Plate tectonics is the most important discovery in Earth Science and is a unique characteristic of our planet. It involves formation of new tectonic plates by seafloor spreading and their recycling back into the deep Earth at subduction zones. This process continuously repaves two-thirds of the Earth's surface. The formation of new oceanic crust represents the largest magmatic system on Earth, and involves the cooling and solidification of magma (supplied from below by partial melting of the Earth's mantle) along the 70,000 km global network of seafloor spreading axes. Understanding the details of how ocean crust forms is therefore critical to understanding the exchange of heat and mass from the solid Earth to the oceans and atmosphere. Since the rocks of the deep oceans are largely inaccessible, scientists trying to understand how magma builds new crust at spreading axes employ geophysical (seismic) experiments to investigate the sub-seafloor. Results are then compared to and combined with observations made on oceanic rocks in ophiolites (fragments of oceanic crust and upper mantle that have been pushed onto the continents and exposed above sea-level) to develop scientific models of seafloor spreading. In the search for magma chambers along the East Pacific Rise (EPR), the most magmatically active spreading axis on Earth, geophysicists have discovered thin (10's m thick) lens-shaped magma chambers (known as 'axial melt lenses') at the top of the lower crust that extend along the EPR. These are thought to sit on top of mushes made up of crystals surrounded by small amounts of magma, that feed melt upwards into the overlying melt lens. More detailed experiments have shown that the physical properties of these melt lenses change along the EPR axis, suggesting that the proportion of melt to mush along the EPR varies on a range of length-scales. Upwards expulsion of magma from the melt lens happens periodically via forceful intrusion of sheets of magma (forming so-called "sheeted dyke complexes"), leading to eruption of lava on to the seafloor. This geophysical picture of the magmatic plumbing system of seafloor spreading axes (based mostly on decades-old inferences from seismic experiments) is incomplete, however, and lacks any constraints on the pathways followed by magma migrating into and out of axial melt lens systems. Lateral variations in seafloor morphology and erupted lava compositions suggest that there must be significant along-axis (3D) transport and evolution of melt, but how extensively this occurs, at what level(s) within the crust, and by what mechanisms remain unknown. These questions have broad implications for the overall process of melt generation and delivery from the mantle and formation of ocean crust, and can only be answered by quantifying melt transport trajectories along a spreading axis in detail and by combining this with determinations of magma geochemistry. This project addresses these questions by directly determining the migration pathways followed by magma as it enters and exits from an axial melt lens system that has been mapped out along a 100 km complete spreading segment preserved in the Oman ophiolite. This provides the world's only on-land analog for fast-spreading axes like the EPR. We will use a technique called 'anisotropy of magnetic susceptibility' or 'AMS' to measure the 3D preferred alignments of crystals resulting from the flow of magma during the formation of crustal rocks. We will then combine these observations with geochemical analyses of rock compositions to establish whether and how 3D spatial variations in magma flow regimes along a fast-spreading axis control the geochemical evolution of magmas during crustal construction. This novel approach will allow us to develop a comprehensive model for the anatomy of the magma systems responsible for forming two-thirds of the Earth's surface, testing and challenging the predictions of remotely-sensed seismic investigations.

Nervous system disorders include common diseases like dementia, and rare genetic disorders, often childhood-onset. In the UK, they affect >944,000 people, forecasted to increase to >1 million by 2025. However, for about 150 rare brain disorders, therapeutic discovery is hampered by their rarity and low commercial incentive. Limited knowledge of disease mechanisms by which the brain cells called neurons die, a process termed neurodegeneration, has also undermined drug discovery. The focus of this proposal is to understand and target common disease mechanisms that underpin several childhood-onset forms of neurodegeneration. Targeting shared pathological mechanisms will allow us to use the same treatment for other rare disorders. One such common mechanism affected in several neurological disorders is a biological process called autophagy. This process has a housekeeping role in cells by removing undesirable cellular components such as protein aggregates and damaged organelles like mitochondria. When autophagy malfunctions, unwanted cellular components build up and the cell may eventually die, with neurons being particularly vulnerable. We recently demonstrated a new paradigm of the pro-survival role of autophagy via maintenance of cellular levels of a metabolite called nicotinamide adenine dinucleotide (NAD). Loss of autophagy disrupted mitochondrial quality control, triggering over-activation of stress responses mediated by enzymes that consume NAD. Depletion of NAD perturbed the mitochondrial electrical potential that led to cell death. Supplementation with NAD precursors restored NAD