University of Birmingham

UKRI Gateway to Research · FY 2025 · 2025-01

Despite recent advances in targeted therapies, ionising radiation and genotoxic chemotherapy remain mainstays in the treatment of cancer. These treatments are responsible for the majority of cures achieved in the clinic, and kill cancer cells by causing catastrophic levels of DNA lesions in the cellular genome, leading to cell death. To counteract the toxic nature of unrepaired DNA lesions, cells possess overlapping pathways for responding to and repairing DNA lesions, collectively termed the DNA Damage Response (DDR). The DDR is regulated by a number of protein modifications, including phosphorylation. The poorly characterised large nuclear protein BOD1L1 has been identified by the Higgs lab to have multiple roles in the DDR, and is key to the repair of lesions induced by both ionising radiation and genotoxic chemotherapies. Separately, I recently identified that BOD1L1 interacts with and suppresses activity of the protein phosphatase PP2A via its regulatory subunit B56. Phosphatases remove phosphate molecules from other proteins in order to change their structure or activity, and are vital to ensure timely and accurate DNA repair. We hypothesise that this new function of BOD1L1 is involved in regulation of the DDR. In this proposal, named PHOSREP, we will investigate the relationship between BOD1L1, the PP2A-B56 complex and the DDR using cutting-edge proximity-labelling approaches combined with phospho-proteomic mass spectrometry, single molecule analyses and DNA repair assays. We will characterise the binding of BOD1L1 and PP2A-B56, determine which protein components of the DDR are regulated by BOD1L1-PP2A-B56 at/near DNA lesions, and determine the importance of these changes in repairing DNA damage caused by ionising radiation/genotoxic chemotherapy. PHOSREP will enhance our fundamental understanding of DNA repair, clarify mechanisms of cancer treatment sensitivity/resistance, and improve the use of genotoxic therapies in the clinic.

UKRI Gateway to Research · FY 2025 · 2025-01

The central requirement of project safety, stability, and resilience of complex underground systems leads to demands for more efficient computational modelling tools to assist design and decision-making during the project life cycle. The concept of Digital Twins (DTs) provides a robust solution to monitor a construction project during its life cycle, predict its behaviour based on integrated holistic computational models, and protect it from hazards by virtually controlling the physical processes with its digital counterpart. Leveraging the power of a computational framework based on CutFEM combined with a BIM platform incorporating CAD-based data, the TwinSSI project will develop a comprehensive DT for underground design and construction. To validate the computational framework, real-scale experiments of tunnel-soil-structure interaction will be performed at the National Buried Infrastructure Facility (NBIF) at UoB. Moreover, the developed DTs will be applied to real case studies co-created with the industrial partners Network Rail and Maidl Tunnel consultants. The TwinSSI project will thus, for the first time, create and validate detailed DTs in the domain of soil-structure interaction modelling. The project outcomes will lead to a new paradigm for project planning and monitoring by geotechnical engineers.

UKRI Gateway to Research · FY 2025 · 2025-01

Music is the mediator par excellence of effective decision-making. Using the Mekong Delta in southern Vietnam as a case study, SoundDecisions applies an interdisciplinary approach and mixed methodologies to prove the bold claim that music performance enables farmers and other workers to listen to their surroundings and think through innovative solutions to immediate environmental and economic challenges. Both Indigenous Khmer Krom and settler Vietnamese who inhabit the Mekong Delta face climate change catastrophe from increased salinisation, reduced freshwater runoff, and intrusive sand mining. Together, they use improvised music to shape how they think about farming, trade, and other economic activities. Furthermore, by connecting with diasporic musicians via global telecommunication systems, they co-curate dynamic forms of musical listening and thinking to build trust, experiment with new solutions to environmental issues, and cultivate choice. These musicians reshape development of the region; and yet, since development emerges from a cultural basis rather than an economic one, the Vietnamese state and economists have not so far recognised their work. How do cultural changes forged by musicians at the intersection of the region's rich natural and cultural resources enable new socio-economic development? What new forms of sustainability might arise from their grassroots attempts to establish new methods of co-existence given climate change realities? The first project of its kind, SoundDecisions undertakes a major programme of archival, ethnographic, and econometric research across three continents to answer these questions. SoundDecisions offers new methodologies for economists to understand the role of music in mitigating climate change and improving economic livelihood, and for ethnomusicologists to use econometric methods to expand their ability to evaluate music's place in the world.

UKRI Gateway to Research · FY 2025 · 2025-01

Nuclear Magnetic Resonance (NMR) is a powerful and versatile atomic-scale probe of magnetic, electronic and structural properties of matter. NMR spectroscopy finds applications in a very broad range of scientific research and innovation areas from quantum and condensed matter physics (e.g., quantum magnetism, correlated electron systems and superconductivity) to materials chemistry (e.g., solar cells, catalysis and battery technology). This method allows unique insights into materials by providing a local (being element-specific) and non-invasive probe of electronic and molecular dynamics as well as local structure, including that of dilute dopants. The proposed Ultra-Low-Temperature NMR (ULT-NMR) infrastructure will address a broad range of scientific challenges, from fundamental science discoveries in exotic quantum states of matter to innovative development in advanced functional materials. We will focus on four primary Scientific Challenges in which we can deliver world-leading research. The first is discovery and understanding of new quantum states that occur only at very low temperatures beyond the reach of current NMR systems in the UK. The second is control of quantum states through combined tuning knobs of magnetic field and pressure, with the effect of this tuning monitored by NMR, building a pipeline towards new quantum technologies. The third is atomic-level structural characterisation of energy materials for which the NMR signal has so far been prohibitively weak; the low temperature will boost the signal-to-noise ratio. Finally, the fourth is quantitative analysis of the dynamics in supramolecular systems that is too fast to be studied at room temperature; cryogenic temperatures will slow these dynamics to allow precise study. Our primary aim is to integrate ULT-NMR into a globally competitive and inclusive environment for research on Quantum Matter Physics and Materials Chemistry that is centred at the University of Birmingham (UoB). We will also proactively support, and share the infrastructure with, the entire UK materials physics and chemistry communities to help them deliver their world-leading results across these fields. To deliver these aims, our objectives are: i) to implement a fully functioning ULT-NMR, ii) to develop and put into practice experimental methods relevant to our four Scientific Challenges, iii) to implement a transparent and fair access management model, iv) to develop a user support and training programme, along with Project Partners with complementary capabilities and expertise, v) to support career and professional development of our staff and vi) to expand the user base and train the next generation of scientists. We will maximise effective use of national resources to help the UK maintain its global leadership across the fields of quantum and functional materials through alliance with complementary national facilities (ISIS Neutron and Muon Source and Diamond Light Source) and Strategic Infrastructure (Midlands Mag-Lab and Tri-Beam Focused Ion Beam at UoB). ULT-NMR will also partner with the national NMR facility at UoB to benefit from its two decades of experience supporting engagement of the UK scientific community with cutting-edge NMR capabilities. The fundamental research enabled by the proposed infrastructure will find applications in energy harvesting and storage, low-energy electronics and quantum technologies including sensing and computing.

