Newcastle University

UKRI Gateway to Research · FY 2024 · 2024-09

The multiplication of airborne laser scans (lidar) in Mesoamerica over the past decade is revolutionising our understanding of the settlement archaeology, as exceptionally large agrarian landscapes of terraces, walls, drained fields etc. have been discovered. However, agriculture - though nodal to pre-Hispanic societies and still today - remains little studied by archaeologists and the evolution of these landscapes needs to be mapped, dated and interpreted. This is precisely the aim of the present project. We propose to export innovative approaches to landscape research to the context of central Mexico. We will implement a state-of-the-art methodology that will combine methods developed by Newcastle's McCord Centre for Landscape, including; Historic Landscape Characterization, tested to date across Europe and the Middle East; dating based on the revolutionary OSL-profiling method developed (see Kinnaird et al. 2017, Turner et al. 2021), and archaeological and geoecological mapping by lidar remote sensing, whose efficacy has been proven by the applicant's work in various Latin American countries (see Dorison et al. 2022). The project is highly timely in three respects: it focuses on ancient agricultural landscapes that are largely under-documented in archaeology, particularly in the Mesoamerican context; it proposes ambitious and innovative methodological developments; and it will record the richness of landscapes endangered by urban growth and profit-farming in Mexico. Among the main results, the project will establish the first detailed dataset for agrarian landscapes in the study area. It will provide unprecedented and long-overdue dating of agricultural remains, because although poorly documented until now, these are at the heart of the debates on the development of complex societies in Mesoamerica. Finally, it will provide important data and approaches to underpin the future management of these landscapes as valuable heritage assets.

UKRI Gateway to Research · FY 2024 · 2024-09

Trypanosome parasites are spread between humans and other mammals by biting insects, and cause three World Health Organisation designated Neglected Tropical Diseases: African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and Leishmaniasis (Leishmania species), together responsible for over 8 million cases each year. Cases of human African trypanosomiasis have decreased from epidemic levels in the 1990's due to sustained surveillance and control programmes. Yet, T. brucei is still endemic in 36 countries and highly prevalent in livestock animals, where it causes an additional economic burden. Understanding the mechanisms these parasites use to proliferate and transmit between hosts is essential to meet the WHO's aims of eliminating African trypanosomiasis as a public health problem by 2030. Like all eukaryotic cells, trypanosomes undergo the tightly regulated cell cycle to divide and multiple. Critically, only trypanosome parasites that stop dividing in the insect mouthparts and preadapt to survive in the mammal are able to infect a new host when vector insects take a bloodmeal. Once injected into the skin and bloodstream, these parasites start rapidly dividing again and spread to various host tissues causing disease. In the case of T. brucei, a mirrored process occurs where some parasites in the human undergo cell cycle arrest and prepare for transmission back to the tsetse flies, which spread them to new hosts across sub-Saharan Africa. When arrested parasites are ingested by a tsetse fly, they being proliferating again to complete the life cycle. Additionally, some Trypanosoma and Leishmania species appear to arrest and persist as dormant forms in mammals for long periods of time without detection by the immune system and may escape treatment. The mechanisms controlling whether trypanosomes continue to divide or arrest are, therefore, highly integral to both the survival and spread of these destructive parasites. Despite its importance, we have virtually no understanding of how or where these processes are regulated, not least because current assays are unable to efficiently discriminate the cell division cycle stages. Using Trypanosoma brucei, I will address three fundamental questions: which genes control whether T. brucei divides or arrests; where in the mammal and tsetse fly are the dividing and arrested forms found; and is cell-cycle-arrest required for transmission? To achieve this, I will take advantage of the amenability of T. brucei to genetic manipulation. I will engineer a novel fluorescent parasite line that will change fluorescent colour as they progress through the different stages of the cell cycle, or stop fluorescing when arrested. The changes in fluorescence can be easily and quickly tracked using both microscopy and flow cytometry, a method which can detect fluorescence of thousands of cells in seconds. Using this approach I will, firstly, perform a targeted gene silencing screen of hundreds of genes to identify those needed to either drive or repress cell division. Secondly, I will track the cell cycle changes of parasites in the different mammal and tsetse fly tissues. Finally, I will test whether preventing cell-cycle-arrest by gene silencing, also prevents T. brucei completing its life cycle in the mammal and tsetse fly. Together, this work will reveal how T. brucei directs its intricate transmission cycles to spread disease, findings that will then be extended to related trypanosomatid parasites. Ultimately, the cell-cycle-regulating proteins identified will be assessed as potential therapeutic drug targets for the treatment of trypanosome diseases.

