During pregnancy, the mother's immune system faces the task of protecting both the mother and her foetus. Mothers rely on nutrients to maintain their physiological condition and immune system, and also to nourish their developing offspring. A key question is: when mothers face challenges to their physiological state, how do they allocate energy to protect themselves and their offspring? When does this result in adverse outcomes, such as pre-term birth? To date, most research on pregnancy exposures involves long-term studies in humans or experiments on laboratory rodents or larger mammals. We have a solid understanding of how nutrition or infections in pregnancy influence birth timing and offspring development. Remarkably few studies have considered the interaction between nutrition and infections, potentially owing to the scale and complexity of studies involved, or because we have yet to develop a clear conceptual framework to develop testable hypotheses about this interaction. Here, I propose a project which tackles these two challenges head on: first, to develop a formal framework on the interplay between nutrition and infection in pregnancy, informed by evolutionary theory, and to test predictions using insect models of pregnancy, in parallel with analysis of datasets from contrasting human populations. I will first conduct a scoping review of human and animal model studies to identify the pathways linking nutrition, pathogen exposure and inflammatory responses in pregnant mothers, and consequences for offspring. I will then develop mathematical models to examine causality: how do energy trade-offs between defending against pathogens or nourishing offspring explain the optimal immune response across pregnancy stages? This formal framework will inform experiments in insects, which are extremely amenable with well-studied mechanisms, including highly conserved immune pathways found in vertebrates. Most research on insect immunity has focused on egg-laying Drosophila. I will use insects which experience pregnancy - tsetse flies and Pacific beetle cockroaches - to yield new insights on the complex interplay between maternal immune responses and nutrition. Both species exhibit almost mammalian pregnancy, nourishing their young with a milk-like substance from modified organs in utero. At the same time, they are evolutionary distant with contrasting diets, thus providing a unique opportunity to study both the specific and general machineries of pregnancy. I will expose pregnant females on diets varying in quantity or quality directly to pathogens, or indirectly activate their immune system. I will then measure responses of mothers and consequences for their young, in terms birth timing, body size and changes in physiology and gene expression. Lastly, I will examine patterns in two human cohort studies, in divergent contexts: the Children of the 90s study in the Bristol region, where diet quality and reported infections align with maternal socio-economic status, and data from the rural West Kiang region in The Gambia, a low-resource setting with strong seasonality in infections and food availability. I will compare how infections at different stages of pregnancy affect offspring, in terms of pre-term birth, child growth and later health, and how such effects change with maternal nutritional state. This project will provide fundamental insights into how maternal nutrition and immune responses interact to determine pregnancy outcomes and longer-term consequences for offspring, across diverse organisms. In the longer term, it can also inform policy to improve birth outcomes: for example, if immune activation in pregnancy cause an increased risk of pre-term birth, what are the nutritional interventions that could reduce this risk? Vaccines result in a mild immune response: what are the risks to mothers and offspring if administered early or late in pregnancy, and do these vary between under- or over-nourished mothers?

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.

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.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

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.