The structure of water and in the way it self-assembles and interacts with dissolved solutes and with hydrophobic surfaces continues to be highly topical. Science ranked the study of water among the top 10 breakthroughs in 2004. The formation and structure of solid state hydrates continues to be a topic of major interest to the pharmaceuticals industry. The problem of interpretation of water structure is complicated by its strong dependence on hydrogen atom positions. Hydrogen atoms cannot be located accurately using X-rays. A meaningful discussion of water structure in the solid state and of its interaction with organic solute species, biological or otherwise, must involve location of H atoms using neutron diffraction. The work must also be backed up by appropriate calculations and corresponding systematic database analysis as well as supporting techniques such as solid state NMR spectroscopy, TGA/DSC and vibrational spectroscopy. This project will amass a body of experimental neutron data on water molecules and clusters within crystals and determine the relative hydrogen bonding energies using calculations based on these experimental coordinates. The key question to answer is what effect does water have on itself and its surroundings and how do water-water interactions compete with water-solute (or, in the solid state, hydrate-host) interactions, particularly in 'large systems' in which many water molecules are present. The insights we will gain will help understand physical properties such as solubility, tendency to form hydrates and the tendency of organic comounds, particularly pharmaceuticals, to adopt more than one solid form.

The brain is a black-box when it comes to understanding disease. It is full of crucial details that could give untold information on how to treat and manage neurological diseases and disorders, but we lack the tools to effectively read those details. While imaging technologies give us a window to observe certain processes, they are often extremely limited. A good example is magnetic resonance imaging (MRI), which has led to countless breakthroughs in the clinic and is used to diagnose and manage patients every day. It is, however, typically limited to a single channel - essentially, we are looking at the brain in black and white instead of colour. This limitation is particularly true when looking at chemical and biological properties of the brain. There are some techniques that begin to allow imaging of multiple signals (i.e. colours), but they are limited to substances present at very high abundances within the brain. A classic example where this would be relevant is in Alzheimer's disease. There is a well-established relationship between the devastating neurodegeneration observed and brain's natural defence system. This co-occurring condition, neuroinflammation, is linked to the long-term deterioration seen in patients, but we struggle to fully understand how they are connected and how they interplay. Much like the classic chicken and egg conundrum, we are often unsure on which comes first or how that comes to be. If we could simultaneously watch how these different processes work at the same time in a living brain, we would significantly improve our understanding and be able to monitor the effects of treatments and interventions more closely. This scenario is not just limited to Alzheimer's disease, but in almost every neurological disease we can think of. Every neurodegenerative disease, brain tumours, stroke, and even mental health issues would all benefit from an improved understanding of the real-time interplay of various biological systems all working - or, more importantly, failing to work - together. I have developed a technique that greatly expands the range and sensitivity of multi-signal MRI by using carefully designed contrast agents in a process called PARASHIFT MRI. This approach allows much lower levels of compounds to be detected in the living brain with multiple readouts available. We have previously demonstrated its approach in the body, and I now aim to focus on applying the technique to study markers of brain disease in much more detail than we are currently able. This pioneering MRI technique will be supplemented by complementary cutting-edge techniques, such as mass spectrometry imaging, to further understand the brain in unprecedented depth. I will focus on stroke and brain cancer as exemplar model systems in the initial stage of my fellowship as they represent clinically vital examples of both acute and chronic inflammation, respectively. Beyond, the findings from my work will have key applications in neurodegenerative disease and across a broad spectrum of neurological disorders. By combining these new tools for comprehensively detecting, characterising, and monitoring brain disease markers, my approach will reimagine how we look at the diseased brain and retrieve untold levels of information to help us tackle this pressing societal burden.