UKRI Gateway to Research · FY 2024 · 2024-08

Acute Myeloid Leukaemia (AML) affects more than 3,000 people each year in the UK and is the most common and difficult to treat acute leukaemia in adults. FLT3 is a receptor that plays an essential role in normal blood cell development and AML. The hormone that binds FLT3, known as FLT3 ligand (FL), stimulates the growth of AML cells but the production of FL in humans in vivo is complex and not well understood. We have previously shown that patients with AML have almost undetectable levels of FL at diagnosis. When treatment is successful, serum FL rises to a very high level but if leukaemia is resistant to treatment, then FL remains low. This observation means that potentially, a blood test for FL can determine the response of AML to treatment. Whether leukaemia responds to the first-line of therapy is a critical factor in patient survival. There are multiple sources of FL, including specialised cells in the bone marrow stem cell niche, immune cells such as T cells, stromal cells and endothelium. In all sites, FL is synthesized as a cell-bound protein before it is cut by an enzyme and released into the circulation. It is likely that FL has two different roles: one to nourish blood stem cells, which is subverted by AML, and the other to stimulate immune cells known as dendritic cells, which also express a high level of the FLT3 receptor. If these two different roles can be disentangled, it may may be possible to develop new AML therapy based on FL. The first aim of my project is to determine whether FL, measured during treatment, can predict the result of the first bone marrow test to assess response. I have initiated the ARC-LITE study to collect samples from patients undergoing treatment for AML to measure FL and compare data, such as the rate of rise and peak level of FL, with bone marrow tests. This will potentially revolutionise the care of patients with AML, providing 'real time' assessment of their progress. It will be especially useful for older patients seeking less intensive treatment with fewer hospital procedures. In the future, I plan to link ARC-LITE with national AML trials currently in set up by collaborators in the NCRI AML Working Group. The second aim of my project is to understand the production and regulation of FL in vivo in more detail. Presently, there is no distinction between the stem cell functions of FL relevant to AML, and the immune functions of FL which may be either beneficial or harmful in the context of treatment for AML. I will study the production and regulation of FL in bone marrow, blood and skin, monitoring patients with AML, using very sensitive single cell analysis to pull apart these different functions. This is important because it may be possible to target FL in the stem cell niche to improve treatment of AML. Conversely, changes in the level of FL that occur during leukaemia treatment may have detrimental effects on the immune system that contribute to the toxicity of chemotherapy. This aim will use state of the art technology with a unique set of samples. It is likely to generate scientific insights informing new therapeutic approaches to AML.

UKRI Gateway to Research · FY 2024 · 2024-08

This study asks: what does an analysis of 21st-century Cuban, Puerto Rican, and Dominican film contribute to our understanding of the relationship between coloniality and ecology; and to what extent, and in what ways, can film build decolonial ecologies? This project aims to show that film is uniquely capable of conveying how contemporary ecologies are shaped by the enduring effects of colonialism, and that film, as both form and practice, can construct a decolonial ecology: one that addresses environmental degradation and disaster while building equality and emancipation. It will do so by focussing on 21st-century Cuba, Dominican Republic, and Puerto Rico: island contexts that have considerable historical, political, and economic differences but share certain geographical conditions. The project thus also aims to establish the value of the insular Hispanic Caribbean to refining our understanding of colonial ecologies, in order to respond justly to global ecological crisis. The research comprises four strands. The first 3 use comparative close analysis and the creative methodology of videographic criticism to focus on how Cuban, Dominican, and Puerto Rican films communicate the complexity of different colonial ecologies in relation to space and place, time, and (im)mobilities. They analyse the aesthetic and narrative choices and creative techniques used by filmmakers to expose and critique the imbrication of colonial legacies with contemporary ecologies. They also show how comparative film analysis can shed light on how contemporary experiences of ecological degradation and crisis are shaped by different (post)colonial, political, socio-economic, and cultural contexts. These strands emphasise how-more than simply representing something-film 'storiates', producing a sense of entanglement that conveys the complexity of lived experience, whilst also speculatively revealing alternative realities. The final strand examines how these speculative possibilities are actualised in emergent, collective practices through the case study of Puerto Rico post-Hurricane Maria: a colonial context affected by environmental disaster. Through film analysis, participant observation, interviews, and participatory action research, it examines how individuals and communities are using film to build decolonial ecologies in contemporary Puerto Rico. It thus seeks to illuminate how film production and exhibition are and can be used in the region to respond to ecological challenges in a way that also addresses (post)colonial inequalities and injustices. Thus, all four strands of the research explore the ways in and extents to which film can reconfigure relationships to the human and non-human world, and thus work towards a decolonial ecology, in the region and beyond. The research aims will be addressed by the following outputs: 1. An open-access monograph that addresses the four research strands. 2. A PDRA-authored, peer-reviewed journal article analysing how a selection of films represent and intervene in the colonial ecologies exposed by Hurricane Maria. 3. A video essay that explores the lived experiences of time produced at the intersection of coloniality and environmental degradation and disaster. 4. An advisory document that serves as a blueprint for the effective creation of community filmmaking projects that pursue decolonial ecologies in the Caribbean. This is one of two co-produced outputs from the Casa Pueblo workshop that will convene filmmakers and community organisations engaged in such projects across the island. 5. A short film about the workshop, produced by Casa Pueblo community filmmakers and co-produced by the PI. 6. A series of public film screenings and roundtable with filmmakers, community activists, and film organisations held at the Festival de Cine Global de Santo Domingo. 7. An online platform featuring the advisory document, short film, video essay, blogs on fieldwork, and invited responses to outputs.