UKRI Gateway to Research · FY 2025 · 2025-01

Context Indonesia is the largest archipelagic country and the fourth most populous country globally, boasting over 17,000 islands located in the tropics with an annual average air temperature of 28 °C. The country is also the second largest fishing nation with 6.7 million tonnes of marine catches and 14.5 million tonnes from aquaculture in 2018, representing nearly 7% of GDP contribution. As much as 95% of the country fishery production is made by small-scale fishers, encompassing approximately 6 million people or 2.5 million households engaged in this vital sector. Furthermore, there are 576 fishing ports in Indonesia and 526 (91%) of them are small-scale operations. Yet around 20% of Indonesia's impoverished population hail from fishing households, highlighting systemic challenges. Many of the communities and ports are without adequate cold storage and ice-making facilities. The current cold storage capacity in Indonesia is only sufficient for 500,000 tons of seafood, starkly insufficient for the colossal 20 million tons of fish produced annually. This shortfall not only leads to extensive food loss due to wasted catch but also constraints economic opportunities due to inability to store catches for longer periods. Consequently, Indonesia contends with significant post-harvest losses estimated at 30%. Aim and Objectives This project aims to develop, deploy, and monitor zero emissions and affordable cooling infrastructure, in the form of a cooling hub, for small-scale fisheries in Indonesia. Research objectives Identify small-scale fishers current and future cooling demand profiles across typical fisheries communities; Develop optimised cooling hub design options that integrates multiple cooling services including cold storage, ice making and other ancillary services; Develop viable business models that ensure affordability and adhere to local context; Understand and mitigate the social impacts of deploying the cooling hub; Assess the environmental sustainability of the cooling hub throughout its life cycle; Develop a blueprint to integrate the cooling hub in wider energy and cooling systems; Co-develop policy interventions that foster sustainable cooling practices. Ayrton Fund Themes and Challenge Areas In addressing this pressing issue, this project aligns with the following two Ayrton themes: lower-cost, flexible clean energy supplies suited to the resources of developing countries. super-efficient demand via innovative services, processes and equipment meeting the needs of poor consumers and enterprises. The project will tackle the following four challenge areas: Sustainable cooling for all Zero emissions generators Energy efficiency Inclusive energy and leave no-one behind Potential applications and benefits Access to robust cooling infrastructure will improve the socioeconomic conditions of small-scale fishers. By ensuring the quality and freshness of their catch, these fishers can command higher prices in the market, thereby bolstering their economic viability. By minimising fish loss, the project plays a key role in curbing the loss of protein and micro-nutrient-rich foods, thereby contributing to efforts to mitigate high rates of malnutrition and harming livelihoods. Furthermore, our project seeks to promote a more inclusive development by actively engaging women and youth in activities with higher economic values. In addition, the integrated cooling service will reduce emissions by using energy efficient equipment and natural refrigerants.

UKRI Gateway to Research · FY 2025 · 2025-01

With falling birth rates and increasing life expectancy we are an ageing society. 20% of boys and 25% of girls born in 2019 are expected to reach their 100th birthday. This would be good news if it were not for the fact that healthy life span has not kept pace with increasing longevity and now on average adults spend the last 15-20 years of life in ill health. Frailty is a major component of ill health in old age and refers to an enhanced vulnerability to stressors, such as falls, surgery or infections, which was demonstrated clearly in the mortality data for the COVID19 pandemic. The transition from robust health to frailty is a critical factor in the loss of independence and places increased pressure on health and social care. All of this has led governments to prioritise the enhancement of healthspan. The Doctorate Network on UnderstandiNg fraIlty tOwards a future of healthy ageiNg (UNION) is a multi-partner joint doctoral research training network with the overall aims of educating 13 Early Stage Researchers (ESRs), advancing the current understanding of frailty, and providing innovative solutions on how healthy ageing can be achieved. UNION brings together world leaders in a range of relevant disciplines (frailty, ageing biology and ageing medicine, inflammation, immunosenescence, immunometabolism, stem cell biology) with state-of-the art technologies including mass spectrometry metabolomics, advanced imaging, artificial intelligence, CRISPR-CAS9 libraries, SPECTRA 35-colour flow cytometry, global and conditional knockout mice. This technological excellence is applied to the clinical situation through unique longitudinal human ageing and frailty cohorts, longitudinal assessment of age-related multimorbidity in animal models and innovative multidimensional frailty indices in humans. Together this integrated activity will provide the highest quality training and research environment in our rapidly ageing society.

UKRI Gateway to Research · FY 2024 · 2024-12

The University of Birmingham's strategic vision, Birmingham 2030, is to grow research activity and to achieve this through investment in brilliant people, outstanding facilities and strong collaborative networks. Our goal now is to do more and better research, tackling the great challenges of our day, breaking new ground and making important things happen. The University of Birmingham has put in place a robust and transparent process for the allocation of the EPSRC Capital Award for Core Equipment. We propose to invest in 9 different items spanning the breadth of research themes aligned to EPSRC remit across the College of Engineering and Physical Sciences (EPS) at Birmingham. We will invest in upgrades to existing equipment, and procurement of items new to Birmingham. As well as investing in our research capabilities to support multiple users, we seek to prioritise benefit to early career researchers, helping to promote a culture of collaboration, internally and externally. Prof. Costas Constantinou (Director of Research, EPS), having responsibility for the equipment strategy, is the Project Lead. Each item of equipment has a Project Co-Lead who has responsibility for that specific item, from procurement through to utilisation including training. Technical support is specific to each item and delivered locally. The success of the equipment will be monitored through usage and other metrics such as initiation of new collaborations, grant applications, journal papers, conference presentations, industry user engagement and teaching related activities (PhD, MSc or UG projects). Again, the PcLs will lead on their respective equipment.