levels, mitochondrial bioenergetics, and protein homeostasis, thereby preventing neuronal death caused by autophagy deficiency. Our goal is to target this mechanism of cell death in rare, early-onset neurodegenerative diseases associated with defective autophagy for developing treatments. We will focus on Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS), and assess generalisability in Lafora disease and neuronal ceroid lipofuscinosis 3 (CLN3 disease). These diseases have no effective cure and are associated with a spectrum of autophagy defects at early/late stages that we and others have demonstrated. We also found lower NAD levels in NPC1 and WS patient-derived neurons where drugs increasing autophagy or NAD improved neuronal survival. Our work will deliver insights into common patho-mechanisms and potential treatments for a range of rare neurodegenerative diseases associated with autophagy defects. First, we will study the contribution of autophagy dysfunction to cell death in rare disease models by analysing the intermediate steps of the cytotoxic pathway involving mitochondrial abnormalities and NAD metabolism. Then, we will use drugs that can correct the autophagy and NAD deficits, and further evaluate their efficacy in rescuing various disease-relevant phenotypes. Finally, we will investigate whether the treatment strategy will work for other rare brain disorders. To test new therapy in clinically relevant cells, we will make neurons from stem cells generated from patients' skin samples. We will use them to study how neurons die from autophagy malfunction that will lead to establishing a common disease mechanism involving autophagy dysfunction and NAD depletion. We will then test medicines already in use for other conditions or used as nutritional supplements to rescue the autophagy and NAD defects for improving the survival of patient-derived neurons, and applicable to multiple rare disease conditions. Our treatment strategy will be put forward in a future proposal for a clinical trial in children with rare brain disorders. The outcome will improve the health of children and have wider societal benefits to the rare disease community, neurologists, basic scientists, and NHS.

Group 6 transition metal hydrazides, (L)M=NNH2, occupy a pivotal position on the pathway for the biological and industrial conversion of N2 to NH3. In nature and in several important model systems this proceeds through a series of electron transfer and protonation steps. Considerable international effort has also been spent on trying to use mid-transition metal hydrazide complexes as reagents for the synthesis of value-added organo-nitrogen products. This holy grail concept of directly using atmospheric N2 as a commercial feedstock would by-pass the high-energy Haber-Bosch (NH3 synthesis) process. However, mid-metal M=NNR2 functional group reactivity is minimal. It is characterised only by transformations involving the NR2 (protonation or insertion/condensation involving N-H groups). No M=N bond reactivity is seen and N-N bond cleavage occurs only under highly forcing conditions using external reductants.Structural data and computational studies explain this: for mid-later metals NNR2 is best viewed as a neutral isodiazene :N=NR2. The more dative nature of the M--NNR2 bond and multiple bond character of N=N reduces the intrinsic reactivity at these two sites. In contrast, our X-ray and DFT results for Group 4 NNR2 systems find them to be reduced hydrazides, [NNR2]2-. Specifically, the N-N bonds are lengthened and weakened as the N-N pi* MOs are occupied; the M=N multiple bond is unsaturated and very reactive, further destabilised by the beta-NR2 lone pair. While sharing a simple formula NNR2 , mid-metal isodiazene and early metal hydrazide ligands are as fundamentally different as Fischer carbenes and Schrock alkylidenes. Just as early metal M=CR2 groups are intrinsically more reactive than later metal M=CR2, so it is for M=NNR2.We have recently developed three methods for making these hitherto undeveloped early transition metal hydrazides with Ti=NNR2 functional groups in very different environments. Preliminary results with a range of organic substrates (terminal and internal alkynes, nitriles, isonitriles, phospha-alkynes, CO2, isocyanates) indicate a wealth of cycloaddition chemistry. Remarkably certain alkynes and nitriles insertion into the N-N bond via a unique single N atom transfer step. We have also found this can be made catalytic so that a 1,2-diaminoalkene is formed catalytically at room temperature from a hydrazine and an alkyne: N-N addition across a C-C triple bond. If the diamination reaction can be extended it could ultimately provide a means of adding any general N-X (X = N, O, P) across any unsaturated C-element bond. This has the potential for a paradigm shift in the synthesis of 1,2-diamine and related compounds.In this project we will therefore develop the virtually unexplored area of early transition metal hydrazide chemistry, capable of delivering high-energy, highly reduced N-NR2 and related functional groups to a range of substrates in a 100% efficient, atom by atom manner. Our very recent synthetic methodology breakthroughs and preliminary reactivity studies provide a perfect and timely platform from which rapid progress can be launched. Working with a leading DFT computational Project Partner, we will deliver a fundamental toolbox for understanding and exploiting this unique reactivity in terms of scope, mechanism and applications in C-N, C-C and general C-heteroelement bond formation.

