Huntington's disease (HD) is a rare inherited disease that causes brain degeneration and is one of the most common inherited dementias. Every case of HD is caused by a mutation in the huntingtin gene that causes cells to produce a harmful protein that is toxic to brain cells. Typically, HD manifests in adulthood between 30-50 years. However, more severe mutations cause symptoms to present earlier. Juvenile-onset Huntington's disease (JoHD) is when HD symptoms start before the age of 21. JoHD is ultrarare making it difficult to study fully, when means it is not well understood and our ability to run clinical trials for JoHD is limited. I have previously reported the first blood test that reflects adult-onset HD progression including the worsening of clinical symptoms and brain shrinkage measured by brain scans. This test measures a brain protein called Neurofilament light (NfL) of which levels in the cerebrospinal fluid (CSF - the fluid that surrounds the brain and spinal cord) and blood (now detectable due to ultrasensitive measurement techniques) tells us about the health of brain cells. In a small number of JoHD patients, I showed blood NfL was much higher than in healthy children. I am now working to gain the much-needed information required to implement clinical trials in JoHD patients. Ultimately, we need robust and sensitive tools called biomarkers that can tell us whether a drug is working. However, the severity of JoHD makes it hard for these young patients to make it to clinic and to take part in research. If we could study JoHD from afar then we could collect enough data to better understand the disease. I have developed a way to collect blood via a finger prick to measure NfL from patients who can take part in this research from their own homes. I hope this will increase the uptake of JoHD patients we can study and allow me to generate the largest cohort of these neglected patients. I am the global Chief Investigator of JOIN-HD, the first global registry study of JoHD. I will use the registry to recruit up to 100 JoHD patients to provide blood for repeated NfL measurements every 6 months over 2-years. INfLUENCE-HD includes a major collaborative effort to use samples from existing human studies including children and young adults, right up to older adults with the HD gene. I will study NfL in these samples to generate a model for how NfL changes throughout the life of a HD mutation carrier. I will include data from brain scans to strengthen these models and provide more detailed information of the disease biology underlying NfL changes. By using existing human supplied by several collaborators, this work can proceed quickly and efficiently. Together, this work will significantly and efficiently advance the role of NfL to help understand JoHD, predict its clinical course and accelerate the development of drugs. Further, home testing of NfL has potential of impacting other neurodegenerative conditions and transforming how patients' disease is monitored within Neurology. As a collaborator with the major pharmaceutical industry players in HD drug development, and an advisor to the Critical Path Institute, which in turn advises governmental drug regulatory agencies, I am ideally placed push this work forward to facilitate developing new treatments for this devastating illness and others.

The dietary vitamin B3, which encompasses nicotinamide, nicotinic acid and nicotinamide riboside, is precursor to the coenzyme nicotinamide adenine dinucleotide (NAD+), its phosphorylated parent (NADP+) and their respective reduced forms (NADH and NADPH). Once converted intracellularly to NAD(P)+, it is used as a co-substrate in two types of intracellular modifications, which control numerous essential signalling events (adenosine diphosphate ribosylation and deacetylation), and is a cofactor for over 400 redox enzymes, thus controlling metabolism. Critically, the NAD(P)(H)-cofactor family can promote mitochondrial dysfunction and cellular impairment if present in sub-optimal intracellular concentrations. Vitamin B3, and other B-vitamins such as thiamine (vitamin B1), riboflavin (vitamin B2) and pyridoxine (vitamin B6) are extracted in their coenzyme forms from food stuff. During digestion, the coenzymes are catabolised to the free circulating vitamins, which are then passively or actively transported across membranes, and salvaged intracellularly to their respective cofactors. Mammals are entirely reliant on a dietary source of vitamin B1 and heavily dependent on the dietary supply of vitamin B3, B2, and B6. Of note, acute deficiencies in vitamin B1 and vitamin B3 effect identical organs, with identical outcomes if left untreated: dementia and death. Conditions such as diabetes and obesity, alcoholism, high fat diet and conditions where therapy impacts nutrition can compromise suitable absorption of these vitamins. The bulk of intracellular NAD+ is regenerated via the effective salvage of nicotinic acid and nicotinamide (vitamin B3), while de novo NAD+ is obtained from tryptophan. Crucially, these salvage and de novo pathways depend on the functional forms of vitamin B1, B2 and B6 to generate NAD+ via a phosphoriboside pyrophosphate intermediate. Nicotinamide Riboside (NR) is the only form of vitamin B3 from which NAD+ can be generated in a vitamin B1, B2 and B6 independent manner and even though NR is a minor component of vitamin B3, the salvage pathway using NR for the production of NAD+ is expressed in most eukaryotes. While major strides have been made in the field of NAD+ biology and NAD+ metabolism, the role of this later pathway and the importance of the interplay between the bioavailability of vitamin B1, B2 and B6 and the pool of NAD(P)(H)-cofactors remain poorly explored. Using our synthetic expertise in nucleotide and stable isotope labelling chemistry, we will generate isotopically labelled vitamin B1 and B3 derivatives. These entities will be used to determine the profile of the vitamin B3 metabolome quantified by mass spectroscopy, under vitamin B1, B2 and B6 depletion conditions, in genetically engineered yeast strains and mammalian (murine and human) hepatocytes. In mammalian cells, these metabolic profiles will be correlated to mitochondrial functions. With this information, we will be able to prioritise the mechanisms cells use to best maintain the NAD(P)(H) pool in time of shortage of vitamin B1, B2 or B6. We predict that the pathway, by which NR is converted to NAD+, provides the means to rapidly yet transiently elevate mitochondrial and cytosolic NAD(P)(H) levels to kick start mitochondrial functions. If demonstrated, this knowledge will help identify new, physiologically relevant, vitamin-B combinations that could better restore mitochondrial function through enhanced bioavailability, in cells and organs where metabolism has been compromised by imbalanced micronutrition. This knowledge will be particularly important in terms of understanding the impacts of a global or partial vitamin B deficiency and vitamin B supplementation on organ functions in relation to malnutrition and over-nutrition.