UKRI Gateway to Research · FY 2024 · 2024-12

Autistic people commonly experience differences in sensory processing which can negatively affect quality of life and mental health. In particular, heightened reactivity to sensory information can result in discomfort, which can make certain spaces and activities (like attending medical settings) disabling. There is a widespread recognition that we need to make spaces and services more sensory-inclusive for autistic people, as reflected in policy and initiatives like quiet hours. However, there is very little information about how to adapt sensory information to make it more comfortable for autistic individuals, without adversely affecting others. This project will begin to provide this necessary information. We will systematically find out the precise sensory parameters that lead to visual discomfort in autistic participants, and whether this differs from typically developing individuals. We focus on the visual system as heightened visual reactivity in autism is currently poorly characterised, yet there is a well-established literature characterising visual discomfort in non-autistic populations which we can draw upon. The project aims to uncover the general stimulus features underlying visual discomfort in autistic individuals, while taking account of individual differences. This will give a more precise characterisation of visual discomfort in autism, which will in turn allow us to uncover the underlying mechanisms. We will work with a group of consultants with lived experience (e.g., autistic individuals and parents of autistic children) to guide the project. In the first part of the project, we will present autistic and typically developing children with a range of visual stimuli (including striped patterns, flickering videos and natural images), either in-person or online, and children will rate how uncomfortable they are. The reason for working with children is that we are interested in how visual discomfort develops, and autistic individuals may 'get used' to sensory stimuli with age. We will identify the visual features that cause the most discomfort in autistic children and whether this differs from typically developing children, while taking account of individual differences. We will also see whether discomfort ratings relate to parent-report and child-report questionnaires, to make links with everyday life and to help begin to understand why discomfort ratings might vary from person-to-person. In the second part of the project, we will take the most and least comfortable stimuli for autistic children and use these to link discomfort to brain activation using EEG (a technique which measures electrical activity at the scalp) and measures of arousal including heart-rate and pupil size. These links will help us understand why autistic children experience more visual discomfort than typically developing children. The project will precisely characterise heightened reactivity to visual information in autism and identify underlying mechanisms. The findings will inform how environments (e.g., patterns of carpets, building frontages) and visual materials (e.g., educational resources, websites) should be designed or adapted to minimise discomfort for autistic people. We will create pathways to impact by holding knowledge exchange events with stakeholders (e.g., designers, architects, educational professionals). By minimising the uncomfortable stimuli that autistic individuals are exposed to, we have the potential to improve mental health and quality of life for autistic individuals. By additionally studying physiological mechanisms, we can link the sensory symptoms experienced by autistic people with underlying physiology, and may be able to develop nonverbal measures of discomfort which could ultimately be used with autistic individuals with few-to-no words.

UKRI Gateway to Research · FY 2024 · 2024-12

Hydroxylation is an emerging protein modification with largely unappreciated and poorly understood roles in fundamental cellular processes and a wide variety of human diseases. Protein hydroxylation in humans is generally catalysed by oxygenases that are dependent on a metabolite called 2-oxogulatarate (2OG, aka a-ketoglutarate). These so-called '2OG-oxygenases' are druggable enzymes with nutrient-sensing capabilities that can render their functions sensitive to (patho)physiological oxygen limitation (hypoxia) and metabolic alterations. Jumonji-C (JmjC) protein hydroxylases are a poorly characterised sub-family of 2OG-oxygenases, several of which remain as functional 'orphans' with cellular targets and functions not clearly defined. Although isolated catalytic pockets are relatively well characterised, the molecular basis for regulated activity of physiologically-relevant JmjC hydroxylase complexes remains unclear. Here, we propose to continue our investigation of a biomedically relevant JmjC enzyme that possesses a unique hydroxylase activity, to reveal the molecular mechanisms underlying its role in human disease. Based on a solid foundation of pre-existing data including protein interaction assignments, functional studies, and novel models (including patient-derived cells and cancer patient 'avatars' (organoids)), we will focus on understanding the structural basis and importance for hydroxylase activity of interaction with an obligate cancer-associated binding partner. We aim to provide a comprehensive understanding of the role of the hydroxylase complex in DNA replication and DNA damage repair (DDR), including structural and functional analyses of its interaction with and hydroxylation of a newly identified substrate that has previously been implicated in similar cellular processes and diseases. The insights gained from this work will then provide a framework for exploration of the impact of hypoxia and cancer-associated metabolites ('oncometabolites') on regulation of this novel pathway. In order to identify new actionable drug targeting opportunities, we will also leverage the information gathered to undertake a structure-guided analysis of the mechanisms by which the hydroxylase complex limits sensitivity to clinically-relevant DDR inhibitors. Importantly, we will continue and expand our published collaborative work developing first-in-class hydroxylase inhibitors, defining the importance of hydroxylase activity in tumour cell viability and the potential for broader application of DDR-focussed therapeutic strategies targeting this (and related) protein hydroxylase complexes. Together, the work will significantly advance our understanding of enigmatic disease-associated protein hydroxylase complexes and assign the physiological target of this unique protein hydroxylase for the first time. This, in turn, will support studies into how the microenvironment can drive genome instability and therapy resistance, and a wider understanding of the importance of protein hydroxylation in health and disease. Importantly, the work will also support the diagnoses of neurodevelopmental disorder patients and identify new actionable therapeutic strategies for the future benefit of cancer patients.

UKRI Gateway to Research · FY 2024 · 2024-12

There are many ways to image inside the human body, but arguably the most sensitive method relies on the uptake of tracer amounts of radioactive substances, which can be quantified by whole body scanners. The detection of key radioactive substances such as iodide relies on the function of a transporter protein, which needs to be in the membranes of cells so that it can act as a kind of pore. The transporter protein NIS is responsible for getting radioactive iodide and related substances inside cells. In addition to imaging, NIS is used to destroy tumours - especially those from the thyroid - and even where the tumour has spread around the body. One critical problem is that NIS is not always located at the outer membrane of cells where it acts as a pore, making the detection of radioiodide less sensitive than it would otherwise be. Our work is focussed on finding new ways of regulating NIS with drugs, so that we can actively target it to the membrane of cells in patients. Together with world-leading experts we will carry out extensive first-of-its-kind drug screening to identify new drug strategies, to understand how they work, and then to apply them. This has the potential to improve thyroid cancer imaging and treatment, to effect a new therapy for breast cancer, and to enhance the many other experimental and pre-clinical settings in which NIS is currently used. Clinically, over a third of a million new cases of thyroid cancer are reported worldwide per year. In general terms, patient outcome is good, but around a third of patients do not respond well to the destruction of thyroid tumours with radioactive iodide. This is particularly a problem where patients have metastases. It is not currently well understood how NIS behaves in metastatic disease. But for patients in whom NIS is not working well, life expectancy is significantly reduced, and around 45,000 people die from thyroid cancer per annum. Interestingly, NIS expression becomes 'switched on' in ~80% of breast tumours, including aggressive triple-negative breast cancers and their metastases. Radioiodide treatment of breast cancer has several attractive clinical features, but while radioiodide uptake into breast tumours and metastases has been demonstrated, levels of uptake are not sufficient to achieve a therapeutic effect. This is because NIS is generally found in a non-functional intracellular location, away from the cell membrane. Radioiodide is a safe and effective modality which has been in clinical use for over 80 years. However, its utilisation has remained largely unchanged since 1942. New breakthroughs and technologies could transform radioiodide treatment, making it more effective for all patients, but with further significant benefits to those thyroid cancer patients who do not respond well to the therapy. However, our work goes beyond this. We wish to pioneer new understanding into the regulation of NIS so that we can apply this to a number of different settings. For instance, via collaborators we will also apply our findings to models of NIS gene delivery and tumour spreading. We hope our work will inform the research of colleagues around the world who already exploit NIS function in multiple settings, adding new insight to these approaches. This ambitious programme of work will therefore use cutting edge approaches to solve the problem of systemically inducing NIS function.

