the past to anticipate the future, weighted by the reality of the present in our ever-changing sensory world. As universal as it is for neural systems to integrate information from the past and present to forecast the future-and the striking impact on quality of life when these functions fail-fundamental empirical questions remain on how sensory, memory and predictive signalling interactions occur from neuronal levels to systems. Substantial scientific progress has been made in studying hippocampal- and non-hippocampal-dependent learning and memory. In parallel, both the prefrontal cortex and hippocampus have now been implicated in non-classical (statistical) learning of sequential sensory dependencies separated in time, a building block for human language and intellect. Moreover, both regions relay 'top-down predictive' signals to the sensory cortex that interface with veridical input from the senses. Integrative theoretical frameworks have emerged, raising important questions that require direct empirical evidence on how neural systems interact during sensory, memory (retrospective) and predictive (prospective) functions. A scientific roadblock has been the paucity of approaches combining memory and prediction tasks, research focusing on one or a few key nodes in the system, and the lack of parallel studies in an animal model and humans using the same task. We propose a timely cross-species neurophysiological approach during an auditory delayed sensory predictions task. Both monkeys and humans can learn the task via statistical learning in tens of minutes, and we will leverage the capability for simultaneous neuronal recordings from the prefrontal cortex, hippocampus and auditory cortex in macaque monkeys (Aim 1) and humans (Aim 2). The task harnesses statistical learning that can induce sensory sequence learning and predictions within minutes, using probabilistically variable sound sequences that manipulate "what" has and will happen and "when" (the delay between the sounds). The cross-species approach will provide new knowledge into the interactions of a neural system integrating functions vital for daily life, and how these compare between the monkey brain and the human brain.

UKRI Gateway to Research · FY 2025 · 2025-01

The proposed project, “CATALYSE”, will develop, and maintain long-term collaborations between Europe, China, South Africa, and Nigeria towards renewable dimethyl ether (DME) fuel production from CO2. This objective will be achieved through joint research in new process systems and material development in direct air capture (DAC) and utilisation. This requires skills and knowledge in experimental study, process modelling, analysis and optimisation, computational material design and catalysis which will be strengthened by the individual mobility of researchers between Europe and the participating countries. There are 14 partners involved in CATALYSE who are world-leading in their respective areas of which there are 3 industrial partners. CATALYSE will start in December 2024 for 48 months. There will be 25 experienced and 32 early-stage researchers to participate in 330 person-month exchange visits. A total of €1.52m funding is requested to support the planned exchange activities. The European partners are experts in process modelling and optimisation, process intensification, computational material design, catalysis, and CO2 utilisation while the Chinese partners are experts in process intensification, green hydrogen production and DAC. The South African partners are experts in DAC and sustainability assessments while the Nigeria partners are experts in renewable energy and green hydrogen production. Knowledge transfer and training will take place through the planned secondments. We will generate at least 30 Journal publications and 30 conference papers. In addition, 2 Special Issues will be published in leading journals such as Applied Energy, 2 Workshops and 2 Special Sessions at major international conferences will be organised to disseminate project results.

UKRI Gateway to Research · FY 2025 · 2025-01

Epilepsy is a serious neurological condition affecting over 650,000 people in the UK. Patients have seizures which can result in loss of consciousness, convulsions, and even increased risk of sudden death. Drugs are only effective for around two thirds of patients, motivating the need for alternative treatments. Brain surgery - where the part of the brain thought to be causing seizures is removed - is an option for many. However, even after the invasive removal of brain tissue, seizures still recur in up to half of patients. The past decades have seen a revolution in our thinking of how to study the brain. Huge datasets have become available to characterise normal brain structure and function. By using these data, we are now able to identify abnormality using mathematical and computational models. In this fellowship I will develop and use advanced computational techniques to analyse pre-surgery data acquired from over 500 people with epilepsy. I will use these techniques to identify brain abnormalities, then use computer software to predict patient outcomes. I will apply these models to new patient data from hospitals around the world to test if the predictions are robust. Finally, I plan to conduct prospective analysis to evaluate patient benefit in real-life clinical settings. If successful this fellowship will lead to predictive and mechanistic models to inform clinical decision making for surgery, with software to facilitate clinical translation.