UKRI Gateway to Research · FY 2024 · 2024-08

PaTHS (Pastoral Tracks Heading South: The evolution of the droveways (tratturi) in Central-Southern Italy) will promote an innovative trans-disciplinary approach to understand how transhumance and its mobility routes shaped the character of Mediterranean landscapes in the long term. Transhumance is a type of pastoralism entailing a seasonal movement of livestock between summer and winter pastures along designated trails. The long evolution of transhumance in Southern Europe generated pastoral landscapes, characterised by unique ecosystems and networks of droveways connecting pastoral sites. Today, the historic landscapes of transhumance are key economic, ecological, and cultural assets, and their sustainable management is promoted by local governments and international organisations. The project will focus on Central-Southern Italy, where the historic transhumance network included about 3,000 km of iconic droveways (tratturi) and where pastoral activities are documented since the Early Neolithic (6th mill BC). To the best of our knowledge, droveways have never been directly investigated using archaeological methods. Furthermore, the correlations between pastoral routes and the wider archaeological and historic landscape have rarely been systematically analysed. The goal of PaTHS is to fill this knowledge gap. By combining landscape archaeology, landscape history, ethnoarchaeology, geosciences, palaeobotany and geospatial analysis, PaTHS will unravel the history of tratturi and the evolution of pastoral landscapes and environments, to promote good management practices and inform future policies.

UKRI Gateway to Research · FY 2024 · 2024-08

This research will be the first sustained geographical study of nature reserves in Jordan and will use interdisciplinary thinking and decolonising methodologies to examine the relationships between resource politics, indigeneity, and postcolonial state formation. Global resource scarcity has seen increasing tensions between states and indigenous groups over the control and management of natural resources. Existing literature often reduces these tensions to simple binaries between states which want to exploit resources and indigenous populations who have traditional, ecological relationships with resources. These tensions are therefore often portrayed as violent indigenous and non-indigenous confrontations. This research brings nuance to these long-held assumptions through a focus on nature reserves in Jordan to investigate how resource struggles occur in everyday sites and are connected to postcolonial state formation, differing social histories and relationships with resources and situated understandings of indigeneity. With resource tensions predicted to increase it is important to understand the everyday spaces in which these struggles occur. By focusing on nature reserves in Jordan, I hypothesise that tensions between states and indigenous populations over resources are the result of (post)colonial state formation, contested understandings of indigeneity, and ideas of resource management rooted in North American and European models. Geographically, this project focuses on nature reserves in Jordan for three primary reasons: it is an understudied postcolonial location; it faces growing natural resource scarcity, especially water scarcity; and indigeneity, resources and national identity are entangled in complex and contested ways. In nature reserves in Jordan, resource tensions are not violent confrontations over extraction of resources such as oil, but instead everyday tensions over how states, NGOs, and Bedouin relate to and understand resources, alongside their role in national identity formation. The control and management of natural resources in Jordan is connected to colonial legacies of land management and the struggles of forming identity and controlling transborder resources as a result of postcolonial state formation. Nature reserves in Jordan illustrate how indigenous identities are selectively incorporated into nature reserves to forge national identity, while indigenous groups are simultaneously displaced from these sites and their relationships with resources ignored. Despite the rise in nature reserves throughout the Middle East remarkably few studies have explored the unique ways resource tensions are connected to (post)colonial state formation and indigeneity in these sites. This research will provide politically urgent insights that move beyond dominant and binary framings of resource tensions by putting this specific instance of (post)colonial state making into dialogue with existing explorations of indigeneity and nature reserves to produce an original re-conceptualisation of the relationships between indigeneity, resources, and postcolonial state formation. This research is taken from a decolonial methodological perspective in which indigenous scholars argue the persistence of colonialism and Eurocentric knowledge systems is in part due to the methods used by researchers. This project will employ a decolonial methodological approach by combining textual analysis of official state narratives of nature reserves with participatory methods that centre Bedouin relationships with resources. The outputs will be co-produced with participants and benefit indigenous communities beyond the end of the project. This research will fundamentally alter the way in which resource tensions between indigenous groups and the state are understood, the links between resource politics and postcolonialism, and the everyday spaces in which these tensions emerge.