UKRI Gateway to Research · FY 2024 · 2024-12

Quantum sensing, imaging and timing will deliver transformative advancements across multiple sectors, including healthcare, infrastructure, transportation, environmental sustainability and security. These technologies make seeing the invisible possible: the inside workings of our brains, the infrastructure buried beneath our feet, the polluting gases in the air around us, the cancers lurking in our tissue or the drones in our crowded skies. These are some of the challenges we are poised to address. Our Hub in Quantum Sensing Imaging and Timing (QuSIT) brings together academic experts and industry partners, collaborating to translate cutting-edge research into tangible innovations. QuSIT will capitalise on a decade of substantial governmental and industrial investments, consolidating expertise and world-class capability from two established UK Hubs: QuantIC, specialising in quantum-enhanced imaging and the UK Sensing and Timing Hub. QuSIT will be a unified centre of excellence, providing thought leadership within the UK's quantum technology landscape, crucial to the National Quantum Strategy. At the heart of QuSIT is a world-leading and diverse team of 45 investigators, comprising both emerging talents and seasoned experts. Their impressive academic track record is complemented by a shared commitment to translating innovation from the laboratory to address real-world challenges. Our researchers have a history of licensing technology to industry and launching their own ventures. The technologies we will exploit are based on both atomic states and entangled photons to create quantum devices that sense and image otherwise invisible optical wavelengths, radio-frequencies, magnetic and gravitational fields, and exploit precision time, including: Optical wavelength translation using non-linear interferometry and non-linear optics Atom interferometry for gravity and gravity gradient sensing Waveguide optics for wavelength conversion Optically pumped magnetometers for zero and high absolute fields Metasurfaces for lightweight and compact optics Wavefront shaping for seeing through obscuration Data fusion of quantum and classical sensor data, using AI and Bayesian Inference Quantum enabled frequency sources to enhance radar systems Our approach revolves around co-creating research with end-users, fostering collaborations between academics and industry players throughout the supply chain, and rigorously testing and refining our innovations through field trials in partnership with our collaborating companies, pursuing new approaches to: Line-of-sight imaging of polluting, or toxic gases and chemicals Monitoring of brain health Screening for concealed and dangerous objects Imaging of underground infrastructure Mid-infrared, holographic microscopes for clinical diagnosis Application of precise timing for the monitoring of congested airspace The hub is supported by companies and other end-users many of which have made significant investments. These include BT, BAE Systems, Department for Transport, Great Ormond Street Hospital, National Grid, National Physical Laboratory, Ordnance Survey and Severn Trent Water. In the increasingly competitive international landscape, QuSIT will provide the vision and have the convening power required to ensure that the UK remains at the forefront of quantum technology internationally, delivering accelerated economic growth and societal benefits through collaboration between academia and industry.

UKRI Gateway to Research · FY 2024 · 2024-12

This project researches hydraulic calcium silicate cements that are used in dentistry. These materials were introduced to dentistry from the construction industry and are used for a range of endodontic procedures (vital pulp therapy, root canal treatment). They are different to other dental materials as they require water to set and the presence of moisture enhances the materials properties. All other dental materials need to be used in a dry field which is challenging for oral procedures. Endodontics is a dental speciality dealing with the management of diseases to the dental pulp which are sequel of loss of tooth structure due to dental caries, acid erosion, wear or trauma. Depending on the severity of the tooth tissue loss and pulp involvement, the dental pulp management ranges from vital pulp therapy where the tooth is dressed with a bioactive material and restored, to root canal therapy (if the pulp is irreversibly damaged or infected) and surgery with placement of a bioactive material at the end of the root for cases that fail. All clinical procedures related to pulp management involve the mechanical cleaning of the pulp cavity, chemical irrigation to reduce the microbial load, followed by the placement of a bioactive material. The materials of choice for such procedures are hydraulic cements such as Portland cement. The hydraulic nature of these materials results in the interaction of the material with the tissues it is placed against and the environmental fluids. This interaction is responsible for the bioactivity of the materials and better interaction of the materials with the host tissues. Due to these characteristics, clinical procedures need to be tailor-made for that specific chemistry. To date, laboratory testing of hydraulic cements is often undertaken in similar ways to the testing of other dental materials with a similar clinical use. This has created a number of problems because hydraulic cements are environment-dependent which add limitations to the relevance of the testing undertaken using traditional approaches. This renders in vitro testing of these materials to be not clinically translatable to their daily use in clinical practice. The quality control evaluation of these materials is also undertaken using standards that were designed for materials of different chemistries and properties whereby the hydraulic cements do not comply as the standards are set for different material chemistries. One such property is solubility as the interaction of hydraulic cements with the tissue fluids produces apparent high solubility that is higher than the set standard. However in vivo, the tissue interactions lead to bioactivity which counteracts the solubility. The lack of updated clinical protocols and standards to which these materials need to comply to, has led to a number associated problems in clinical use. These include material extrusion out of the tooth (leading to formation of foreign bodies in the patient tissues), failure to set, leading to material disappearance from the surgical site which results in treatment failures and the need for revisions/repeated treatments. Vital pulp therapy and root canal therapy are procedures that are undertaken daily by all dental practitioners, but guidance with appropriate clinical protocols and materials that comply to adequate standards are necessary to protect patients from the undesirable effects of inappropriate management

UKRI Gateway to Research · FY 2024 · 2024-11

Effortlessly executing a sequence of movements from memory like typing to unlock a phone, or signing a document is something most individuals take for granted. However, when these dexterous movements are affected by neurological and neurodevelopmental conditions, as is the case for millions of people in the UK, it can have a profound impact on quality of life and re-entry into the workforce. Unfortunately, our understanding of how the brain organises and plans skilled sequences of movements across the brain for fluent and accurate execution is limited, which hinders the development of effective interventions and rehabilitation. This project aims to address this fundamental knowledge gap by conducting pioneering research on the brain-wide mechanisms underlying skilled action planning and coordination. By employing state-of-the-art multimodal neuroimaging, non-invasive neurostimulation, and developing a novel brain-computer interface (BCI) application, the project will focus on neural activity prior to movement onset and uncover how to causally modify the neural organisation of actions shortly prior to their initiation to promote fluent and accurate performance. First, the project will focus on establishing whether the type of action (typing vs handwriting), its movement characteristics (fused, discrete) and the way we practice (rigid vs flexible) influence how the brain pre-organises elements which make up an action sequence produced from memory. Here, magnetoencephalography (MEG) and electroencephalography (EEG) will be used concurrently to determine whether parallel pre-planning of movements is a universal mechanism employed across different types of dexterous actions and how it can be modified through practice. Next, the project will probe the relationship between dynamic activity - neural oscillations in key brain areas for the retrieval and control of well-trained actions, in particular the motor cortex, the striatum (basal ganglia), and the hippocampus. Concurrent EEG and functional magnetic resonance imaging (fMRI) will facilitate the source reconstruction of electrophysiological signals from subcortical areas. This will shed light on how the brain's electrical and characteristic oscillatory pattern changes across the brain contribute to the information transmitted during the planning and execution of sequences, settling long-standing debates in the field of motor control and cognitive neuroscience. Finally, this project will pioneer non-invasive brain stimulation to modify neural activity patterns during the planning to enhance the fluency and coordination of action sequences. This will be done by applying non-invasive brain stimulation, and by designing a brain-computer interface to help individuals recognize and learn beneficial activity states that enhance the correct pre-organisation of movement patterns before their execution to improve fluency and accuracy of the movements. The outcome of this innovative research will pave the way for future applications in clinical settings involving behavioural training, non-invasive stimulation of subcortical areas and brain-computer-interface technology, particularly for individuals with neurological and neurodevelopmental conditions who are affected dexterous skill learning and production.

