We request support for a state-of-the-art Metaljet single-crystal X-ray diffractometer equipped with an automated robotic sample changer. This equipment will underpin a variety of current research projects in the South-East region of the UK and will enable many more in the future. X-ray crystallography is the most important technique for determining the structures of crystalline solids. The UK boasts a history of pioneering discovery in crystallography, including several Nobel Prizes. Today, the strength of the research base is such that the UK leads the world in crystallography. The reach and impact of the technique is remarkable, spanning chemistry, life sciences, materials science, condensed matter physics and earth sciences, and incorporating a broad community of industrial and academic users. The vision for our proposal is to enable rapid structure determination across length scales, from small molecules and supramolecules to chemical-biological systems and extended solids. Examples of these materials include catalysts, molecular magnets, pharmaceutical ingredients, polymers, amphiphiles, drug molecules bound to biological targets, energy materials and metal-organic frameworks. Many of these materials form as very small crystals that are difficult or impossible to measure in full on existing in-house diffractometers, which limits the value of the structural information and acts as a barrier to its downstream implementation. We propose to use striking recent advances in diffraction technology, including the availability of X-ray beams with unprecedentedly high brilliance and detectors with very high sensitivity, that will enable the measurement of such crystals. The resulting information will enable the development of more accurate structure-function relationships for the materials of interest. The automated robotic sample changer will provide game-changing capability. Conventional approaches to single-crystal measurements can be time-consuming, requiring hands-on effort to mount, centre and measure individual crystals. The robot will allow multiple consecutive measurements of single crystals without the need for human intervention. Automation then allows the quality of the crystals to be ranked and the best one selected for further measurements. This will be of immediate benefit to the majority of the user base, whose samples will be measured in full in Sussex. It will also benefit users with samples that require further measurement at high-demand synchrotrons because the best crystals can be identified in advance, ensuring efficient use of beamtime. The equipment and the research it will enable are aligned with EPSRC Themes in Physical Sciences, Quantum Technology, Healthcare Technologies and Manufacturing the Future. The proposed equipment will add significant value to EPSRC investment in at least 20 reseach areas across the user base. This will grow over the lifetime of the diffractometer. The UK is world-leading in analytical science. X-ray crystallography, along with other analytical methods such as NMR spectroscopy, microscopy, and mass spectrometry, are at the heart of the most important research. A major aim of our project is, therefore, to enhance national strategic provision in analytical science in a broader sense.

Nuclear Magnetic Resonance (NMR) is a tremendously powerful and versatile analytical technique for the investigation of the structure and dynamics of molecules from the simplest chemical species to complex biomolecules. The key limitation of NMR is that is suffers from low sensitivity because the obtainable nuclear spin polarization is small; lengthy signal averaging is therefore necessary making NMR slow which hinders new applications and because of finite equipment access even limits routine exploitation. This project will develop a new method for photochemically generating nuclear spin-hyperpolarization which by increasing sensitivity and reducing experiment times will provide the opportunity for a number of exciting new applications of NMR to be explored. To observe a magnetic resonance signal spin-polarization is required, that is more nuclear spins (which act like tiny bar magnets) must line up with than against the applied magnetic field (or vice-versa). Even in strong magnetic fields, however, typically less than one in ten thousand nuclei do so at room temperature. The polarization of electron spins is higher than that of nuclear spins (by ~660 versus protons) making them more sensitive probes of molecular environment, but most molecules don't have the unpaired electron spins needed to use electrons as probes directly. However, a number of Dynamic Nuclear Polarization (DNP) techniques are under development which aim to generate nuclear hyperpolarization (greater than equilibrium polarization) by transfer of polarization from thermally polarized electrons to nuclear spins. However, these techniques rely on microwave pumping of the electron spins which causes problems with sample heating, and for liquid state NMR the biggest gains come when long pumping periods are combined with rapid heating and dissolution of molecules polarized at very low temperatures. Such approaches generate large nuclear hyperpolarizations but cannot be rapidly repeated hence little time-saving is achieved. Such methods