UKRI Gateway to Research · FY 2025 · 2025-01

The ability to selectively prepare new molecules on demand is critical for almost every aspect of our lives, from plastics to pharmaceuticals. However, there is an increasing awareness that controlling the connectivity of new molecules is not enough and it is also essential to be able to precisely tailor their three-dimensional shape. For example, drug discovery programmes are increasingly shifting their focus away from traditional two-dimensional candidates towards three-dimensional (chiral) molecules that allow exploration of novel, biological and chemical space. To date, work in this area has centred almost exclusively around tetrahedral carbon atoms. I will explore an exciting alternative class of three-dimensionality known as atropisomerism, in which two flat fragments are linked together in a twisted arrangement. There is currently significant interest in this area, as the well-defined shape and structure of such molecules is ideal for applications in materials science, catalysis and medicines. This project will apply this idea to prepare novel analogues of amides (arguably the most important nitrogen-containing motif in the natural world) containing a key twisted carbon-nitrogen bond. I will develop new methodology for their synthesis based upon “multicomponent” reactions in which multiple readily available building blocks can be combined in a single operation, directly leading to formation of the desired product. This strategy promises unparalleled efficiency, providing direct access to the desired targets along with water as the sole by-product, whilst simultaneously achieving complete control over the three-dimensional shape of the new molecules that are produced. Moreover, this method will allow us to control the sense of twisting (i.e. clockwise or anticlockwise) allowing a single set of building blocks to be selectively combined to access multiple targets with different three-dimensional structures. This project will develop novel reaction systems to make useful nitrogen-rich 3D materials that will impact across various scientific disciplines, including new bioactive molecules with clear applications in drug discovery and agrochemistry.

UKRI Gateway to Research · FY 2024 · 2024-12

Invited application from Newcastle University to the EPSRC Core Equipment 2024 Call

UKRI Gateway to Research · FY 2024 · 2024-12

Astronomy, and science in general, can be challenging and inaccessible to those with Special Educational Needs (SEN). One contributing factor is a tendency to rely on visual representations of information. These are inaccessible to the blind and vision impaired (BVI), and those with other needs who benefit from alternatives to visual communication. This can contribute to lower science attainment. For all English state-funded Key Stage 2 pupils, 81% reached expected science attainment levels in 2023; however, for BVI pupils, and across all SEN pupils, this is only 60% and 43%, respectively (2023; UK Statistics Authority). With over 1.5 million pupils identified as SEN in England alone (UK Government Statistics, 2022-2023), this is a significant part of the pupil population. Audio Universe is our project that uses sound, and other multi-sensory approaches, to communicate astronomical data and concepts. We create more inclusive educational resources for those who find visual-only communications challenging or completely inaccessible.  Our long-term goal is to help raise science engagement and attainment levels of those with special educational needs (SEN). With modest funding, we have already created novel educational movie clips about the Solar System, where information is communicated through both sound and with traditional visuals. This includes a feature-length planetarium show called Audio Universe: Tour of the Solar System. This was co-created with the BVI community, BVI pupils and SEN specialist teachers. It is available in four languages and has been used across the UK, and internationally. We have further created complementary, multi-sensory educational workshops. Our evaluation studies with planetarium audiences, school pupils, and teachers have demonstrated that these resources have increased the science engagement with SEN audiences. Furthermore, they have been thoroughly enjoyed by the wider general public and school pupils, demonstrating that these resources can be used as part of truly inclusive experiences. We now aim for such SEN accessible experiences to be available and adaptable to the unique needs of individual planetaria and wider science centres or communicators, and to be updatable with cutting-edge research. This is crucial to ensure a long-term legacy and sustainability of our previous work. In collaboration with Project Partners of UK-based planetarium leaders and other communicators, we propose: To build a freely available Toolkit to enable the production of customisable and bespoke audio representations of astronomical data and concepts. These will be made for use in the planetarium, for online viewing, and for Virtual Reality headsets. We will also work directly with an international planetarium software provider, with the longer-term goal of embedding audio representations directly into the software itself.  Support the astronomy communication community to develop complementary, multi-sensory educational activities.  Provide good practice guidance for the use of these resources with SEN audiences.  Throughout the design and development stages we will work with focus groups of astronomy communicators, SEN pupils, specialist teachers, and the wider general public. These groups will enable regular cycles of evaluation and development to ensure that our Toolkit, and the related guidance documentation, is appropriate and well designed for both the communicators and for the target audiences. The Toolkit and documentation will then be shared widely online, and disseminated through networks of planetaria, science centres, and science communicators. This work is underpinned by our STFC-funded research in both astrophysics and in turning data into sound (sonification).