UKRI Gateway to Research · FY 2024 · 2024-11

The growing plastic pollution (e.g. micro- and nanoplastics, MNPs) has shown to pose potential threats to human health. Especially, microplastic particles have recently been found in the placentas of unborn babies and in infant's feces with significant amounts. Recent researches on placental barrier (PB) suggests that particle accumulation in the PB can impact placental functions and elicit indirect placenta-mediated developmental toxicity. The accumulated particles may also pass through the PB to directly affect the developing foetus. However, it is still unknown whether/which/how MNPs can pass through the PB into unborn babies, and the research potential risks of MNPs exposure during the early development stage is very much in its infancy. Currently, three key questions limit the depth of research: 1) How to detect and quantify the MNPs in the PB? 2) What is the fate of MNPs within and beyond the PB (i.e. the translocation and the transformation of MNPs after crossing the PB)? 3) What effects does translocated MNPs on placenta structures, functions and fetal early development? Due to the complexity of PB system and the low amount of MNPs actually entering the PB, localizing and quantifying MNPs will be a challengeable task. Additionally, current testing on PB and developing foetus is mainly focused on animal models with poor predictive power. Thus, novel approaches are urgently needed to enable a breakthrough in our understanding of the ability of MNPs to cross the PB and trace their biological effects on placenta, developing foetus and the early development stage of human. The project EMBRACE proposes combining novel metal labelling technique with a dynamic in vitro chip-based PB model and advanced cell analysis technologies to assess MNPs translocation behaviors acrossing PB and potential risks in placenta and early development.

UKRI Gateway to Research · FY 2024 · 2024-11

Introduction: We have a hidden universe inside our bodies - the gut microbiota! This exciting world of tiny organisms may hold the key to helping infants that have iron deficiency anaemia (IDA). A new research project is seeking to uncover how these microscopic heroes, especially Bifidobacterium bacteria, interact with our bodies to outcompete potentially 'bad' bacteria for iron (which is normally limited in the gut), which may improve infant health. What is Iron Deficiency Anaemia?: Iron deficiency anaemia happens when our bodies don't have enough iron to make strong and healthy red blood cells. Without these cells, we feel tired, weak, and unwell. Millions of people, including infants and children, suffer from this condition. Normally, iron supplements (drops or fortified foods) are given to boost iron levels, however there are side effects such as diarrhoea which is linked to unhealthy changes in the types of bacteria found in the gut who can more readily access this 'free' iron. The Power of Early Life Gut Microbiota: Inside our gut, there's an active community of microorganisms, and among them, Bifidobacterium stands out as a true friend. These tiny heroes can do amazing things, like helping our immune system and breaking down food. Next we want to find out how some special types of Bifidobacterium can also take up iron more efficiently. This may help with development of new probiotics that help reduce some of the nasty symptoms that can happen during iron supplementation in infants with IDA. The Research Proposal: Our team of researchers from the University of Birmingham and Durham University, are embarking on a mission that is supported by one of the UK government research councils - BBSRC. We'll study how the early-life gut microbiota, especially Bifidobacterium, absorbs and uses iron. By understanding these interactions, we hope to find new beneficial bacterial therapies that could be used together with iron supplementation strategies in IDA infants - making them healthier and stronger. The Quest to Discover Microbial Superpowers: Our team will conduct exciting experiments with special lab tests and will even use baby poo samples! We want to learn how Bifidobacterium and other tiny microbes use iron uptake systems. While the research is just starting, it holds a lot of promise. This knowledge could open doors to smarter ways to treat and prevent diseases and conditions, like IDA, in at-risk infants.

UKRI Gateway to Research · FY 2024 · 2024-11

The self-directed use of image and performance enhancing drugs (IPEDs; e.g., anabolic steroids) is a growing public health concern with a recent estimate suggesting between 328,000 and 687,000 men in England currently using non-prescribed Anabolic Androgenic Steroids (AAS). IPED use is associated with multiple adverse health effects including cardiovascular (e.g., cardiomyopathy), neuroendocrine (e.g., gynaecomastia), hepatic and neuropsychiatric (e.g. depression). Given the prevalence of use and health concerns, there is a clear need for healthcare provision to meet the needs of this group, but evidence shows they are reluctant to engage with healthcare due to perceived (or actual) stigmatisation by healthcare professionals, lack of evidence-based advice and a perceived lack of appropriate knowledge amongst healthcare staff. Harm reduction services are uniquely placed to provide initial engagement with IPED users by offering non-judgemental services such as needle and syringe exchange programmes, but they face significant challenges. Change, Grow, Live (CGL) is a Third Sector charity and the largest provider of clinical services for drug and/or alcohol users in the United Kingdom. They provide multiple needle and syringe programmes (NSP) offering clean equipment and harm-reduction interventions to injecting drug users. Originally developed for opiate injectors, NSPs have seen increasing numbers of IPED injectors accessing services, with some areas now serving more IPED clients than opiate injectors. However, a recent survey highlighted that, compared to other elements of their jobs, CGL staff felt most poorly equipped to provide advice around IPEDs. Further evidence from a workshop with CGL staff highlighted a significant need for relevant evidence-based training around IPED use. From a client perspective, evidence shows NSP workers are often not seen as credible information sources, with IPED users preferring peer advice and specialist forums, often seeing NSPs as simply a source of equipment, rather than an opportunity for engaging with healthcare. Staff training and harm reduction initiatives therefore need to incorporate client perspectives to ensure they are adequately meeting their needs. Staff training in this area should be evidence-based to ensure that staff can speak with authority, increasing staff confidence when engaging with IPED clients. Equally, clients should be able to discuss their IPED use openly with staff that have an understanding of potential issues and how best to manage them. Finally, to ensure the training achieves its goals of improving staff confidence and understanding in relation to IPED use and improvements in engagement with IPED clients, the training should be properly evaluated. The findings from the evaluation can then inform future training developments to improve healthcare provision for IPED clients. This project will use a mixed methods approach to explore staff training needs in relation to IPED use and client perspectives on specialist harm reduction services. A staff training programme will then be developed and delivered across the UK by the Fellow, who has extensive experience in this area, guided by his mentors from the University of Birmingham and CGL, who are globally recognised experts in the field. The programme will then be properly evaluated and refined to provide the basis for in-house training for CGL, ensuring they can continue to provide appropriate training beyond the project timeline. The Fellow will also produce two scientific papers for publication and present findings at both national and international conferences.

