Huntington's disease (HD) is a fatal neurodegenerative disorder characterised by the loss of vulnerable neurons in the brain. The disease is caused by an increase in the size of a repeated DNA sequence which encodes for the amino acid glutamine in the huntingtin (HTT) protein. If the number of glutamines in the HTT protein increases beyond a critical length, it misfolds and clumps together to form protein aggregates, disrupting many vital cellular processes. Notably, other genes can significantly modify the onset of symptoms. This suggests there are many potential therapeutic targets in the human genome capable of significantly altering disease. Studies in patients and disease models have revealed that mutant HTT (mHTT) affects many cellular pathways, including intracellular vesicle trafficking. This is a vital process for the movement of proteins and nutrients between different parts of the cell. Previous work by our laboratory and others has shown that vesicle trafficking defects in HD are at least partly due to a family of proteins called Rab GTPases. These proteins are vital for nearly every aspect of vesicle trafficking, and the function of several Rabs is impaired in HD and other related disorders, including Parkinson's disease. Interestingly, the non-mutant HTT protein may be important for the normal function of some Rabs, which may contribute to their dysfunction in HD. We and others have noted that increased expression of three Rab GTPases - Rab5, Rab8 and Rab11 - reduces disease-relevant symptoms in cultured mammalian cell and fruit fly models of HD. While the role of these Rabs in HD has been explored, little is known about the importance of the ~60 other mammalian Rabs. To address this question we performed a systematic screen of 130 mammalian Rabs and associated genes and identified 8 that modulated mHTT toxicity in mammalian cells. Several additional Rabs have also been identified in independent screens for genes that alter mHTT toxicity and/or misfolding. In this research proposal we aim to further investigate the role of Rab GTPases in HD and explore their therapeutic potential. Notably, this will include the first characterisation of the role of Rabs in peripheral immune cell dysfunction in HD by analysing patient-derived samples. Immune cells are hyper-reactive in HD, producing inflammatory molecules that may contribute to progression of the disease, and Rabs contribute to the secretion of these molecules. Understanding Rab dysfunction in HD is critical for determining their disease and therapeutic relevance, the mode of action of disease modifying Rabs and for formulating therapeutic approaches. We will address this by investigating whether the amount, function or cellular location of candidate Rabs is altered in HD models and patient samples, and how this impacts upon Rab-dependant processes. To validate the protective properties of candidate Rabs, and prioritise them for further study, they will be tested in fruit fly and mouse HD models, allowing us to study the impact of mHTT and Rabs on the complex interactions that occur between cells in living multicellular organisms. Promising candidates will be tested in physiologically relevant human HD model cells, including neurons and immune cells from patients. Drug-like compounds which alter Rab function will also be tested, and alternative methods for targeting them explored. To further inform potential therapeutic approaches and prioritise candidates the mechanisms by which they modify HD relevant-phenotypes will be studied. Our preliminary findings suggest that many candidates increase the clearance of mHTT from the cell, and we will confirm these findings using additional HD models and approaches. In total, this work will help define the role of Rab GTPases in HD, assess their therapeutic potential and inform therapeutic strategies. As Rab dysfunction has been implicated in several diseases these findings may also have broader significance.

In 2011, NERC began a scoping exercise to develop a research programme based around deep Earth controls on the habitable planet. The result of this exercise was for NERC to commit substantial funding to support a programme entitled "Volatiles, Geodynamics and Solid Earth Controls on the Habitable Planet". This proposal is a direct response to that call. It is widely and generally accepted that volatiles - in particular water - strongly affect the properties that control the flow of rocks and minerals (their rheological properties). Indeed, experiments on low-pressure minerals such as quartz and olivine show that even small amounts of water can weaken a mineral - allowing it to flow faster - by as much as several orders of magnitude. This effect is known as hydrolytic weakening, and has been used to explain a wide range of fundamental Earth questions - including the origin of plate tectonics and why Earth and Venus are different. The effect of water and volatiles on the properties of mantle rocks and minerals is a central component of this NERC research programme. Indeed it forms the basis for one of the three main questions posed by the UK academic community, and supported by a number of international experts during the scoping process. The question is "What are the feedbacks between volatile fluxes and mantle convection through time?" Intuitively, one expects feedbacks between volatiles and mantle convection. For instance, one might envisage a scenario whereby the more water is subducted into the lower mantle, the more the mantle should weaken, allowing faster convection, which in turn results in even more water passing into the lower mantle, and so on. Of course this is a simplification since faster convection cools the mantle, slowing convection, and also increases the amount of volatiles removed from the mantle at mid-ocean ridges. Nevertheless, one can imagine many important feedbacks, some of which have been examined via simple models. In particular these models indicate a feedback between volatiles and convection that controls the distribution of water between the oceans and the mantle, and the amount topography created by the vertical movement of the mantle (known as dynamic topography). The scientists involved in the scoping exercise recognized this as a major scientific question, and one having potentially far reaching consequences for the Earth's surface and habitability. However, as is discussed in detail in the proposal, our understanding of how mantle rocks deform as a function of water content is remarkably limited, and in fact the effect of water on the majority of mantle minerals has never been measured. The effect of water on the flow properties of most mantle minerals is simply inferred from experiments on low-pressure minerals (olivine, pyroxenes and quartz). As argued in the proposal, one cannot simply extrapolate between different minerals and rocks because different minerals may react quite differently to water. Moreover, current research is now calling into question even the experimental results on olivine, making the issue even more pressing. We propose, therefore, a comprehensive campaign to quantify the effect of water on the rheological properties of all the major mantle minerals and rocks using a combination of new experiments and multi-physics simulation. In conjunction with 3D mantle convection models, this information will allow us to understand how the feedback between volatiles and mantle convection impacts on problems of Earth habitability, such as how ocean volumes and large-scale dynamic topography vary over time. This research thus addresses the aims and ambitions of the research programme head on, and indeed, is required for the success of the entire programme.