At near-noon local times, at locations in the high arctic near 80 degrees North and South, the magnetic fields which originate in the conducting core of our planet extend upwards and are magnetically connected to the dayside magnetopause. This subsolar magnetopause is the point where the magnetic field of the Earth first touches the highly supersonic solar wind flow, and the interplanetary magnetic field of solar origin which is embedded in it. This creates the magnetospheric cusps, which are the primary entry points for energy of solar wind origin into the regions of space controlled by the terrestrial magnetic field, and the atmospheric regions which underlie them. This energy transfer occurs through a process called magnetic reconnection. As such, this crucial region of near-Earth space is fundamental to understanding the flow of energy, mass and momentum throughout the Earth's magnetosphere, ionosphere and upper atmosphere, and hence in our understanding of "space weather". The magnetospheric cusps are longstanding areas of research interest, but their highly variable nature, in both space and time, makes them a highly challenging region to fully understand. Here we describe a multi-instrument research programme based around an exciting new NASA space mission, TRACERS, due for launch in late 2022, on which the proposal PI is a named collaborator. The TRACERS programme relies on coordination with ground-based instrumentation. Of particular interest for TRACERS is the Svalbard region, an area of the high arctic uniquely well instrumented with, for example, numerous optical instruments and the NERC-funded EISCAT Svalbard radar. Around northern winter solstice Svalbard is in darkness at noon, and for ~10 days the moon is below the horizon. Such conditions offer a unique opportunity for multi-instrument cusp experiments involving cusp auroral optical observations. Our multi-instrument research programme requires the construction and deployment of a new state-of-the art digital imaging radar system, the Hankasalmi auroral imaging radar system (HAIRS). HAIRS will look northwards from Hankasalmi in Finland, having a field of view centred over the Svalbard region, revealing the ionospheric cusp region electrodynamics at high spatial and temporal resolution over a ~1 million square kilometre region of the ionosphere. In this programme, low earth orbit measurements of energetic ions precipitating from the cusp region taken by the twin TRACERS spacecraft will provide measurements of the temporal and spatial structuring of the cusp reconnection processes. Magnetically conjugate measurements of the footprint of the reconnection line from HAIRS and associated ground-based instrumentation, will measure the length and the location of the reconnection line. HAIRS will provide an analysis of the boundary motion, and of the convection velocities detected near the boundary, allowing a calculation of the reconnection rate mapped down to the ionosphere. Such a combination of instrumentation will provide an unprecedented opportunity to understand the temporal and spatial behaviour of cusp reconnection and its role in controlling terrestrial space weather. Outside of the science programme described here, HAIRS will offer vital complementary datasets to support the upcoming NERC-funded EISCAT 3D radar system at lower latitudes in Scandinavia, coming on stream in 2021 which will also lie in the HAIRS field of view. HAIRS will also directly complement the Solar wind Magnetosphere Ionosphere Link Explorer (SMILE), launching in 2023, a joint mission between the European Space Agency (ESA) and the Chinese Academy of Sciences (CAS). The innovative SMILE wide-field Soft X-ray Imager (SXI), provided by the UK Space Agency and other European institutions, will obtain unique measurements of the regions where the solar wind impacts the magnetosphere, regions which are directly magnetically connected to the area under study in this programme.