UKRI Gateway to Research · FY 2024 · 2024-11

Many assembly and disassembly tasks in manufacturing have small clearances and limited accessibility, such as shaft-hole insertion/separation and bolt-nut assembly/disassembly. Using robots in these contact-rich tasks is more complex than those having no physical contacts (e.g. computer visual inspection) or simple contacts (e.g. cutting, welding, pick-and-place). The deployment of robots in contact-rich tasks has been limited to date. The contact-rich tasks that involve complex shapes, small clearances or deformable materials are particularly challenging to robotise due to the likely events of jamming and wedging. Our previous research has investigated techniques that allow robots to learn contact-rich skills (e.g. complex motion plans and force control policies) using two main AI-based pathways: (1) self-learning from trial-and-error, and (2) learning from human demonstrations. The two participating universities, Birmingham and Sheffield, have research experiences in (1) and (2), respectively. A key challenge observed in the current research is that in many cases a robot's contact-rich skill cannot be performed by other robots of different motion properties (e.g. accuracy, precision and stiffness), or be applied to a new task with variations (e.g. differences in object geometry, shape, and materials). This is because a robotic contact-rich skill, i.e. control policies and motion plans, is usually acquired for a specific task and cannot be adopted by new robots or in new tasks. STAMAN's vision is to create AI-based mechanisms to allow robots to share and recreate obtained digital skills (e.g. motion and force/torque control strategies) to allow easy automation scale-up for contact-rich tasks. This includes considering two research questions: 1) For skill transfer - how can a contact-rich skill be quickly transferred to a different robot (e.g. transferring a bolt-nut separation skill from a high-precision robot to a low-precision robot)? 2) For skill augmentation - how can existing contact-rich skills be used to create new contact-rich skills (e.g. augmentation of rigid-material skills to deal with soft materials)? The project will develop a portfolio of research into the science of digital skills for contact-rich tasks, focusing on common manufacturing tasks such as bolt-nut assembly/disassembly, peg-hole insertion/separation, and shaft-ring assembly/disassembly. The ability to transfer and augment digital skills for contact-rich tasks will allow automation systems to be implemented on a larger scale, with minimal manual setting and fine-tuning required. STAMAN aims to create transferrable and augmentable digital skills that will underpin the development of mass machine skills for future manufacturing, similar to how industrial robots have contributed to modern mass production. The proposed research encourages more use of robots in assembly (e.g. automotive, aerospace, electronics, etc.) and disassembly (e.g. repairs, remanufacturing and recycling), and thus directly contributes to the UK's Made Smarter initiative and the circular economy goals.

UKRI Gateway to Research · FY 2024 · 2024-11

Planets orbiting both stars of a binary system -circumbinary planets- are challenging what we think we know about how exoplanets are assembled, and how their orbits subsequently evolve. Because they orbit one another, binary stars disturb the process of core accretion that creates planets. But, instead of changing the number of planets created, the two stars instead affects circumbinary planets' masses and orbital separations, thus shining an unexpected light onto which planet formation processes are truly important. With its ambitious programme, CandY will consolidate circumbinary planets as an unavoidable corner of exoplanetary science, crucial for the study of planet formation, and the study and interpretation of exoatmospheres. To better our understanding of planet formation, the CandY project will perform the first systematic study of circumbinary planets. CandY will develop a suite of new analytical methods, and conduct three ambitious observing campaigns that will lead to the detection of dozens of new circumbinary planets, including some all way down to rocky masses. In parallel, the CandY team will study the atmospheric composition of circumbinary planets for the very first time in order to reveal yet more clues about these exotic worlds. During the CandY project, we will record every similarity, and any difference between the population of circumbinary planets and the population of exoplanets orbiting single stars. This systematic exercise will create a leap in our understanding about how planets are produced and which processes dominate planet assembly and their subsequent orbital migration. In addition, circumbinary planets have unique orbital properties amongst exoplanets. Their orbital dynamics boost their probability to experience transits easing exo-atmospheric investigations. Moreover, circumbinary exoplanets are the only transiting planets for which seasonal atmospheric variations can be studied.

UKRI Gateway to Research · FY 2024 · 2024-11

Multicellular organisms need to maintain the right balance between removing unwanted cells and stimulating tissue recovery for optimal health, especially when facing various stresses like heat, radiation, pathogens, and toxins. To achieve this balance, apoptosis, a major form of cell death, is often employed to remove damaged or less healthy cells. However, we still do not fully understand how apoptosis and the subsequent tissue recovery are coordinated. An interesting discovery is that cells undergoing stress-induced apoptosis release signals that stimulate compensatory cell proliferation, known as apoptosis-induced proliferation (AiP). AiP is essential for wound healing and tissue regeneration in various organisms including Hydra, Drosophila (fruit-flies), and mice. Uncontrolled AiP, on the other hand, can contribute to tumour development and cancer recurrence in pathological conditions. Hence, understanding how AiP is regulated provides valuable insights into the connection between stress-induced cell death and tissue recovery, with implications for human diseases. To study the regulation of AiP, we have used Drosophila as a model organism due to its advanced genetic tools and evolutionarily conserved cell signalling pathways. Previously, we have revealed that caspases, key enzymes driving apoptosis, also trigger AiP. In particular, the Drosophila caspase-9 (Dronc) initiates c-Jun N-terminal Kinase (JNK) signalling, a stress response signalling pathway, leading to AiP. More recently, we further uncovered that actin filaments inside cells undergo reorganisation to activate AiP. However, the regulatory mechanisms of actin remodelling that drives AiP remain unclear. We have now identified a membrane-associated scaffolding protein, named CASK (calcium/calmodulin-dependent serine protein kinase), which plays a critical role in regulating actin remodelling and JNK activation in AiP. Interestingly, we observed an increase in intracellular calcium in AiP signalling cells. Loss of CaMKII, a calcium-dependent kinase that interacts with CASK and mediates calcium signalling, inhibited AiP. We hypothesise that CASK works together with calcium signalling to control actin remodelling and AiP. Importantly, upregulation of human CASK has been associated with several types of cancer including the colorectal cancer, but the underlying mechanism is not known. Using a Drosophila intestinal tumour model, we observed that loss of CASK suppressed tumour growth, suggesting a direct relevance of the proposed basic research to understanding how diseases develop. Building on these initial findings, this proposal aims to unveil the roles of CASK and calcium signalling in AiP, and their significance in tissue regeneration and growth control. To achieve this, we propose three scientific objectives: 1) investigate how CASK regulates AiP and its role in tissue regeneration, 2) examine calcium and actin dynamics in AiP and how CASK regulates them, and 3) elucidate the roles of CASK in intestinal tumourigenesis. Completing this project will reveal CASK as a novel molecular link connecting apoptotic stress response to tissue recovery, and will highlight its crucial role in controlling tissue growth. This will significantly advance our understanding of AiP and its relevance to human diseases, including cancer. Therefore, this research aligns with the BBSRC Strategic Priorities on "understanding the rules of life", "bioscience for an integrated understanding of health", and "the replacement, refinement, and reduction (3Rs) in research using animals", as we use the fruit-fly Drosophila to address questions directly relevant to humans.