UKRI Gateway to Research · FY 2024 · 2024-08

Over the past century, leading UK researchers working under the auspices of the British School at Athens (BSA), British Institute at Ankara (BIAA) and British School at Rome (BSR) - members of the British International Research Institutes (BIRI) - have generated heritage science collections - archaeological ceramic, lithic and botanical samples and geological reference collections - of international significance for addressing big-picture questions concerning the human past in the Mediterranean. These collections have substantial research value from ancient technologies and economies to innovation and societal change, with unparalleled value for investigating mobility of objects, raw materials and humans. Newcastle University works closely with the BIRI and has an international reputation for research in heritage science especially in artefacts and archaeological archives as well as substantial expertise in collections management. Of particular interest to Newcastle, 50-years of scientific study of Mediterranean ceramics at the BSA has created a collection of unrealised potential. These fundamental collections, however, remain inaccessible to most researchers. The BIRI Collections represent an ideal model for building a versatile and powerful heritage science collections management system. Underpinning and contextualising these data are significant related excavation and ethnography archives. Our collaborative programme will address the need for a heritage science collection management system and related digital infrastructure by focusing on a meaningful subset of BIRI collections laying the groundwork for future expansion. Using new technologies (set to international standards), we will build infrastructure to transform the potential of these unparalleled heritage science resources for international researchers and the public serving two key purposes: 1. To make primary data freely accessible. Providing access to this infrastructure will enable researchers to explore inherent, meaningful spatio-temporal networks of information in diverse collections, so that they can explore and analyse relationships between objects, people and places. 2. To enable the combination of collections and the creation of thematic stories through custom web themes, available for public and educational programs from school children to post-doctoral researchers. The data and the technology have been selected to ensure a meaningful research resource and a proof of concept for compatible expansion. Requirements for infrastructure include: Standards-based, findable and accessible to humans and machines, enabling research potential for humanities and social sciences including the use of machine learning to characterise digital images (e.g. of material thin sections). Cultural heritage aggregators will be able to consume linked open data published by the infrastructure. Remote access will include browsable catalogues of downloadable data as well as custom web themes that bring public education value through engaging storytelling. Tools that enable collaborating organisations to add data to websites sustainably without requiring ongoing IT development; facilitating collaborative research.

UKRI Gateway to Research · FY 2024 · 2024-07

Context: Cells are the building blocks of life, and it is essential we understand how they function individually and collectively within their wider context to decode the "rules of life" that dictate normal and abnormal cellular function at the systems level for wider societal benefits. These rules are relevant to the cellular engineering and biotechnology applications that underpin the development of cellular therapies, also helping to improve the security and environmental sustainability of our food sources. Specifics: the human body is composed of ~37 trillion cells whose collective behaviour ultimately determines the health and longevity of our species. Moreover, unicellular communities such as pathogenic bacteria harbour hidden heterogeneity in the form of functional differences that lead to Anti-Microbial Resistance (AMR) akin to therapeutic escape mutations in cancer. There is a pressing need to develop and apply transformative technologies that can measure this heterogeneity at the single cell level in order to exert some control and further our understanding. "Cytometry" comes from the Greek words "kytos" (cell) and "metria" (measurement) and describes a broad field of transformative technologies that make multiple high-throughput measurements of single cells at "population" scale. While always analytical in nature, there are cytometry technologies that can physically isolate (sort) cells from heterogeneous samples based on defined features allowing for further analyses of purified or enriched sub-populations. So called "cell sorters" were developed in the 1960s and have evolved incrementally over the years (more measurement parameters, multi-population simultaneous sorting capabilities and speed) but a major limitation is a lack of morphological or spatial information. Cell shape, size and signal localisation are key features of many important biological processes. This application is to secure funds to purchase the first image-capable cell sorting system that combines high-throughput full-spectrum based fluorescence profiling with simultaneous 6-population cell isolation. Enables: This will open up novel and exciting avenues for decoding the rules of life at the single cell level but at population scale. Specifically, it will enable work into anti-microbial resistance (AMR); cell fate determination toward healthy ageing; and cellular engineering/biotechnology.

UKRI Gateway to Research · FY 2024 · 2024-07

This application represents a joint bid from Newcastle, Northumbria, and Durham Universities to acquire a state-of-the-art cryogenic transmission electron microscope. Cryo-electron microscopy (cryo-EM) is a powerful imaging method that has revolutionised structural biology, with rapid technology development over the last decade enabling the visualisation of dynamic and flexible biomacromolecules and assemblies. Currently, there is no cryo-EM instrumentation in the North East of England, despite the region having research strengths and expertise in structural biology across the lead institutions. Our vision is to future-proof these North East institutions in next-generation cryo-EM. This proposal will equip the region with an indispensable tool to study dynamic macromolecular complexes that are not readily amenable to X-ray crystallography. The proposed instrument is a new class of cryo-electron microscope that: enables timely and efficient sample optimisation through real-time screening and preliminary analysis, thereby addressing a key bottleneck in the cryo-EM workflow; is a user-friendly instrument for training structural biologists in cryo-EM, a highly valued skill set in academic and industrial careers; is a cost-effective platform for building cryo-EM capability and expertise at the institution level. The instrument will be housed within the Newcastle University Structural Biology Facility, that is already equipped with a suite of X-ray crystallography and IT resources. This Facility will therefore become a hub for North East researchers to pursue and collaborate on biomacromolecular structure determination for both fundamental and translational research. The instrument will be managed through an organisational structure of operational, strategic, and user groups, with representation from all three institutions, to ensure effective day-to-day operation and decision making. The instrument user-base composes some 30 research groups from the three lead institutions, with a strong track record in studying diverse biomacromolecules across the kingdoms of life. The team of applicants also includes technology specialists with expertise in different applications of electron microscopy, as well as early-career researchers building their structural biology research portfolios. The instrument will enable research to advance the frontiers of molecular biosciences across the BBSRC strategic challenges of sustainable agriculture and food, renewable resources, and integrated understanding of human health. We therefore request funds for the purchase of a 100 kV cryo-EM instrument with direct electron detector. While we will conduct a WTO compliant tender process, a microscope in this class is currently only available from ThermoFisher Scientific. We have engaged with them to test the microscope with our samples, undertaken site survey to develop a delivery and installation plan, and have secured a highly favourable discount and service package. The cross-institution partnership makes a clear commitment to build complementary strengths in bioscience, biomedicine, and biotechnology; to attract researchers and resources to the North East; and to place the institutions at the forefront of structural biology. As endorsement of this commitment, the three institutions have committed to provide matched contribution totalling 30% of the equipment cost, as joint capital investment.