In October and November 2010, Merapi volcano (Java, Indonesia) had its biggest eruption since 1872. Merapi, which literally means "Fire Mountain" in Javanese, is one of Indonesia's most active and dangerous volcanoes with a history of deadly eruptions. Before 2010, these eruptions have usually been characterised by several months of viscous lava effusion at the summit of the steep-sided volcano, forming lava domes which, when big enough, collapse gravitationally generating relatively small pyroclastic flows. These flows are mixtures of lava dome fragments, smaller volcanic particles (ash) and hot gases that travel down the flanks of the volcano at high velocities of > 100 km/hour and, in the case of Merapi, typically reach distances of a few kilometres from the volcano. With a few exceptions only, this eruptive behaviour has been so typical of Merapi for at least the last two centuries that the pyroclastic flows generated by the gravitational failure of lava domes are often referred to in the literature as Merapi-type nuées ardentes (glowing clouds). In 2010, the eruptive behaviour of Merapi has changed. The unforeseen, large-magnitude explosive events were very different to previous episodes that followed Merapi's usual pattern of dome growth and collapse. On 26 October 2010, pyroclastic flows, generated during explosive eruption phases, swept down the flanks of the volcano, killing at least 34 people. The events were preceded by enhanced levels of seismicity and summit deformation that started in early September 2010. After days of high level activity, with glowing avalanches from a newly formed lava dome, pyroclastic flows and sporadic explosions generating a 7-km-high, sustained eruption column on 4 November, an unusually large explosive eruption on 5 November generated pyroclastic flows that extended up to 15 km from the volcano. Associated surges swept across Merapi's south flank, devastating villages and causing more fatalities. Since then, the death toll has risen to > 300 people, making this eruption the worst volcanic disaster at Merapi in 80 years. This project seeks to exploit a "once-in-a-century" opportunity to capitalise on these unexpected events at Merapi through a detailed investigation of the rocks formed during the 2010 eruption. These rocks preserve a record of the sub-surface processes that operated inside the volcano before the eruption occurred. Through the use of modern micro-analytical techniques and measurements of different radioactive isotopes that decay quickly within months, decades or millennia in the rocks, we can unravel these processes (which are the driving forces behind the unusual explosive behaviour of Merapi in 2010) and their timescales. The shortest radionuclide, 210Po, has a half-life of only 138 days and can tell us about the degassing of the magma and other processes that occurred in the weeks and months before the eruption. Because of its short half-life, 210Po must be analysed quickly after the eruption and before it has decayed completely to its daughter isotope 206Pb. Once we have established where in the crust beneath Merapi the magma feeding the 2010 eruption has come from and the processes of pre- and syn-eruptive crystallisation and degassing during magma ascent to the surface, we will compare the results with analytical data we have already collected on rock samples from the preceding eruptive episode in 2006, which followed Merapi "normal" (i.e. less explosive) eruptive behaviour. Ultimately, we will attempt to link the results obtained by analysing the rocks from the eruptions to the surface manifestations of these processes (e.g., seismic signals, ground deformation, gas flux) recorded through continuous geophysical monitoring of the volcano by our Indonesian colleagues.

On the afternoon of 3 July 2019, a violent explosive event (called paroxysm) affected the entire crater terrace of Stromboli volcano in Southern Italy, generating two pyroclastic flows that advanced for about 1 km across the sea beyond the coastline. The eruptive column rose for about 4 km above the summit and was accompanied by intense fall of scoriae and pumice, mostly around the village of Ginostra in the southwestern sector of the volcano, setting the vegetation on fire and causing one fatality and one injured person. The death toll could have been much higher, considering that during the summer months there are hundreds of tourists climbing the volcano every evening. In fact, on the afternoon of 3 July 2019 there were 230 people waiting to start their climb. Stromboli is well-known as the lighthouse of the Mediterranean for its persistent "normal" Strombolian activity, consisting of low-energy explosions occurring every 10-20 minutes from multiple vents located in the crater area. This persistent activity is accompanied by lava flows at intervals of several years and, occasionally, is interrupted by discrete violent explosive events, such as the one that occurred on 3 July, which lasted several minutes, fed a km-long vertical column of gas, scoria and pumice that launched blocks up to 2-3 km from the source. In the last century there have been about 17 paroxysms with the strongest one, also associated with a tsunami, on 11 September 1930, and the most recent ones on 5 April 2003 and 15 March 2007. Paroxysms are sudden, infrequent and highly damaging events that are very difficult to forecast. Previous work at Stromboli has shown that each of the last 4 paroxysms over 70 years of recorded eruptive history were preceded by lava effusion. In particular, the two most recent paroxysms in 2003 and 2007 occurred after the effusion of a similar cumulative volume of lava over a period of a few weeks to months preceding the large explosive events. These considerations have led to the current hypothesis that the volume of the effusive activity can be used to forecast future paroxysmal events. However, the 3 July 2019 did not play by this rule; it was preceded by very limited effusive activity only two minutes before the explosive event. At the same time, and rather untypical for the most recent activity of Stromboli, effusive activity started immediately after the explosive event, accompanied by intense explosive activity, and is still ongoing at the time of writing (early August 2019), raising concerns about the possibility of a second paroxysm. It is clear that in order to enhance our ability to forecast such deadly events, it is crucial to understand their driving mechanisms. We propose to exploit this unique opportunity to capitalise on this unexpected event on 3 July 2019 through a detailed petrological and geochemical investigation of the eruptive products to unravel pre- and syn-eruptive magma ascent and degassing processes and their timescales, magma storage and crystallisation conditions as well as magma mixing processes and their timescales prior to eruption. This is a unique opportunity to obtain, for the first time, crucial and novel information on the processes and timescales of magma ascent and degassing of such a disruptive event using the solid eruptive products that directly probe the underlying magma plumbing system. As the clock on the short-lived radionuclide 210Po (half-life = 138 days), which is one of our probes for determining the timescales of magma ascent and gas transfer, is already ticking, funding this proposal is time-critical.