UKRI Gateway to Research · FY 2024 · 2024-11

The International Centre-to-Centre collaboration focuses on a significant area of research activity at the three Universities: Pathological Fractures. Fracture rates are expected to surge as the population ages and therefore constitute an urgent, unmet clinical need. Recent co-creation and engagement activities, by the principal investigator, with clinicians and patients, has noted the need for optimised, patient-specific minimally invasive approaches, fracture prevention and the use of localised delivery of therapeutic agents to reduce infection, disease burden and improve bone quality/fixation. The aim of the Centre-to-Centre is to respond to this clinical need and develop an International Centre of Excellence in Research of Pathological Fractures building on the substantial synergies that exist at the three institutions. These include: University of Leeds (UoL): Advanced assessment of medical devices, substantial investments in research for spinal fractures arising from bone metastases (EPSRC Programme Grant: Oncological Engineering) and peri-prosthetic fractures (Zimmer-Biomet). Uppsala University: Additive Manufacturing for the Life Sciences (VINNOVA funded Competence Centre) and Soft Bone (EIT Health funded) a new generation of low modulus materials designed to fix and prevent fractures in the vertebrae as well as augmentation of the disc. ETH Zurich: Advanced imaging and modelling for pathological fractures (FHT Singapore) and fracture modelling in metastatic disease (EU funded METASTRA). We have further support from 4 industrial partners and UoL. We will bring these attributes together into a more holistic, multidisciplinary collaboration that would significantly enhance the scope for generating novel underpinning engineering science together with appropriate impact through our industrial and healthcare partners. The objectives, building on and enhancing the activities outlined above, are: (1) An integrated, multiscale, Fracture Prediction Modelling Framework to identify bones that are at risk of fracture in given pathologies so as. a. to aid prophylactic interventions to reduce this fracture risk and enable pathology-specific approaches, b. utilise modelling to improve the design of patient-specific/custom made implants. Developed from research at ETHZ and UoL. (2) Develop a Framework for Prophylactically Amenable, Pathology-Specific, Minimally-Invasive interventions to support the load-bearing bone and prevent fracture so to a. significantly inhibit instability, bone pain and, in the vertebra, the potential for spinal cord injury, with the aid of the modelling developed in objective 1 b. develop tools and interventions for hip peri-prosthetic fracture. Developed from the research at Uppsala in the Additive Manufacturing for Life Competence Centre and SoftBone and the UoL. (3) A new generation of innovative coatings specific to treatment requirements including reduction in infection & disease burden, promotion of bone growth and enhanced fixation. a. to take advantage of the material and cement technologies outlined in objectives 1 and 2 to provide better functional outcomes. Based on the research at Uppsala and UoL. The proposal is underpinned by a set of cross-cutting themes which are: (1) Responsible Innovation is central to this activity and includes the appropriate (a) ethical principles ensuring that the research benefits a wider set of stakeholders including patients, (b) patient and clinical co-creation and meaningful interactions so as to enhance the overall design process and (c) appropriate mechanisms that enhance impact including dissemination, continued patient engagement and exploitation. (2) Workforce development, to ensure that both researchers and investigators have the appropriate knowledge for the successful execution of the research and wider career aspirations. (3) Equality, Diversity and Inclusion, of both the researchers and the patients involved.

UKRI Gateway to Research · FY 2024 · 2024-11

The principal objective of DANIO-ReCODE is to provide world-class doctoral training to a new generation of early-career researchers interested in understanding the complex and multilayered process of tissue regeneration. DANIO-ReCODE will combine the multidisciplinary expertise of 15 research laboratories at renowned EU and UK scientific institutions to unravel the regulatory mechanisms of heart, brain, and eye regeneration by employing the unique and highly tractable zebrafish model system. Unlike humans, teleosts can repair damaged tissues or even regrow entire appendages. In mammals, regeneration is rare, limited to skin, liver, and toes. Regenerative medicine, however, promises to restore tissue function via the use of stem cells, tissue engineering, and the production of artificial organs, with its importance being recognised as one of the EU strategic missions. A fundamental gap of knowledge is the understanding of the shared and distinct regulatory mechanisms defining regeneration in highly regenerative species and those with lower regeneration potential such as mammals. Since the vertebrate gene complement is highly conserved, applying the knowledge of regeneration mechanisms from non-mammalian models such as zebrafish could identify genetic underpinnings, which when manipulated in mammals, could strongly boost the mammalian regenerative potential. DANIO-ReCODE will thus nurture a cohort of exceptional doctoral candidates and turn them into interdisciplinary experts in computational and developmental biology, providing comprehensive training that spans experimental work, bioinformatics, visualisation, and industry applications. Through the integration of state-of-the-art genomics, computational, and data visualisation techniques, DANIO-ReCODE will result in an enhanced understanding of molecular determinants implicated in vertebrate regenerative processes while providing new avenues for the repair or replacement of damaged or diseased tissues and organs.

UKRI Gateway to Research · FY 2024 · 2024-11

The primary aim of this fellowship is to create resources and a toolkit that will offer tailored support options for criminal justice staff who work on distressing material. The outputs from this fellowship will include the development of comprehensive training materials designed to enable professional trainers to effectively teach staff how to recognise and respond to signs of psychological distress. Additionally, the fellowship aims to raise awareness around sign and symptoms of distress and build resilience among professionals by offering practical tools and resources to manage distressing situations, thus enhancing their overall wellbeing. The prevalence of vicarious and second-hand trauma among professionals, especially those in the criminal justice system and emergency response, underscores the importance of this project (Duran et al, 2021; Duran and Woodhams, 2022, 2023, 2024). These individuals regularly encounter traumatic situations, leading to second-hand traumatic stress, burnout, symptoms of depression, and reduced job performance. Existing support mechanisms often lack the specificity required to address the unique challenges faced by these professionals. Therefore, a tailored toolkit can bridge this gap, providing them with the necessary resources to cope effectively. Combining insights from psychology, sociology, and technology ensures a holistic approach to addressing and supporting staff wellbeing, which is crucial for developing effective interventions and support systems. This interdisciplinary approach will increase the toolkit's potential effectiveness and applicability across various professional settings.