UKRI Gateway to Research · FY 2024 · 2024-06

Graveyards and cemeteries, once extramural, are now at the heart of Britain's towns and cities, often frequented by dog walkers, joggers, and tour groups. They were once places for burial and mourning, but urban transformation over the past two centuries has led to the disappearance or repurposing of many graveyards. This has fractured long-standing social bonds and erased shared histories. We use Ballast Hills Burial Ground (BHBG) in Newcastle upon Tyne as our urban inheritance case study. This post-medieval, non-conformist burial ground near the city centre holds the remains of over 12,000 individuals, including many paupers and marginalised individuals. Despite its historical richness, BHBG largely has been erased over the past century, resulting in limited public awareness of it. Once a gated burial ground on Newcastle's outskirts, it now is a flattened, green space in the thriving Ouseburn Valley, known for its culture and creative communities. Most gravestones have been taken down, with only a few remain upright, a sombre testament to its past use. This project aims to revive BHBG within Newcastle's historical landscape, resurrecting its history and enabling future research and stewardship. Combining archival research, archaeology, and community engagement, we intend to integrate this historic place into Ouseburn's cultural heritage and British history. The revival of BHBG is especially relevant today, shedding light on marginalized communities and promoting equality, diversity, and inclusion, particularly for the long-forgotten non-conformists. Given its diverse history and uses as a shared green space, connecting evidence is critical for shaping the site's future along with involving academics, residents, and the descendants of the deceased. This research unites history, library and information studies, human geography, and archaeology with a focus on public engagement through three aims. Aim 1 - enhancing BHBG resource accessibility through a comprehensive audit, conversations with resource holders, a gravestone inscription inventory, and a resource plan to prioritising future actions. Aim 2 - collating stakeholder interests by creating a stakeholder map to identify, analyse, and prioritize stakeholders, leading to a community engagement plan with two participatory activities. Aim 3 - discovering BHBG's historical significance through a desk-based assessment, emphasizing its local, regional, and national importance during the post-medieval period, and developing a research framework tailored to BHBG, linked to related sites in the UK. Achieving these aims will pave the way for subsequent inquiries, sparking new research questions and, inevitability, the opportunity for additional funding. Our engagement strategy supports co-production and communicating findings through public talks, blogs, and other academic outputs, drawing inspiration from Crossbones graveyard in London, a site that has attracted religious, feminist, radical, and artistic interventions. We aim to demonstrate proof of concept that harnesses BHBG communities to safeguarding the shared ancestry of marginalized individuals, families, and those seeking religious freedom. The benefits of this project are manifold, including the creation of an open-access integrated resource that will facilitate in-depth academic and genealogical research on buried individuals, non-conformist practices, social history, and the experiences of marginalized groups in the North East.

UKRI Gateway to Research · FY 2024 · 2024-06

Around 10% of the female population have Hashimoto thyroiditis as judged by positive thyroid peroxidase antibodies in their blood, and approximately 50% of these people progress to thyroid failure, manifest as thyroid underactivity (hypothyroidism) over several decades. When seen under a microscope, there is progressive destruction of the thyroid cells by inflammatory lymphocyte white blood cells, which are targeted to destroy the thyroid hormone producing cells. Once thyroid underactivity is recognised, the standard treatment is thyroid hormone replacement using levothyroxine tablets. However, about 10% of patients remain dissatisfied with standard levothyroxine treatment, typically leaving fatigue, muscle aches and cognitive symptoms often referred to as 'brain fog'. Multiple randomised clinical trials have shown that improvement in the blood thyroid hormone levels or adding tri-ioidothyronine (T3, the active thyroid hormone) does not help these people. This raises the possibility that the thyroid inflammation itself rather than the consequent hormonal deficiency is responsible for the residual symptoms in hypothyroid patients. We will perform a double blind, randomised controlled trial of an immunosuppressant/ anti-inflammatory drug called mycophenolate, which will kill off the lymphocytes in the thyroid and reduce the thyroid inflammation. Forty-eight women with Hashimoto thyroiditis will be in the trial for 16 weeks, with thirty taking the active mycophenolate and eighteen taking placebo. The primary outcome measurement will be the change in the number of inflammatory lymphocytes in thyroid samples taken before and after the experimental treatment by fine-needle aspiration. We will also perform a multimodal investigation including fatigue, other symptom and quality of life questionnaires, cognitive tests, blood 'acute-phase' inflammation markers, cytokine assays and functional imaging of the activity of inflammatory cells in the thyroid by FDG-PET. This will demonstrate whether thyroid inflammation can be reduced by mycophenolate and whether this will improve the persistent symptoms and poor QoL for these patients. Mycophenolate is now an inexpensive drug and if successful, this treatment could improve the health of around 100,000 working-age women in the UK who have Hashimoto thyroiditis and who have persistent symptoms during conventional levothyroxine treatment.