The proposed research concerns the most important human malaria parasite, Plasmodium falciparum. Malaria is one of the world's most debilitating infectious diseases, killing over half a million people every year and affecting several hundred million. Most of the deaths occur in young children in sub-Saharan Africa, but adults can also suffer from malaria throughout their lives, reducing quality of life and retarding economic development in endemic countries. The lack of an effective vaccine and the emergence of drug-resistant parasites mean that there is now an urgent need for research leading to a better understanding of the malaria parasite, and hence to new vaccine targets and treatment strategies for this disease. The malaria parasite causes illness via the infection of red blood cells. It multiplies inside these cells and modifies their surfaces with proteins called PfEMP1s that bind to the walls of blood vessels. This is crucial for parasite survival as it removes infected cells from the circulating blood and protects them from passing through the spleen, which might recognize and destroy them. It also contributes to disease, with severe malaria being particularly associated with the accumulation of infected cells in vessels of the brain and placenta. It is therefore of great interest to malaria biologists to understand the mechanisms that control the expression of these adhesive PfEMP1 proteins. PfEMP1s are not expressed uniformly by all malaria parasites: instead, individual parasites regularly switch between different variants. This allows them to stay ahead of the immune system and sustain a chronic infection for months or even years. The parasites have a large, variable family of 'var' genes for different PfEMP1 proteins and they vary the expression of these genes by so-called 'epigenetic switching'. Furthermore, var genes recombine very readily to generate new variants, so each parasite strain - of which there are many hundreds circulating in endemic areas - has a unique repertoire of possible surface proteins. This is one reason why immunity to repeated malaria infections is slow to develop in humans: every new parasite strain looks different to the immune system, so people can be re-infected repeatedly throughout their lives. Understanding and ultimately interfering with the expression, switching and recombination of var genes, and thus the variant expression of PfEMP1 proteins, could be a key to more effective immune control of malaria. Therefore, this research focuses on a new biological mechanism that the parasite may use for switching between var genes and for generating new variants. Our recent work has showed that an unusual DNA structure called a G-quadruplex that is concentrated around var genes seems to affect both these processes. To investigate this further, we now propose to map the G-quadruplexes throughout the Plasmodium genome, both in DNA and also in the messenger molecule, RNA. We will use a range of cutting-edge genome-wide technologies to do this, and will then check whether the distribution of the structures changes when the enzymes that unwind them are removed. These studies will lead to a better understanding of the mechanisms underlying var gene dynamics, and may ultimately inform new strategies to combat malaria, since var genes - and the adhesive proteins that they encode - are central to malarial disease. The outcomes of the research will be published in open-access scientific journals and presented at international conferences. They will be communicated to the general public via summaries on appropriate websites and via science writing in magazines and/or online. Work such as this remains vital as long as the malaria parasite continues to cause an immense burden of human disease.

Ocean circulation patterns especially within the deep ocean are a major player in global heat exchange and therefore force and stabilize climate patterns. In the North Atlantic, deep water masses are influenced by two main factors changing deep water strength and composition over time, the potential of water exchange with the Arctic Ocean and the development of the Northern hemisphere glaciation. The overflow across the Greenland-Iceland-Scotland Ridge, one of only two areas, where Arctic Ocean waters are exchanged with the world's oceans, can be shut off by the periodically strong pulsation of the Iceland mantle plume or in more recent times by glaciation of the Northern Seas and its surrounding land masses. In such an event, deep water circulation within the North Atlantic slows significantly, leading among other effects to a colder and more unstable climate in Western Europe.In this project, we propose to reconstruct the past behavior of deep water currents within the North Atlantic, by analyzing downhole logging data collected during IODP Expedition 395 "Reykjanes Ridge Mantle Convection and Climate". The drill sites are located in a transect along 60N, which represent a millennial scale archive of deep ocean sedimentation and current behavior ranging up to 12 Ma in the past to the Miocene. Downhole logging data will be collected after coring and has the advantages of being an in-situ continuous measurement through the strata, bridging potential gaps in core recovery. Recent experiments to measure current strength within the Atlantic has revealed, a decline in current strength in the recent past making the current circulation the weakest in the last millennia. Years of especially weak Atlantic currents correlate with an increase in weather events such as storms and floods within the British Isles and the rest of Western Europe. Understanding the past behavior of deep ocean circulation will therefore allow us to inform climate models used to predict severe weather events and use these predictions to minimize their impacts.