The Lewy body (LB) diseases include Parkinson's disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB). The hallmarks of all of these diseases are aggregates of a protein called a-synuclein, forming Lewy bodies (LBs) in specific populations of neurons in the brain. The diseases can also have an overlap in clinical symptoms, which can make diagnosis difficult. These diseases are very complex, with their exact cause still largely unknown, although it is suggested that both genetic and environmental factors can alter a person's risk. Although a number of studies have recently searched for new genes that may make an individual more susceptible to these diseases, most of the identified genetic changes are very common, and only have a very modest effect on increasing one's likelihood of developing disease. It is known that the expression of genes relies not only on a person's specific DNA code (their genome), but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are chemical tags added to the DNA that turn genes on and off and can be influenced by external factors such as the environment in which cells dwell. Major genetic differences between the sufferers of people with LB diseases and unaffected individuals have been hard to identify, therefore scientists have speculated that epigenetic differences are involved in the diseases and could be the major way in which environmental risks can alter the expression of genes. In the case of Alzheimer's disease (AD) we, and others, have recently published some of the first studies showing that epigenetic changes are consistently seen in AD brain samples. We hypothesise that epigenetic changes also play a role in LB diseases and we propose that we can identify epigenetic signatures that can distinguish individuals with LBs based on their diagnosis, genetics, degree of brain pathology, symptoms and, in the case of PD, the presence of dementia. In order to address this we have the following research objectives: AIM 1: To identify specific epigenetic signatures of different LB diseases in post-mortem brain samples. These can teach us about the underlying biological differences between these diseases. AIM 2: To identify specific epigenetic signatures that are associated with neuropathological markers, regardless of clinical diagnosis. These can teach us about the biological basis behind the selective vulnerability of particular cell types in the different diseases. AIM 3: To identify specific epigenetic signatures associated with psychosis, regardless of underlying pathology or clinical diagnosis. This can teach us about the underlying biology driving these symptoms. AIM 4: To identify specific epigenetic signatures that can distinguish PDD from PD. These can teach us about the underlying neurobiology and risk factors associated with developing dementia. In order to address our hypotheses we propose to analyse epigenetic changes in the different Lewy body diseases, in two brain regions: the substantia nigra (SN), which is affected in the middle stages of disease, and the prefrontal cortex (PFC), which is affected in the later stages of disease. We will use state-of-the-art cell sorting methods to determine which cell types are driving these changes, before focussing on those altered in neurons. We will then determine which of these genes are specifically altered in neurons containing LBs. Finally, we will demonstrate that epigenetic changes in these genes are causing disease pathology by using cutting-edge genetic editing technology in cell culture. Looking to the future, as epigenetic changes are potentially reversible, these changes could represent novel drug targets.

Understanding what forces shape the tremendous diversity observed on our planet is one of the main goals of evolutionary biology. This requires a detailed understanding of how new species arise, as species form the basic unit of biodiversity. Nowhere is our lack of understanding of species formation more apparent than for the most diverse component of global biodiversity: the bacteria. This is problematic, because bacteria play fundamental roles not only in global biogeochemistry and ecosystem functioning, but also in health and disease and many industrial sectors, from agriculture to biotechnology. It is therefore vital to be able to identify bacteria, to understand how they originate, and how and why they are functionally different, and to know whether functions can potentially be transferred between them. A popular model describing the divergence of bacterial types is the 'Stable Ecotype Model'. In this model, successive beneficial mutations allow a population to adapt to its environment. Two populations inhabiting different ecological niches will accumulate different beneficial mutations and so both 'ecotypes' will gradually diverge through differential adaptation. However, bacteria are known to not be purely clonal; they can also engage in 'parasex', transferring short fragments of DNA between different individuals. This 'bacterial sex' is often very important, being able to create more genetic variation than does point mutation in many species. One important way