will not make feasible the time-consuming multi-dimensional experiments needed to examine complex biological molecules, or speed-up NMR analysis to enable high throughput screening for medical diagnostics. The project will use a short pulse of laser light to hyperpolarize electron spins to hundreds of times their thermal polarization and then rapidly transfer this large hyperpolarization to the nuclei, achieving nuclear spin-hyperpolarizations far in excess of those possible when using thermally polarized electrons. This will provide a room temperature nuclear hyperpolarization method that can be combined with the high repetition rates conventionally employed in NMR when signal averaging or incrementing experimental parameters. This project will exploit the as yet under-utilized Radical Triplet Pair Mechanism (RTPM) by which a stable radical interacts with a short-lived triplet state generated photochemically from a suitable precursor, resulting in electron spin-hyperpolarization of the radical. Such hyperpolarization can be conveniently observed by Electron Paramagnetic Resonance (EPR) spectroscopy. EPR will be used to investigate the key interactions giving rise to this effect, and in particular the effect of confining the radical and triplet molecules in cage-like structures on the size of the hyperpolarization generated. By restricting the relative separation of the radical and triplet molecules, and hence increasing their chances of encounter in solution, the electron hyperpolarization generated will be maximised. The effect of this encapsulation on the efficiency of the transfer to nuclear hyperpolarization will also be assessed. This project will test and further develop the underlying theory of the RTPM and provide a proof of principle that this method can be used as a new way to enhance sensitivity in NMR experiments, a result with potentially far reaching applications throughout analytical and medical science.

We use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) to study the structure of biomolecules that form the intricate machinery of cells and organisms. Their structure determines how they work and interact with each other and forms the basis of considerable human effort in understanding cutting edge bioscience. We are proposing to purchase the world's first TXO-HF NMR cryogenic probe technology and use it to make ground-breaking discoveries in areas such as neurodegenerative conditions like Parkinson's disease, design the structure of new biomolecules, or the production of antiviral, antibiotic and antifungal compounds. We can also use this new NMR data to design or repurpose drugs to make them more potent and even look at what happens to next generation drugs when your body tries to metabolise them. We have already identified >£30m of funded research programs, national collaborations and doctoral training programs that this instrument will underpin from day one, and we are working with a range of national networks who will allow us to increase this substantially over the lifetime of the NMR instrument. The new probe will enable this research because NMR shares the same basic ideas as the whole-body MRI scanners that are found in hospitals. However when studying molecules in bioscience, it is difficult to get enough sample to detect with our NMR spectrometer and the 'standard' atomic nucleus that MRI studies (the proton), tends to be so abundant that it gives very 'noisy' spectra with too many signals for us to be able to interpret. The solution to these problems is to use an NMR 'cryoprobe' that has very sensitive detection and is optimised to look at other types of atomic nuclei that tend to give more spread-out signals. Some NMR systems have started to use carbon and nitrogen nuclei, but what makes this TXO-HF system we are going to install especially powerful is that it can also use a further nucleus, fluorine, that is uniquely powerful as a probe because it is rare in most natural systems. This means we can use cutting-edge biosynthetic techniques to introduce fluorine into the molecules we study and then follow it's behaviour without all of the background noise that is found with proton-based NMR and thus study some very difficult problems in biology. There are many more important and complex scientific questions to answer with this new equipment and to do this we have teamed up with many partner universities, national NMR network programs and biopharmaceutical companies. By bringing all of these different groups together we are ensuring we maximise the number of people and have a broad expertise that can be applied to the scientific challenges we face. As the national picture of how universities work together evolves, sharing (expensive!) unique and sophisticated equipment like this becomes ever more important. Therefore part of what we are seeking to do with this equipment is use it as an exemplar to encourage collaboration and training for our skilled research technical professionals who run these instruments, as well as to inspire the students who themselves will go on to be the bioscience researchers and NMR spectroscopists of the future. To do this we have engaged with a dedicated team who champion this idea and through which we hope to make the equipment even more impactful and sustainable.