UKRI Gateway to Research · FY 2024 · 2024-12

The availability of in vitro models of the human retina in which to perform pharmacological and toxicological studies is an urgent and unmet need. Most drug studies are performed in vivo in experimental animals, but this approach is far from optimal because there are fundamental, structural and functional differences between the rodent and human retina. The advent of organoid technology has made possible the generation of three dimensional (3D) self-organised laminated and light-responsive retinal organoids from pluripotent stem cells (PSCs), a powerful tool for disease modelling and drug discovery. However the lack of microglia and vasculature currently limits their utility in two ways: firstly, it is known that microglia and vasculature play an important role in retinal development and disease, and secondly, the vascular system is necessary to prevent formation of necrosis in tissues that grow beyond 500µm diameter because of impaired diffusion of oxygen and nutrients. The vascular cells in the retina interact closely with the retinal neurons and glial cells, forming the retinal neurovascular unit (NVU), which together with the retinal pigment epithelium (RPE) form the core of the blood retina barrier (BRB). The BRB mediates highly selective diffusion of molecules from the blood to the retina and maintains retinal homeostasis. Alterations of the BRB play a crucial role in the development of retinal diseases, thus dynamic modelling of human BRB in highly desirable. Current conventional co-culture models of retinal organoids with endothelial and microglia cells bypass the developmental processes that lead to formation of spatially organised retinal NVU and BRB. Furthermore, the mesodermal origin of microglia and vascular cells, and ectodermal origin of neural retina, provide a significant barrier for the generation of vascularised immunocompetent retinal organoids incorporating NVU/BRB. Our aim is to reach beyond the state of the art to combine multiple organoid types in 3D culture to generate vascularised immunocompetent retinal assembloids that combine the neural and mesodermal cells and provide all the components of retinal NVU/BRB. To achieve this goal, we will generate PSC-vascular organoids that contain endothelial cells, pericytes, smooth muscle, astrocytes and microglia, and assemble those with novel blood-generating heart-forming and retinal organoids to make vascular immune competent functional retinal assembloids. Combining cardiac contractility with blood-like flow can provide significant improvements to the development and function of retinal assembloids in a tractable fashion with the potential to reduce animal usage and increase their use in drug discovery and disease modelling.

UKRI Gateway to Research · FY 2024 · 2024-12

With the need for the development of novel hydrogen-compatible combustion devices, physical understanding of the flame behaviour and the identification of thermoacoustic instabilities at relevant combustor operating conditions for hydrogen-air swirl flames will help speed up the development of hydrogen combustors, in line with the UK government's net-zero vision. The proposed research will offer potential benefits to industry and contribute to the progress of science in the areas of fluid dynamics, turbulence and net-zero combustion. These include (i) An advanced Direct Numerical Simulation (DNS) database for hydrogen-air premixed swirl flames under representative combustor operating conditions. (ii) A comprehensive understanding and a detailed analysis of the behaviour of the Precessing Vortex Core (PVC) under non-reacting and reacting flow conditions. (iii) Identification of the combustor operating conditions for which hydrodynamic/thermoacoustic instabilities exist. (iv) An in-depth analysis on extinction strain rates and heat release rate for lean hydrogen premixed flames. The outcomes of this project will offer knowledge on the flame stability limits and will contribute to the development of hydrogen based power generation and propulsion devices (e.g. gas turbines used for power generation and aircraft engines).

UKRI Gateway to Research · FY 2024 · 2024-10

Quantum thermodynamics investigates the fundamental concepts of thermodynamics in the quantum regime, paving the way for innovative nanoscale thermal machines. Quantum thermal machines are poised to play an important role in the "second quantum revolution", which is brought about by the advent of quantum technologies that rely on the features of quantum superposition and entanglement. Developing thermal devices that harness quantum features to improve their performance beyond classical counterparts is one of the main objectives of quantum thermodynamics. Crucially, as the success of quantum technologies depends on our ability to monitor and control low-temperature systems, developing more precise low-temperature thermometry becomes important. On the other hand, at the fundamental level, our world is characterized not only by quantum features but also adheres to the principles of relativity. While relativistic effects, such as the motion of physical systems and spacetime curvature, have been shown to improve quantum information processes, their implications for quantum thermodynamics are largely unexplored. In the ReQuT project, we seek to leverage the principles of relativity and quantum thermodynamics to enhance the efficiency of quantum heat engines and develop high-precision quantum thermometers. Ultimately, ReQuT will generate foundational breakthrough progress in the development of a relativistic quantum thermodynamics theory, which so far remains a matter of controversy. To accomplish its ambitious goals, ReQuT adopts a highly interdisciplinary approach and has devised a well-rounded work plan, as well as detailed dissemination and communication strategies. The project will be integrated into the Quantum Matter Research Group at Newcastle University's School of Mathematics, Statistics and Physics, part of the Joint Quantum Centre Durham-Newcastle.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