UKRI Gateway to Research · FY 2024 · 2024-06

How life originated on our planet is one of the great unsolved scientific questions. While no rocks survive from this early in Earth's history, clues can be gained from scraps of evidence from biological 'fossils' still present in microorganisms today, a consideration of what early Earth environments were probably like, and by looking at similar environments on the modern Earth. Together the evidence is consistent with an origin of life at warm to hot (< 150 deg C) alkaline hydrothermal vents ('hot springs'), where iron-rich minerals helped react hydrogen gas from the hydrothermal vents and carbon dioxide from the oceans or surface water into the organic 'building blocks' of life. One problem, however, is that experiments trying to mimic this chemistry under relevant conditions have only formed very short organic molecules of 3 carbon atoms in length or less. These are too short to build the larger organic 'building blocks' of life; most importantly cell membranes essential for separating the cell (the basic unit of life) from outside water to allow the control of chemical gradients and later evolution of internal biochemistry. In ORIGINS we will build on exciting new experimental results from a pilot study at Newcastle University where we have formed long chains of organic molecules (including the building blocks of cell membranes) on iron-minerals under conditions mimicking the mixing of alkaline hydrothermal vent fluid with water at < 100 deg C. We will determine how different iron-minerals and water chemistries can form the key organic building blocks of early life. We will then aim to show how these organic building blocks can, given the right conditions, lift off the minerals and self-assemble into 'protocells'; membrane-bounded organic spheres with a strong resemblance to modern microbial cells; a key stepping-stone to life. Finally, we will take the first steps to test if these protocells can use metal-mineral clusters embedded within them to generate further organic molecules, grow, and replicate. ORIGINS will have impact on both Earth and beyond. Research will be linked to an outreach program in the NE of England, using interactive workshops to inspire school age children to continue with science-based subjects. ORIGINS will also aid the search for life elsewhere in our solar system. Icy moons such as Jupiter's moon Europa and Saturn's moon Enceladus are thought to have similar alkaline hydrothermal vents at the bottom of their deep ice-covered oceans, and samples of them brought up by hydrothermal plumes to the moons' surfaces or expelled into space. We will link into the recently launched European Space Agency JUICE (Jupiter Icy Moons Explorer) mission, recently started on its eight year journey to explore Jupiter's icy moons. Samples of the organic molecules and protocells made in ORIGINS experiments will be used to test the ability of identical instruments to those on the JUICE spacecraft to detect organic molecules on the moons' surfaces prior to its arrival.

UKRI Gateway to Research · FY 2024 · 2024-06

When we hear conversation in unfamiliar languages, it can seem fast, with sounds run together and few distinct words. In fact, sounds flow rapidly and overlap in all spoken languages, but knowledge of our own language allows us to use various unconscious strategies to extract words and to interact in fluently-timed conversations. One key strategy for effective spoken interaction is listeners' generation of timing predictions. Sounds are often lengthened at important points in speech, such as the start of words and the end of conversational turns. To detect lengthened sounds, it seems that listeners use the rate of the speech they have already heard to generate expectations about how long upcoming sounds will be. When sounds are longer than expected, listeners can interpret that as an important point in the speech stream, such as the start of a new word. Although there is good evidence that listeners make timing predictions to interpret speech, theoretical understanding of how this is achieved is very limited. In particular, it is unclear what features of speech support listeners' use of timing prediction. For example, one theory about language processing in the brain implies that very regularly-timed speech is more useful for listeners in making timing prediction, but another theory implies that the irregularly-timed flow of natural speech supports timing predictions. These theories also have different implications for understanding how timing predictions are affected by acquired disorders, such as in people with aphasia (PWA) due to stroke. Aphasia typically arises due to interruption to blood-flow in the brain which causes damage in language-processing areas. PWA usually have difficulties producing spoken language, such as specific words or grammatical phrases. PWA can also have problems in understanding speech, but these may be less immediately apparent, despite having a profound impact. The project will test both people with typical language skills and people with aphasia in order to improve understanding of how they produce timing predictions. As these are so important for natural interactions, our findings will have implications for the design of devices using artificially-generated speech, from satellite navigation interfaces to augmentative communication systems for people with speech difficulties. We will test how timing predictions are generated using a new listening task ("nonword segmentation") in which listeners hear short meaningless sequences of syllables, "nonword targets" (e.g., "libeku") followed by longer sequence of syllables, "carrier utterances" (e.g., "mimasikonebubilibekududi"). When listeners hear a nonword target in a carrier, they have to respond by pressing a computer key as quickly as possible. Over multiple trials, with careful variation in targets and carriers, this task will allow us to build up a picture of timing prediction. Importantly, our pilot studies have shown that longer initial consonants make target detection easier, but only when targets are quite late in carriers. This supports the theory that listeners build up timing predictions based on speech already heard, but to fully test this, we need to explore how timing predictions are affected by a range of factors: - Regular or irregular carrier utterance timing. - Hearing speech in noise and/or with meaningful linguistic content. - Hearing familiar voices and accents. - Seeing as well as hearing speakers. Because PWA have variable speech production and perception difficulties, we will test their ability to make timing predictions compared to age-match listeners without aphasia. One theory implies PWA should have relatively good timing predictions compared to their overall language, but another theory implies poor timing prediction in PWA. Ultimately such work will boost understanding of speech perception and comprehension can be affected in aphasia and how any difficulties may be remediated.