We propose a new imaging platform that combines ultra-fast confocal imaging with the the nano-fluidic functionality delivered by an integrated Fluidic Force microscope (FluidFM-UFCLSM). The proposed capability opens a new phase of exploration of biological systems by enabling characterisation of localised biochemical and physiological processes. The proposed capability provides new avenues for specific applications such as new antimicrobial agents, functional genetics and the development of sustainable crops. The unique design of FluidFM-UFCLSM enables accommodating an array of complex biological samples to perform quantitative and predictive characterisation of biofilms, tissues, whole plants, small animals, insects, mucosal membranes, food systems and tissue scaffold hydrogels. The unique feature of FluidFM-UFCLSM is it will enable study of the smallest units of biological organisation such as proteins as well as larger objects such as cells, tissues and organs. The use of FluidFM-UFCLSM cuts across many disciplines and delivers benefits to a broad range of research topics in the areas of biofilm formation, plant science, tissue engineering, food science and cell physiology. Some examples of FluidFM-UFCLSM applications are: 1) Elucidate anti-microbial resistance and the localised mechanisms underpinning quorum sensing 1) Probe interaction between immune cells with lung epithelium as one of the key pathways of Covid-19 pathogenies 2) Uncover the secrets of plant development and mechanical signalling to develop new resistant crops 3) Probe the effect of nutrition on gut microbiome and associated health outcomes 4) Explore new plant-mimetic materials for designing new food-compatible films for environmentally sustainable food production The broader areas of impact will be achieved by supporting emerging areas research that targets the major problems and challenges of food security, improved nutrition, animal and human health, combatting antimicrobial resistance, microbiome research, industrial biotechnology, waste valorisation, sustainable agricultural and synthetic biology.

Understanding and characterising the behaviour of fluids is fundamental to numerous industrial and environmental challenges with wide-ranging societal impact. The CDT in Fluid Dynamics at Leeds will provide the next generation of highly trained graduates with the technical and professional skills and knowledge needed to tackle such problems. Fluid processes are critical to both economic productivity and the health and environmental systems that affect our daily lives. For example, at the microscale, the flow of liquid through the nozzle of an ink-jet printer controls the quality of the printed product, whilst the flow of a coolant around a microprocessor determines whether or not the components will overheat. At the large scale, the atmospheric conditions of the Earth depend upon the flow of gases in the atmosphere and their interaction with the land and oceans. Understanding these processes allows short term weather forecasting and long term climate prediction; both are crucial for industry, government and society to plan and adapt their environments. Fluid flows, and their interactions with structures, are also important to the performance of an array of processes and products that we take for granted in our everyday lives: gas and water flow to our homes, generation of electricity, fuel efficiency of vehicles, the comfort of our workplaces, the diagnosis and treatment of diseases, and the manufacture of most of the goods that we buy. Understanding, predicting and controlling Fluid Dynamics is key to reducing costs, increasing performance and enhancing the reliability of all of these processes and products. Our CDT draws on the substantial breadth and depth of our Fluid Dynamics research expertise at the University of Leeds. We will deliver an integrated MSc/PhD programme in collaboration with external partners spanning multiple sectors, including energy, transport, environment, manufacturing, consultancy, defence, computing and healthcare, who highlight their need for skilled Fluid Dynamicists. Through a combination of taught courses, team projects, professional skills training, external engagement and an in-depth PhD research project we will develop broad and deep technical expertise plus the team-working and problem-solving skills to tackle challenges in a trans-disciplinary manner. We will recruit and mentor a diverse cohort from a range of science and engineering backgrounds and provide a vibrant and cohesive training environment to facilitate peer-to-peer support. We will build strengths in mathematical modelling, computational simulation and experimental measurement, and through multi-disciplinary projects co-supervised by academics from different Schools, we will enable students to undertake a PhD project that both strengthens and moves them beyond their UG discipline. Our students will be outward facing with opportunities to undertake placements with industry partners or research organisations overseas, to participate in summer schools and study challenges and to lead outreach activities, becoming ambassadors for Fluid Dynamics. Industry and external engagement will be at the heart of the CDT: all MSc team projects will be challenges set and mentored by industry (with placements embedded); each student will have the opportunity for user engagement in their PhD project (from sponsorship, external supervision and access to facilities, to mentoring); and our partners will be actively involved in overseeing our strategic direction, management and professional training. Many components will be provided by or with our partners, including research software engineering, responsible innovation, commercial awareness and leadership.