The efficiency of drug discovery has been falling for decades such that, for each new molecule that reaches the consumer, estimated research and development costs are in excess of $2 billion. The drug discovery process involves the design of, usually, a small organic molecule that is capable of binding to its target in vivo with therapeutic benefit. Part of the problem is that during this pipeline too many molecules are synthesised in the lab, at great expense, that turn out not to have the required binding affinity. A computational model that is capable of reliably predicting binding from structure is needed. Allied with structural biology methods, such as x-ray crystallography and cryo-electron microscopy, computational structure-based biomolecular simulation is an important part of the solution. At the simplest level, biomolecular simulation can be used to 'animate' the static pictures solved by structural biology, by finding the forces on the atoms, and hence solving for their dynamics. But we can also move beyond this, and use rigorous thermodynamics to predict the effects that changes in structures of potential drug molecules will have on binding to their target. Such approaches were employed by computational researchers all over the world during the COVID-19 pandemic to urgently provide new understanding of the SARS-CoV-2 virus and to design inhibitors of its function. Although we know that the forces on the atoms should be calculated using the equations of quantum mechanics, these are much too computationally costly to solve routinely for biological problems. Instead the dynamics and interactions of biological molecules are typically computed using a simplified computational model, known as a force field. The force field models the atoms as bonded by springs, and interacting with each other through electrostatic and van der Waals forces. The strengths of these interactions are modelled by thousands of adjustable parameters, which have been tuned to reproduce experimental data. These force fields are an important enabling technology for biomolecular simulation scientists, and the accuracy of their predictions depends on the realism of the force field model and its parameters. Traditionally, force field models evolved over periods of many decades. Design decisions taken early in the process became 'baked in', since re-training the model with new design rules was infeasible. The Open Force Field Initiative is an academic-industrial partnership aiming to advance the science and software infrastructure required to build the next generation of molecular mechanics force fields. In one example of our work from the first period of the Fellowship, we have co-developed a flexible framework to extend the Open Force Field software stack with custom force field models. In a proof-of-principle, we were able to train and test a new generalised force field model in a matter of weeks, rather than years, with improvements in accuracy over traditional force fields. My vision for the renewal period of the Future Leaders Fellowship is to deploy this software infrastructure to rapidly move from new hypotheses to trained force field models, with unambiguous determination of the effects of design decisions on model accuracy. For example, I will test whether machine learning models trained on high-level quantum mechanical datasets yield accurate force field atomic charges, and whether accurate protein force field models can be built using the new force field models described above. Force field models that show requisite accuracy will be deployed in molecular design workflows. Through working with the project partners in the pharmaceutical industry and at an open science antiviral discovery initiative, I will showcase the accuracy improvements in structure-based biomolecular simulations that will translate to improved efficiency of the drug discovery pipeline.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