UKRI Gateway to Research · FY 2024 · 2024-06

In the treatment of any medical condition, the benefits of pharmaceutical care must be balanced against the risks of harm. For all drugs, this removal is carried out by the kidneys (to some degree) and critically - if doctors don't get this balance right - drugs can cause toxicity to this organ with catastrophic consequences. Currently, physicians rely on rules of thumb and their clinical experience to maintain this delicate balance for the majority of patients. This deteriorates to guesswork for new drugs, paediatric and geriatric patients, or other patient groups whose bodily make-up deviates from the rest of the population. This project focuses on one type of drug toxicity which arises through the precipitation of drugs in the urine which can cause mechanical damage to the kidneys. Acute Kidney Injury (AKI) is poorly diagnosed, ineffectively managed and has been recognised as a condition of global concern. As such, the most effective approach to reducing the healthcare burden of this condition is to prevent it from happening at all. Precipitating Drug induced Acute Kidney Injury (P-DAKI) is one of the most common causes of AKI, resulting from the precipitation of crystals in the kidney which can cause direct damage to this organ. Physicians generally rely on their clinical experience to reduce the risks of and effectively respond to P-DAKI, but this is clearly not enough as recent estimates suggest that P-DAKI occurs in 5% of patients treated with high-dose IV amoxicillin. This lengthens hospital stay and in some cases can lead to death. P-DAKI has also been thought to occur in up to 40% of patients treated with oral antiretrovirals such as indinavir and although atazanavir and darunavir superseded indinavir to reduce this risk, crystalluria still occurs. This project will take a systematic approach exploring the interface between the chemical fundamentals of the drugs known to cause kidney damage and the chemical composition of urine itself. The ultimate aim is to build clinically relevant tools and guidance to enable physicians to predict the risk of kidney injury. We aim to significantly reduce the risks of P-DAKI by understanding drug behaviour in artificial and human urine with the view to identify specific chemical characteristics that predispose drugs and their metabolites to crystalluria.

UKRI Gateway to Research · FY 2024 · 2024-06

Developing renewable energy sources and reducing carbon dioxide emissions will require a basket of different solutions. Biology offers some good options. Microbiology offers some really exciting ones. Microscopic, single-celled bacteria are used to living in extreme environments and often perform (bio)chemical reactions that plants and animals cannot do. Many bacteria retain the ability to grow in the complete absence of oxygen. Under such conditions a special enzyme called formate hydrogenlyase is produced in the cell. This enzyme oxidises formate to carbon dioxide and two electrons, and those two electrons are channeled down a molecular wire in the protein and used directly to generate hydrogen gas (H2). Formate hydrogenlyase are attached to the cell surface when they do H2 production and, somehow, they use this activity to transport other hydrogen ions (protons) across the membrane, which can be used to make ATP for cellular energy. On the face of it, formate hydrogenlyases must use the same mechanism to do this that is also found in the human mitochondrion (making ATP for the human cell). It should be easier and quicker to study this mechanism in bacteria and therefore make new discoveries about the fundamental rules of life. What about societal impact and benefit? Most enzymes in the world are reversible. The reverse reaction of formate hydrogenase would be to take H2 and carbon dioxide and generate formic acid. Thus, running formate hydrogenlyase in reverse should allow a bacterium to use hydrogen as a substrate to capture carbon dioxide as soluble formic acid. Using renewable H2 would be even better, as this would make this form of biological carbon capture really sustainable and useful to society. Harnessing this enzyme activity - either within cells as a "whole cell biocatalyst" or outside cells as an isolated protein - has the potential to help reduce carbon dioxide emissions from a whole range of sources, and to convert that CO2 waste into more useful products.