in which bacteria engage in parasex is transformation: the uptake of free DNA from the environment, followed by recombination of that DNA into the genome. Recombination has important implications for the Stable Ecotype Model for two reasons. First, adaptation within an ecotype is expected to proceed faster because different beneficial mutations arising at the same time in the population can be combined into a single most fit (i.e. well-adapted) genome (rather than the beneficial mutations competing against each other in different individuals). Recombination could thus speed up adaptive divergence (i.e. formation of novel ecotypes). However conversely, recombination could also slow down adaptive divergence when an ecotype takes up DNA originating from a different ecotype to create hybrid genotypes that are not well-adapted to either niche. This proposal will for the first time experimentally test the hypotheses: 1) whether transformation within an emerging ecotype promotes adaptation 2) whether transformation between two different emerging ecotypes hinders adaptive divergence In collaboration with my proposed international project partners Dr. Pal Jarle Johnsen (University of Tromso, Norway) and Dr. Gabriel Perron ((University of Ottawa, Canada), a real-time evolution experiment will be used to evolve the frequently transforming species Acinetobacter baylyi in two distinct resources (niches). The availability of DNA for transformation will be manipulated to 1) increase the diversity of DNA from bacteria adapting to the same environment and 2) provide bacteria with DNA from bacteria adapting to the other environment. Subsequent competition experiments will be able to reveal whether adaptive divergence is promoted or hindered respectively. Understanding what ecological and evolutionary mechanisms cause a common bacterial ancestor to diversify into ecologically and genetically distinct types is of crucial importance to microbiology. Real-time controlled evolution of evolved phenotypes will enable us for the first time to test the influence of the key evolutionary variable, recombination, on the first steps in bacterial speciation.

My project focuses on the current refugee crisis in Calais, answering the following question; what are the reasons for the police violence that has been, and continues to be, directed towards refugees in Calais? I will consider the impact of this violence, such as human rights and mental health implications, and how state violence against refugees could be reduced. There have been refugee camps in and around Calais for two decades, and although the 'Jungle' was destroyed in 2016, there remains some several hundred refugees in the area. These refugees have faced, and are facing, violence and intimidation from the French CRS Police in Calais; this has been well-documented and I witnessed it first hand as an undergraduate when researching and volunteering as part of my dissertation. Despite this violence not being a recent phenomenon, there is very limited understanding as to why the violence occurs and what this means for human rights research. My project will answer four sub-questions to address this: 1) Is the violence necropolitical? 2) Which political relationships shape the CRS Police? 3) Is there a politics of fear? 4) What does the violence mean for the refugees? I am of the belief that there will be no single answer to explain the violence. There is a complex socio-political environment both locally and globally surrounding refugees and immigration, and this project aims to unpick and understand the various factors surrounding the situation in Calais. We live in a world where populism and right-wing beliefs are becoming more prevalent in our politics and societies, whilst media reinforces fear of the unknown and fear of 'migrants'. These are some possible factors to consider when understanding how the state violence is 'permitted.' This project will involve undertaking overseas fieldwork. I will be liaising with organisations in Calais, such as 'Care 4 Calais' and 'Calais Migrant Solidarity' and volunteering with them whilst gaining fieldwork data. I am proposing a minimum of one week every other month in Calais during the first and second year of my PhD, ensuring a minimum of 12 weeks spent in Calais itself. The situation in Calais changes frequently so fieldwork taking place over this longer period will allow me to capture this constantly changing picture. I also would benefit from difficult language training. Learning Arabic, the dominant language spoken by refugees in Calais, would allow me to engage better with them in conversation and support. I propose a ten-week intensive course during the first term of my PhD, taking place at the University of Exeter. This will be a critical piece of research for human rights and security, whilst also benefitting the field of socio-politics. This project could have a wide impact academically and within NGO and government circles, and gain the refugees more attention required to have their human rights better protected. This is an issue which cannot be ignored, nor the impact of it denied, any longer.