Urban planning and design play a key role in supporting children's play and mobility in public space, with the ability to play and move freely around neighbourhoods offering a wide range of health and wellbeing benefits to children (Wood et al., 2019). While there have long been concerns about the loss of childhood freedoms in Britain, these have now become extremely pressing with a range of organisations and professionals raising the alarm (LUHCC, 2024). Austerity policies in recent years have resulted in increasingly impoverished environments for children and the Covid-19 pandemic exposed stark inequalities in children's access to leisure space (Casey & McKendrick, 2023). In parallel, concerns about public health and climate change are influencing government policies in support of active travel. However, some have highlighted that these need to go much further to address children's needs (Russell & Stenning, 2021). Many proposed solutions, such as playgrounds and supervised spaces, are based on outdated ideas about children (Russell et al., 2023). Furthermore, past attempts to change the environment to support children's play are not well understood. This fellowship aims to address this important omission through building on and disseminating my doctoral research into the development of postwar housing landscapes in Britain. My ESRC-funded doctoral research (title: Housing Landscapes and the Politics of Play: From Parker Morris to Byker c.1955-c.1995) illuminates the origins of this crisis in children's play and mobility. It examines the creation of national policies for housing and play in the postwar period and how these manifested in the redevelopment of neighbourhoods in one city, Newcastle upon Tyne. It also contextualises and provides a useful conceptual lens for examining contemporary attempts at citizen-participation and experiments with street layouts. Importantly, the fellowship will allow me to consolidate, build on and disseminate my research, which has relevance for academia, government, built environment professionals and advocates promoting children's play and mobility. Limited additional research, identified as necessary in my doctoral research, will address the lack of knowledge about the governance of postwar housing landscapes during the 1980s and 1990s. This will enable me to complete a draft monograph closely based on my doctoral research and this limited additional research. In addition, the fellowship will allow me to develop a second strand of my doctoral research in an academic paper. This will examine the 'mundane governance' of play streets and the role of planners and engineers in the reimagining of street layouts in the 1960s and 1970s. This is highly relevant to current debates about low traffic neighbourhoods. Disseminating my research findings to positively impact the lives of today's children and harness the current interest in this agenda is a key aim. A national impact and knowledge exchange event will be developed in collaboration with the national social change organisation Playing Out. This will engage policymakers, practitioners, academics and advocates to think about the future through critically examining historical and contemporary issues relating to children and public space. I will also share the findings of my research at an international conference and through the built environment trade press. In addition, I will share outputs of the new research with the Byker Living Archive community project. Finally, I will undertake oral history training to support the fellowship and future research plans and will apply for an ESRC New Investigators Grant.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

Classic galactosemia is a rare disorder of galactose metabolism, with very disappointing outcomes, representing a heavy burden on the patients' quality of life and on the healthcare systems. Its current standard of care, a galactose-restricted diet, fails to prevent cognitive, neurological, social and fertility impairments. This proposal aims to advance the frontiers of galactosemia successful treatment, using a small molecule-based approach. Our approach aims to address the root cause of disease, which is the toxic accumulation of galactose-1-phosphate, through inhibiting the GALK1-catalysed biosynthesis of this metabolite. GALK1 (galactokinase 1) is a valued, validated therapeutic target, with demonstrated proof of concept in cell-based and animal disease models. Our proposal applies structural based approaches towards hit optimisation of GALK1 inhibitors, combining expertise and track record in computational chemistry (Daniel Cole), medicinal chemistry (Celine Cano) and structural biology (Wyatt Yue) at Newcastle University. Prior to this proposal, our project team has: established GALK1 protein production, activity and binding assays, and co-crystal structure determination in place for a drug discovery programme; identified and verified three compound series able to inhibit GALK1 via an allosteric binding mode; applied computational de novo design, docking and molecular dynamics to optimise ligand design towards targeting GALK1; and progressed, using fewer than 60 follow-up compounds, from inactive fragments to three promising inhibitory series, enabled by computational and medicinal chemistry, and enriched through a wealth of co-structures. Through 3 work packages, our project team will apply computational and medicinal chemistry approaches to the design and generation of new compounds based on our chemical starting points, and characterise the binding, potency, and selectivity of these compounds in biophysical and structural assays. Based on the assay profiles we will identify one series for focused efforts to fine-tune compounds through design-synthesis-assay cycles. Finally, we will determine the ability of our best compounds to target GALK1 and generate functional impact in human cells. Through this proposal we set out to de-risk early-stage drug discovery for a rare disease, to advance our chemical starting points into validated hits, and to deliver a promising compound paving the route for lead development. There is a clear downstream pathway for development: Through engagement with US-based Galactosemia Foundation and the EU-based Galactosemia Network, the project lead has networked and collaborated with clinical and research leaders in the field (Bosch, Amsterdam; Gozalbo-Rubio, Maastricht; Riviera, Lisbon; Treacy, Dublin; Lai, Utah). These collaborators will be key to characterising our lead inhibitors arising from this proposal in their cell-based (patient-derived fibroblast and iPSC lines) and organism (zebrafish, mouse) models of disease for in vitro and in vivo efficacy through metabolic flux, enzyme activity and phenotypic analyses. Additionally, we have identified and engaged in discussion with biotech/pharma partners with potential interest in the GALK1 inhibitor programme. Working together, our vision is a first-in-class small molecule inhibitor to treat classic galactosemia.