UKRI Gateway to Research · FY 2024 · 2024-11

Summary Mental skills are adaptive psychological capabilities that enable individuals to successfully reach behavioural goals in a positive way. Examples of mental skills include regulating emotions, imagining success, and problem solving. Mental skills training (MST) is a sport psychology approach which supports athletes and exercisers to reach sport performance goals and adhere to positive and consistent exercise behaviours, whilst also promoting mental and emotional wellbeing. However, access to MST is limited, even among elite athletes—and efforts to widen access via digital modalities have not yet been effectively and optimally realised. By partnering with MST app developers Get Ahead Mindset and adhering to contemporary evidence-based frameworks and methodological approaches, this fellowship will utilise and further develop my skills in co-designing, evaluating and widely disseminating digital gamified approaches to train emotion regulation skills that stimulate positive behaviour change. Specifically, I will engage in training and development in human centered co-design within MST app development, and related business enterprise. I will also conduct further research that seeks to understand athletes' and exercisers' experiences of acceptability (how much something can be accepted and enjoyed) and feasibility (how easy or realistic it is for something to function as intended) of Get Ahead Mindset's new MST app. Knowledge exchange and impact generation related to the training and behavioural research components of the fellowship will be conducted via a free public engagement workshop at The Exchange in Birmingham, online blog posts and academic dissemination.

UKRI Gateway to Research · FY 2024 · 2024-11

Dimensionality is hugely important in low-temperature physics, the study of materials and the behaviour of electrons and other excitations in solid crystals. The underlying mathematics and the resulting observed behaviour of a material or system is hugely and fundamentally different and exotic if its character becomes two-dimensional rather than the familiar 3D. Even more fascinating and elusive is the fuzzy halfway ground of how a system behaves as it is pushed from one regime to the other - '2.5D'. A nascent revolution in alternatives to silicon-based electronics is increasingly turning to the physics of 2D materials to design new devices to overcome the challenges of ever-increasing miniaturisation and an ever-mounting drive to become more energy efficient. 2D layered crystals have unique advantages in this regard, as they can be cleanly and easily thinned down to single layers of atoms (as with the famous example of graphene), then stacked together in nigh-unlimited complex configurations to combine their exotic properties. To design and use these systems at an application level, it is essential that the underlying physics, and with it both the limitations and possibilities intrinsic to the materials are fundamentally understood and tested. Furthermore, this research can inform potential new avenues to explore and the synthesis of new designer materials to fulfil established criteria. A large volume of recent work on low-dimensional physics has focused on thickness control, to tune towards the `true 2D' limit of the atomic monolayer. A complementary approach is to tune the interactions from 2D to 3D by applying hydrostatic pressure - an extremely clean and powerful tuning parameter in a van-der-Waals (vdW) material. These materials are formed of strongly-bonded flat planes of atoms, linked only by the extremely weak van-der-Waals chemical bond - akin to static electric attraction. Applying pressure to such a system overwhelmingly has the effect of pushing the crystal planes together, strengthening bonds between them and allowing ever-increasing crosstalk. This will often have profound effects on the conductivity and magnetism seen in the system, including the discovery of exotic new states of matter. I will use extremes of low temperature, high pressure, magnetic and electric fields to search for new functional and multifunctional quantum materials and tune existing systems into novel states, focussing on fundamental properties of transport and of magnetic and charge order in 2D materials. I will focus on fundamental properties of transport and magnetism in low-dimensional van-der-Waals materials, and then to nanoscale devices built from stacking individual atomic layers of different 2D materials together. Extreme-conditions tuning of these nanodevices is a completely new and exciting research direction that brings together two very different fields of research with essentially no overlap - my unique background across these two areas, and quantum computing, will allow me to build a new interdisciplinary programme to explore exciting new physics. These devices additionally harbour great potential for new technologies as well as blue-skies science interest. I am partnering with industry, and academic collaborators in electrical engineering, chemistry and materials science, to explore pathways to practical applications of the new materials, behaviours and architectures to be discovered. Potential uses are in new times of electronics and memory such as spintronics or low-power transistors, flexible electronics and precision sensors. I will also look to harness the exotic 'topological' properties of new 2D materials to build fault-tolerant new qubits for quantum computing, drawing on my expertise and contacts in this field.

UKRI Gateway to Research · FY 2024 · 2024-11

Protein arginine methyltransferases (PRMTs) are enzymes that regulate the behaviour of proteins in the cell by adding a chemical methyl group to the amino acid arginine. This in turn regulates several important cellular processes and is significant for human health because PRMT levels are higher in cancer cells. This is important as it is now thought that cancer cells highjack PRMT functions and that this enables them to grow and evade chemotherapy treatments. Because of this, PRMTs are now priority drug targets for several global pharmaceutical companies, however, the precise mechanisms by which PRMTs contribute to cancer and therapy resistance are still largely unknown. Without this knowledge, successful translation of PRMT drugs into the clinic will be challenging. One of the first proteins identified as methylated by PRMTs was a protein called histone H4. Histones enable the packaging of DNA into a structure called chromatin, and their chemical modification is important for gene expression and DNA repair. Whilst it has been appreciated that PRMTs regulate these cellular functions, there has been an inability to define the actual significance of histone H4 methylation because PRMTs also methylate other proteins that are involved in gene expression and DNA repair. This has thus led to a substantial knowledge gap in an important area of cancer biology. Some cancers are driven by mutations in histones, so called "oncohistones". We have taken advantage of a newly identified cancer-associated oncohistone mutation that occurs at a site targeted by PRMTs, providing us with a clinically relevant tool to understand how PRMT-mediated methylation of histone H4 regulates gene expression and genome stability. In this project, we will investigate in fine detail how this oncohistone regulates cancer cell behaviour and if it is a driver event in cancer development. We will use state-of-the-art techniques to determine if effects of oncohistone expression are due to deregulated PRMT methylation or the substitution of an arginine amino acid for another. We will determine mechanistically how the oncohistone affects gene expression and DNA repair, and if the recruitment of proteins to DNA is altered. The impact of our study is far reaching, clinically important and timely because PRMT inhibitors are in phase I clinical trials for cancer treatment. It will enable us to define the importance of PRMT-dependent histone H4 methylation and explore how it regulates gene expression and genome stability, and how this contributes to cancer growth and chemoresistance. Crucially, it will provide insight into how PRMT inhibitors can be used in combination with agents that by modulating chromatin and/or DNA repair, thereby maximising their clinical potential and ultimately benefiting cancer patients.