This project will address a first-order challenge in volcanology - understanding the controls on transitions in eruption style and intensity during the most hazardous eruptions. Most silicic eruptions begin with a high-energy, high-hazard explosive phase, then either wane and stop, or transition to hybrid and effusive behaviour that produces relatively short-range lava flows with much lower hazard potential. Understanding the timing of these transitions, and of the end of an eruption, is a major challenge that impacts hazard assessment and eruption response. Existing models assume that a transition from explosive to effusive behaviour is driven from below by a change in either the magma ascent rate or by the permeable release of pressurised gas, effectively 'defusing' the explosive potential. However, these bottom-up models fail to explain two fundamental aspects of silicic volcanism: (i) simultaneous explosive-effusive behaviour that was witnessed directly during the 2011-12 eruption of Cordon Caulle (Chile) and subsequently inferred elsewhere, and (ii) widely documented evidence for in-conduit pyroclast sintering preserved in the deposits from all phases of these eruption types. Members of the project team have used this evidence to develop a new paradigm for explosive-effusive transitions in silicic eruptions (Wadsworth et al., 2020) in which transitions are driven from above by shallow welding of fragmented magma and occlusion of the shallow conduit. In this 'cryptic fragmentation' paradigm, all silicic eruptions are explosive at depth, even when apparently effusive at the surface. This new idea demands a wholesale re-evaluation of silicic volcanic systems. Our new model proposes that apparently effusive lava is generated directly from explosive volcanism, assembled by the viscous amalgamation - sintering - of hot volcanic ash and pumice in the volcanic conduit in the shallowest parts of the Earth's crust (see CfS). The cryptic fragmentation model was developed in response to evidence from crystal-poor silicic systems. In this new study we go further, and propose that the model also applies to crystal-rich intermediate systems, which are much more common, and pose a global hazard. This hypothesis is based on abundant evidence from crystal-rich systems, similar to that summarized above. This project will deliver: (1) New analysis of dome-forming and crystal-rich lavas worldwide using existing samples from multiple laboratories. We will constrain the textures in the groundmass - with a focus on pore-textures indicative of sintering petrogenesis - and macro-scale textures associated with breaking and sintering, such as fractures will with partially sintered particles. This new textural work, coupled with analytical and petrophysical measurements, will underpin our extension of the cryptic fragmentation model to crystal-bearing magma systems. (2) A comprehensive suite of new experimental volcanology measurements of sintering rates with multiphase magmatic particles - glass with crystals. Relying on the PI's large body of experimental and theoretical sintering work, we will develop new experimentally-validated models for sintering rates with crystals in systems under elevated pressures, in the presence of magmatic volatiles, and under shear stresses. For the first time, this will push sintering theory to magmatic conditions and allow the first quantitative test of sintering rates at volcanoes. (3) We will apply these sintering rate equations to active crystal-bearing volcanic eruptions of the past at the same sites from which the sample suites were collected, with a focus on Colima volcano (Mexico) via engagement with stakeholders at volcano observatories. Cryptic fragmentation model reference: Wadsworth, F.B., Llewellin, E.W., Vasseur, J., Gardner, J.E. and Tuffen, H., 2020. Explosive-effusive volcanic eruption transitions caused by sintering. Science advances, 6(39), p.eaba7940

Over 8.5% of the world's adult population suffer diabetes. If poorly treated, diabetes leads to very high blood sugar levels which worsen the disease and lead to complications such as kidney failure and blindness, shortening life expectancy by 10 years in the case of type 2 diabetes (T2D). Pancreatic beta cells are in charge of secreting insulin in response to rises in blood sugar. Failure of beta cells to secrete enough insulin contributes to the development of diabetes. Importantly, the prevalence of high-blood sugar accelerates beta cell failure and contributes to beta cell loss by mechanisms which are not yet clear. A better understanding of the process leading to beta cell failure is vital for the development of drugs capable of stopping the development of T2D. MiRNAs are small RNA molecules that do not produce proteins themselves but are capable to reduce the rate at which other proteins (their "targets") are produced. MicroRNAs exist in beta cells that regulate important functions such as their capacity to produce and secrete insulin. Also, changes in the levels of certain miRNAs in beta cells are associated with the development of T2D. We have recently made three important findings. Firstly, when mouse and human beta cells are exposed to high levels of glucose, their levels of the miRNA miR-125b (miR-125b-5p) go up. Secondly, the introduction of additional miR-125b in the beta cells of mice causes them to produce and secrete less insulin and develop diabetes. We have also observed that reducing the amount of miR-125b in human beta cells in culture improves their capacity to secrete insulin in response to glucose. Accordingly, we hypothesize that beta cell selective inhibition of miR-125b has the potential to protect beta cell function from hyperglycaemia. Thirdly, we have seen that high levels of miR-125b lead to the appearance of enlarged lysosomes while low levels of miR-125b lead to changes in mitochondria morphology and in the content