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.

The Centre for Advanced Electron Spin Resonance (CAESR) is a collaboration of researchers from the Oxford University Departments of Physics, Chemistry, Materials, Biochemistry, and Pathology. It was founded in 2006 with substantial support from EPSRC and the University to provide modern equipment and an academic focus for Oxford's multi-disciplinary research in electron spin resonance (ESR). CAESR has been spectacularly successful. It has nucleated a world-leading community of ESR spectroscopists in Oxford, and its stakeholders now extend well beyond the original group of co-applicants. It has established a national and international reputation as a centre of excellence in ESR. CAESR's scientific productivity and the research projects that it supports are now significantly constrained by two limitations of the existing equipment: (i) the availability of only two frequencies, 9.5 GHz (X-band) and 95 GHz (W-band); and (ii) a severe shortage of experimental capacity at the "work-horse" X-band frequency. We propose to reinforce CAESR's facilities with a Bruker Elexsys E580 X/Q-band pulsed electron spin resonance spectrometer. It will augment CAESR's facilities with a third frequency (Q-band, 35 GHz), and it will offer the experimental capacity needed by CAESR's growing community of participants. This instrument will significantly enhance CAESR's existing research projects and enable an exciting portfolio of new activities, covering a wide range of EPSRC priority areas and addressing each of EPSRC's Physics and Chemistry Grand Challenges. It will allow CAESR to apply ESR in innovative ways to new scientific problems and to lead methodological developments in ESR. The instrument has two features that will make it unique in the UK: high-power at Q-band, offering the shortest, highest-bandwidth pulses available; and an arbitrary waveform generator, allowing the direct synthesis of complex pulses for the first time in a turn-key ESR system. For 20% of the time, the instrument will be accessible to the wider UK ESR community through collaboration with the CAESR community, and via a contract with the EPSRC National EPR Facility based in Manchester. Young scientists from the Integrated Magnetic Resonance Centre for Doctoral Training (based in Warwick) will have the opportunity to explore the cutting-edge experimental capabilities offered by the arbitrary waveform generator and high-power amplifier incorporated in the new instrument, during annual training sessions at CAESR. The instrument's manufacturer, Bruker, seeks to strengthen links with CAESR by offering salary support for the Technical Manager. Through this interaction Bruker will receive first-hand feedback on instrument limitations, possible upgrades and new technical and methodological developments, and CAESR will receive preferential technical assistance in operating the instrumentation beyond its normal use-cases.

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.

A latticework of bony trabeculae stiffens the internal spaces of many bones. Trabeculae transmit forces between joint surfaces and bone shafts and maintain the integrity of vertebrae. Bone loss is a normal physiological response to reduced mechanical load, occurring during bed rest, in sedentary lifestyles, and during the weightlessness of spaceflight. Bone loss is also a normal, undesirable, part of ageing which occurs particularly rapidly in women after menopause. Reduced bone mass is strongly associated with increased fracture risk. Peak bone mass is obtained in humans in early adulthood. Strategies to increase peak bone mass and to slow its physiological loss are of great interest to ensure healthy ageing. In addition to bone mass (bone volume fraction, BV/TV), bone architecture is thought to play a crucial role in trabecular bone's force transmission and fracture resistance. Bone architecture is defined by standard measurements such as trabecular thickness (Tb.Th), spacing (Tb.Sp), interconnectedness (Conn.D), anisotropy (DA) and rod-plate geometry (structure model index, SMI). The bulk behaviour of trabecular bone in physiological loading is almost entirely determined by BV/TV: this is intuitive because the more bone matrix there is per unit volume, the greater the overall volume can resist applied load. Once a higher failure load has been reached, however, the behaviour of trabecular elements dominates collapse of the overall structure. Each trabecula might fail by buckling, shear or crumpling. Bone biologists believe that plate-like trabeculae resist higher loads than rod-like trabeculae and that plate-like trabeculae convert to rod-like trabeculae during bone loss, creating a 'double-whammy': reduced bulk resistance to load due to decreased BV/TV and reduced resistance to trabecular element failure due to rod-like geometry. Whether a plate-to-rod transition actually occurs in bone loss is now in serious doubt, because the paradigm is based on flawed SMI measurements. I recently showed that variation in SMI during bone loss is dominated by increasing amounts of concave portions of the bone surface, which the SMI theory assumes are not there or have a negligible contribution. There is a high correlation between SMI and BV/TV even when the underlying architecture has not changed. SMI is a fundamentally broken measurement that does not do what bone bioscientists use it for. Over 850 papers have cited SMI and a common interpretation when seeing BV/TV and SMI results together is that bone loss is associated with a plate-to-rod transition, however, this is merely an artefact of SMI's design that obscures any true relationship. Statements linking bone loss and plate-rod transition have been repeated often enough to have become an accepted dogma in the bone field. This project aims to overturn the dogma there is a plate to rod transition in bone loss using 3D X-ray microtomography (XMT) image data sets archived from previous experiments. To measure rods and plates independent of BV/TV, the PDRA will validate a new method, ellipsoid factor (EF), that defines rods and plates by the shape of the biggest ellipsoid that fits within each bony region. Rods can fit long, javelin-shaped ellipsoids, while plates can fit flat, discus-shaped ellipsoids. The PDRA will use image data collected on RVC's XMT instrument, images from my project partner Phil Salmon at Bruker microCT, and from other collaborators worldwide, and aim to increase our current pool of ~150 images from 3 studies to ~1000 images from ~20 studies. Having identified rods and plates in bone samples, the PDRA will correlate rods and plates with mechanical behaviour using finite elements analysis in the physiological load range for bulk behaviour and overload range for trabecular element failure behaviour. The primary benefit of the work is improved understanding of true geometric and mechanical changes in bone loss, along with the new EF method and free software.

NMR spectroscopy is arguably the most widely employed tool in materials, chemical and biomolecular research sciences for the study of atomic structure and behaviour. It has a uniquely powerful ability to probe the chemical structure at atomic level, combined with sensitivity to their motions and changes in chemical environment. The importance of NMR spectroscopy has been recognised by the UKRI's recent and largest-ever investment of £20 M in NMR spectroscopy in a UK-wide network of NMR spectroscopy facilities in 2018 which was matched by substantial provision of ongoing support through expert personnel and specialist infrastructure by the host institutions. Together these and previous significant capital investments made by UK research intensive universities, research councils and medical charities position the UK at the forefront of NMR technologies and will enable a very wide range of scientific investigations with a depth that was previously impossible. To ensure that we maximise the value of this capital investment, this proposal aims to establish a national NMR network in the physical and life sciences, Connect NMR UK, integrating the three main existing interdisciplinary communities (UK solid-state NMR; liquid-state, biological NMR; UK NMR managers group) and two learned societies (Royal Society of Chemistry NMR Discussion Group; Institute of Physics Magnetic Resonance Group) and connecting all of these NMR facilities through a central web portal, annual discussion forum, workshops and training scholarships. This will ensure we link the NMR solutions provided by the latest instrumentation and personnel, centred around the very- and ultra-high field NMR facilities, with the challenges being tackled by the UK's leading scientists. Providing these scientists with access to the cutting edge capabilities, sharing knowledge from the experts in these NMR facilities with the wider UK scientific community and exchanging best practice between the experts will ensure maximum value is obtained from the UKRI research council investment.