UKRI Gateway to Research · FY 2024 · 2024-06

Our genetic code is like a recipe book: we need instructions and ingredients to produce the cells within our body. The ingredients are called genes, and in healthy cells, enhancers provide the instructions that say which genes are to be switched on and when. In patients with blood cancers, some enhancers get moved to new locations within the genetic code, and because of this they end up switching on the wrong gene. This is known as 'enhancer hijacking' and has been shown to contribute to the development of cancer. To understand how enhancers instruct the wrong genes we need to learn about the communication between enhancers and genes in both healthy and cancer cells. We also need to shut down these enhancers to prevent communication and record the response of the cells. By stopping enhancers communicating with the wrong genes, we hope to kill the cancer cells. We can edit the genomes of cancer cells in the laboratory, making alterations to regions within enhancers to shut them down. This can help us understand how enhancer hijacking works, and develop new treatments to reverse the effects of the hijacking (i.e., to stop the wrong genes from being switched on). However, identifying the most important parts of the enhancers is difficult, and the laboratory experiments are time consuming and expensive. In this project, we will develop and test a new computer programme which can identify these important sites, and predict the effects of the genome editing experiments. It will be possible to quickly mimic an experiment using the computer programme, trying many different scenarios before going into the lab. This will accelerate and improve the targeting of the experiments, saving time and money, and revolutionise the way we design our experiments. As well as this, the computer models will provide new insight and understanding of how enhancers switch on the wrong genes to cause disease, and how genes and enhancers communicate more generally. This work is important because the changes to the genetic code that we are interested in are found in patients who do not respond well to current treatments. By understanding how enhancers communicate with genes, we can look to block this interaction. In the longer term, this will enable us to develop more specific treatments that only target the cancer cells, reducing side-effects of treatment and improving the lives of those living with cancer. Our team brings together researchers with very different skill sets - laboratory-based cancer biology and computational biophysics. Having both of these aspects will be crucial for taking this exciting work forward. We have successfully worked together for over three years and have already published new findings for the scientific community. The experimental protocols that we will use are already established within the group and the computer model that we plan to build on has already proved successful in multiple projects. By continuing this successful collaboration, together with our project partners, we hope to make significant contributions to knowledge about how hijacked enhancers communicate with genes. If successful this approach could be applied to many different cancers which involve enhancer hijacking.

UKRI Gateway to Research · FY 2024 · 2024-06

Children's social care has long been in crisis with reports of abuse, growing numbers of children entering care, declining numbers of carers and diminishing quality of care. The 2022 inquiry into children's social care in England and Wales called for a radically different mindset alongside significant investment to 'reset' the care system and ensure it effectively meets children's needs. The state of care in the present day has in part resulted from an enduring lack of attention to and understanding of child and family perspectives about welfare needs and experiences from the long view. Meaningful transformations to current care systems cannot happen without a deep understanding of the complex contexts in which children's care has developed over modern history, and a comprehensive knowledge of how children in both the past and present have felt about their diverse experiences of care. Caring Communities offers a critical and timely intervention into what will be a radical programme of transformation for the children's social care system over the next decade. This project provides the first major cultural and affective study of children's care between 1800-present that will help shift this mindset to imagine new and radical possibilities for children's social care in the future. It develops an innovative, interdisciplinary framework that combines historical research with creative and participatory approaches to privilege the subjectivities, voices, and views of Care-Experienced people and to elucidate new understandings about care practices and experiences across time. Crucially, the research sheds important light on the complex interplay of emotions, care, and politics and explores how these have shaped care practices in the past and present. The project draws attention to the multiple ways in which current understandings, policies, and practices are the result of long-term processes of cultural, political, and social change and thus embedded in the past. It adopts a historical vantage point while collaborating creatively with partners including major UK care agencies (Coram, The Children's Society, Who Cares? Scotland) and Care-Experienced groups to emphasise the relevance and significance of historical forms of care to current policy and practice, offering a unique opportunity to generate new thinking about the value, meaning and impact of distinct care practices. Taking a historical perspective that is attentive to current policy and practice means that the project offers significant and meaningful ways of approaching the study of children's care for the benefit of policymakers, practitioners, carers, and care agencies. The Future Leaders Fellowship (FLF) will fundamentally change the way we think about social care: this research uses historical evidence and collaborates with care professionals and recipients to confront ideas about what care is, what it does, its value, and crucially, what it could be. In addition, it fosters innovative creative and participatory techniques to develop insights that will shape debates about the future of care that cannot be derived from conventional historical methods alone. Embedding collaboration and co-production from the start, the project offers Care-Experienced groups a platform to make a significant contribution to ground-breaking research and the opportunity to demonstrate that the history of children in care is really the story of all children's care. In creating a better understanding about the world of children's care over time, the FLF will generate an emotionally- and historically-informed framework for developing compassionate and effective practices for the future.

UKRI Gateway to Research · FY 2024 · 2024-06

The Solar Aviator project seeks to demonstrate a lightweight solution to develop light-powered and wireless electronic devices used by defence personnel for communication and data acquisition. The Royal Airforce require an ongoing energy source for ground troops who secure and protect airfields. Such operations require ground troops to carry a lot of heavy kit. Additionally, where personnel are in the field and battery energy sources run out, light weight solar energy sources would help maintain contact on operations such as an evacuation. We have developed a solution to this operational need: printable solar cells which can be deposited on fabric, plastic, or foil for integration into portable electronic devices or wearable technology under various light conditions. This project exploits recent results proving that the power generated under ambient light by a high efficiency photovoltaics with the area equivalent to a mobile phone can power sensors and IoT devices. We now propose a wearable self-powered communication technology.

Other NSERC · FY 2024

4704 - Biogeography and Landscape, 4102 - Remote Sensing, 4900 - Plant and Tree Biology, 4710 - Terrestrial Ecology, 4707 - Plant Ecology, 5500 - Animal biology, 6100 - Food Science and Technology, 4711 - Wildlife Management