of genes related to mitochondrial function. Lysosomes and mitochondria are subcellular organelles very important for the recycling of cellular components and waste and for energy production, respectively. Thus, we hypothesize that miR-125b regulates beta cell function by modulating lysosomal and/or mitochondrial function. Both processes are essential for adequate beta cell function and are altered in diabetes. Additionally, we have demonstrated that miR-125b targets the cation-dependent lysosomal mannose-6-phosphate receptor (M6PR) which transports lysosomal enzymes to lysosomes for their adequate functioning. Nevertheless, the role of M6PR for lysosomal and secretory function in beta cells hasn't been studied. Thus, the specific aims of this proposal are to determine: 1. Whether and how selective elimination/reduction of miR-125b in beta cells prevents T2D progression 2. The role of miR-125b in lysosomal and mitochondrial function 3. The function of M6PR in beta cells To achieve these aims we will use a combination of - Mice deleted for/overexpressing miR-125b selectively in beta cells. The use of mice is necessary since maintenance of glucose homeostasis requires interplay between all metabolic tissues and therefore these experiments need to be done in the context of the whole body. - Donated human islets, modified to contain more or less miR-125b. The use of human samples is essential to ensure the translatability of our findings to the clinic. - Mouse and human beta cell lines, modified to contain more or less miR-125b or M6PR, which allow to study biological processes in detail and reduces an unnecessary use of animals. MiRNAs are novel candidates for drug targeting and our study will provide preclinical data on the potential of beta cell miR-125b inhibition for the treatment of T2D. It will also provide new fundamental insights into how beta cells work in health and disease, which, in the long term, could reveal new ways to treat diabetes.

Over the past two decades, improving seismic and geodetic data have revealed that many faults accumulate their slip via a suite of phenomena that are not predicted by conventional friction laws: via slow earthquakes, or fault slip events whose average slip rates are between 0.1 microns/s and 1 mm/s, a factor of 1 thousand to 10 million slower than the 1 m/s slip rates typical of earthquakes. Slow earthquakes are now found at most subduction zones, where they accommodate about half of the plate interface slip in the region down-dip of the seismogenic zone. But currently, we do not know which fault zone processes generate the aseismic slip we observe in slow earthquakes. It is important to improve our understanding of slow earthquakes because they occur next to the seismogenic zone. They are capable of triggering large and damaging earthquakes. In this project, we focus on the smallest but most abundant slow earthquakes: tremor. Tremor consists of hundreds to millions of small, closely spaced, slow earthquakes. The earthquakes can be rapidly observed and could be used to track larger-scale aseismic slip variations and to assess whether that slip could trigger hazardous seismic slip. But like other slow earthquakes, tremor remains poorly understood. The goal of this project is to determine which physical process creates tremor and limits its slip rates to around 1 mm/s. Several explanations of tremor's low slip rates have been proposed. It is possible that tremor is governed by the same frictional sliding process that governs normal earthquakes. Tremor may be slow only because the fault's frictional strength or normal stress is low, and thus is unable to drive rapid slip. Alternatively, a more novel physical process could limit tremor's slip speeds. Changes in pore fluid pressure might pull the fault shut, inhibiting rapid slip. Or tremor could be a collection of failed earthquake nucleations, which arise because of stress perturbations on a nominally stable fault. In the proposed work, we will use targeted seismological analysis to assess five proposed models of tremor generation. We will test specific model predictions using high-quality seismic data from some of the best-observed tremor in the world: that near Parkfield, CA. To test our model predictions, we will first examine how tremor is related to shorter and longer slow earthquakes. If tremor is governed by the same novel fault zone physics that governs larger slow earthquakes, there should be a continuum of slow earthquakes with a wide range of sizes and slip rates. The presence or absence of the continuum will be important for constraining the processes governing large and small slow earthquakes, as only a few of the proposed models of large slow earthquakes are consistent with the continuum's wide-ranging slip rates. We will search for 0.05 to 1-second-long events in this continuum using recently developed seismic analysis techniques. And we will examine the clustering of tremor, in order to (1) identify larger, hours-long slow earthquakes potentially within the continuum and (2) to constrain the relationship between tremor and larger-scale slip. Finally, to further test the models, we will move into the details of individual tremor events and probe the evolution of slip in individual tremor earthquakes. We will closely examine the seismic signals produced by tremor in order to determine how tremor's earthquakes' durations, sizes, and complexities vary from event to event. These data will let us determine how much of tremor's properties are controlled by particular rheologies and how much is due to local fault zone structure. By pursuing a suite of features that can test our models, we will be able to determine which physical processes generate the numerous small earthquakes that constitute tremor, so that we may better understand slow earthquake slip and more confidently use tremor to track large-scale slip at depth.