Quantum networks promise to revolutionise computing and communication, with the underlying idea to link individual or small clusters of qubits via a photonic channel. Amongst many potential architectures, colour centres in wide bandgap semiconductors provide a versatile platform and considerable progress has been made, particularly with the negatively charged nitrogen vacancy in diamond (NV) (see ref. 1 for a recent review). NV-centres fulfil many of the criteria necessary for a spin qubit, but also have several inherent disadvantages. Most notably, NV centres have poor optical properties and scalability is hindered by the challenge of fabricating devices from diamond. Colour centres in hBN [2] are an interesting alterative and have shown considerable early promise, thanks to their excellent optical properties, potential for photonic integration and recently the report of optically detected spin resonance [3]. This project will build on our recent work, using multicolour laser excitation to control and stabilise hBN colour centres [4], with an integrated microwave and photonic platform to control and investigate their spin properties. Ultimately, this will allow us to probe their potential as a spin qubit, with applications in quantum information, communication and nanoscale sensing. This project will be funded by an EPSRC ICASE award and the successful candidate will work with Oxford Instruments Plasma Technology, including research placements at their Technology and Applications Laboratories. The 4 year studentship is jointly funded by an Industrial Cooperative Awards in Science & Technology (ICASE) award from EPSRC and Oxford Instruments Plasma Technology. It is of total value around £119,000, which includes approximately £20,000 towards the research project (travel, consumables, equipment etc.), tuition fees, and an annual, tax-free stipend starting at approximately £17,500 per year for UK/EU students (see https://www.exeter.ac.uk/pg-research/money/fees/ for further information about individual fee status).

The processes of life are dynamic and it is change on a molecular level that enables organisms to grow but to also adapt to and survive in different environments, such as the ability to cause disease within a human host. My research focuses on the human fungal pathogen, Candida glabrata, which can cause illness in humans ranging from allergic reactions, infections such as thrush which affects ~75% of women at least once, to serious disease in patients that have impaired immune systems. These fungi are increasing in incidence and the reason for this increase is not understood. However, it is clear that the fungus can defend itself against high levels of stress and antifungal drugs used in treatment regimes. My hypothesis is that C. glabrata has evolved the capabilities to withstand a challenge from the combination of environmental and imposed drug stresses. Firstly, to look at C. glabrata, I will take advantage of my recent discovery of the sexual cycle in this fungus which offers novel methods to test hypotheses about evolution and pathogenesis. Pathogens of humans (microbes that can cause infection), such as C. glabrata, are successful because they adapt effectively to environmental stresses encountered within the host body. Upon recognition by host immune cells, C. glabrata is engulfed and exposed to a combination of stresses. In contrast to other pathogenic fungi, C. glabrata is highly resistant to stress allowing it to survive the host immune defences. This suggests that resistance to both antifungal drugs (a stress brought on by medical intervention) and natural host-induced stresses are essential for establishment and progression of infection. The molecular mechanisms underpinning antifungal resistance and the response to individual stresses, have been investigated in isolation, however little is known about how C. glabrata adapts to combinatorial stresses. The mechanistic explanation of stress adaptation will yield new insights into Candida infection. Using my newly discovered sexual cycle in C. glabrata, I have generated a series of related strains of the same fungal pathogen that have increased resistance to combinatorial and drug stresses. I will sequence their genomes (a process for analysing DNA) to identify the critical genes involved in stress resistance and characterise the mechanisms of C. glabrata stress responses. My preliminary data and publications demonstrate that the C. glabrata response to in vitro (performed in the lab outside of the human body) combinatorial stress is similar to that observed upon phagocyte engulfment (when immune cells recognise pathogens and try to remove them). At the level of gene expression, there is an up-regulation of genes (the process by which information encoded in a gene is used to make more proteins) encoding functions related to stress adaptation and nutrient recycling overlap. Understanding this regulatory network and the role that selected components (different genes) play in stress resistance, is essential to the development of future drug regimes.