Five percent of children have disabling hearing loss. These children often experience delayed speech and language development. Although the majority of these children attend mainstream schools in the UK, only 34% achieve two A-levels (or the equivalent), compared to 55% of their hearing peers. Mild-to-moderate hearing loss (MMHL) is the most common hearing impairment in children. However, despite the effect of their hearing impairment on development it is the least understood form of hearing loss in children. This means there is an urgent need for research on this group in order to meet the goal set by the National Deaf Children's Society (the UK's biggest children's hearing charity and a partner on this project) of making sure that "by 2030, no deaf child will be left behind". Children with MMHL are prescribed auditory technology (AT) to assist them. Hearing aids are more advanced and accessible than ever, and assisted listening devices - where a talker's speech is streamed directly to the hearing aid to reduce the effects of a noisy background - are now common in classrooms. However, AT is designed based on how adults communicate: adults generally look at the person they are talking with and ask for information to be repeated when they do not hear clearly. On the other hand, children with normal hearing do not look. It is unknown if children with MMHL look at the talker while they listen. This has an impact on the effectiveness of the AT algorithms. PI Stewart has shown that children with MMHL do not have the same improvements in attention, memory and learning as adults do when using AT. This could be due to 1) the children are not wearing their AT; 2) the ATs are "too much of a good thing" and have short- or long-term effects on key hearing and listening skills (e.g. children have found that they can hear without turning to look at the talker); or 3) the ATs are not appropriate for children. To test these hypotheses, we will first systematically review children's AT usage across the UK. Second, we will gather data on the developmental impact of ATs over an 18-month period. Key hearing and listening skills including working out where a sound came from and combining audio with visual information will be assessed. Third, we will assess how children with MMHL communicate with adults and children. We will do this in a research lab in the form of a classroom where eye and head movements and brain activity can be measured. This will allow iCAT to evaluate if AT algorithms (e.g. designed for the listener to look at the talker) are appropriate for children. iCAT will work with industry, audiologists and teachers of the deaf throughout the project to ensure change towards providing child-appropriate ATs for the benefit of children with MMHL. Through the publication of white papers, iCAT will work with UK-based charities and professional bodies to create evidence-based recommendations for policy regarding the use and fitting of the AT in children with MMHL.

The biology of animals is in part a function of the microbes they interact with. During digestion, for instance, food is broken down both by enzymes secreted by our digestive system and those secreted by the microbes that live within the gut. In many insects, microbe-host interactions are even more developed. Bacterial symbionts live inside the cells of the insect body, and these are passed from a female to her offspring via her eggs: heritable symbiosis. We know a lot about how these symbionts affect the individual they infect. One particularly interesting impact is male-killing, where the bacterium passes from a female to her eggs, and kills those which develop as males. We know male-killing bacteria are common: they are present in many species, and, where they are present, can be present in the majority of individuals - this produces insect populations where males are rare. However, we know little about how these bacteria affect insect ecology or evolution. A variety of researchers believe these symbionts may drive changes in the way male and female insects are formed during development, sex determination. The hypothesis is simple - where symbionts target males only, natural selection counteracts this by favouring new ways of making a male that escape male-killing. This study will examine this theory for a recent case of evolution of the blue moon butterfly to avoid the action of male-killing bacterium called Wolbachia. We have documented the spread of a mutation that rescues male blue moon butterflies from Wolbachia-induced death. This project will establish what this mutation is, whether it involves changes in a gene called 'doublesex', which defines male and female characteristics in insects. A second aspect of male-killers is that they may drive very strong natural selection to rescue males. The intensity of selection is such that the changes that occur to rescue males may be otherwise deleterious. A second aim of the project is to establish if this is true, and whether the mutation (beyond rescuing males) degrades male and female function. In completing this project, we will present the first direct test of the theory that the processes that make males/females different can be driven by microbes. This is an enigmatic link that would make clear the interdependence of insect and microbe evolution.

This project is concerned with the process of core formation in growing planetary bodies. The sample material is a meteorite (technically an H6 ordinary chondrite) that contaims 'metal' in the form Ni-Fe-S. Presently, our understanding based on experiments is that under non-hydrostatic conditions, deformation mechanisms (shearing) provide local high permeability pathways for liquid metal segregation independent of surface tension effects. The role of deformation in promoting segregation (sometimes referred to as percolation) in a partially-molten silicate matrix challenges the long-standing idea that core formation in planetary bodies requires a magma ocean. However, only a small number of laboratory experiments on natural samples have been done to date. As important as they are, these experiments cannot provide robust information on the detailed fluid dynamics of liquid metal transport during shear, nor comment significantly on the wider scale implications of deformation driven porous flow in core formation other than through speculation. The required level of information can only be obtained from numerical modelling. Experiments do however provide critical textural and geometrical information and in natural samples, geochemical data pertinent to pore-scale flow. We offer a combined approach that uses textural data from real meteorites, deformed under laboratory conditions, as input data for our numerical models. The result will allow us to explore the microscale physics and chemical ramifications of Fe metal-silicate melt segregation in the wider context of planetary core formation.