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The twin objectives of RegulaTomE are to determine the importance of transcriptional regulation of the metabolic pathways defining quality traits in tomato and to identify such transcriptional regulators at the molecular level. The selected quality traits include antioxidant capacity which impacts shelf life and nutritional value as well as traits determining fruit flavor and over-ripening which influence organoleptic properties and shelf-life. RegulaTomE will use the natural variation available in introgression lines (ILs) resulting from wild species crosses to tomato to assess the importance of transcriptional regulation, identify additional regulatory genes and assess underlying genetic and epigenetic variation. RegulaTomE will assess the potential for direct or indirect use of natural variation from an untapped wild species resource for crop improvement. To identify genes regulating metabolic pathways using the Solanum lycopersicoides ILs, and to capture genetic and epigenetic variation for application to gene discovery and tomato improvement, resources need to be developed, including a genome reference sequence for S. lycopersicoides and metabolite, DNA methylation and transcriptome profiles of IL fruit. RegulaTomE will lead to regulatory gene identification and new tools for metabolic engineering of fruit quality. The natural variation in fruit quality revealed by the S.lycopersicoides ILs could be applied to tomato improvement either directly through introgression into cultivated varieties or indirectly through the identification of target loci and corresponding allelic variation making positive contributions to quality traits within S. lycopersicum breeding germplasm. The outputs of RegulaTomE will provide a framework of understanding as well as tools, in the form of genes, target loci and molecular markers, to support development of longer shelf-life, more nutritious and more flavorsome fleshy fruits in other horticultural crops.

The purpose of this research is to understand how and where in the body the novel hormone fibroblast growth factor 21 (FGF21) acts to reduce food intake, decrease body weight and regulate body fat. This hormone was first discovered over ten years ago, but we are uncertain about which tissues in the body produce it, where it acts, and what its normal role in our biology is. Our previous research has exploited seasonal cycles in body weight in the Siberian hamster, as this provides a natural animal model of body weight gain in summer (fat state) and loss in winter (lean state). Using this model, we have already found that FGF21 is more effective at reducing appetite and causing weight loss in seasonally fat hamsters. This is a hugely important finding, because responses to other major metabolic hormones are often decreased in states of high body fat. The fact that obesity is an insulin- and leptin-resistant state presents challenges for using these pathways to manage body weight disorders. Understanding the natural biology of FGF21 should therefore have important implications for pharmaceutical and/or nutritional treatment of obesity as this pathway is likely to be amenable to manipulation. The first objective is to determine which tissues respond to FGF21 treatment by changing their uptake of glucose and fatty acids. This will be achieved using a small animal positron emission tomography (PET) scanner, which allows uptake of these metabolites to be observed non-invasively in living animals. We will also test in vitro whether FGF21 can promote fat breakdown. These studies will identify which tissues are the primary targets of FGF21 action, and confirm whether actions on glucose and fatty acid uptake underlie the whole body effects on fat depots and body weight. The second objective is to investigate the hypothesis that FGF21 also acts in the brain to reduce food intake and to increase energy expenditure. Other metabolic hormones such as leptin and ghrelin are known to signal from fat and the stomach respectively to the brain to regulate our appetite. Our preliminary studies also provide evidence that FGF21 can act in the brain. We are particularly interested in actions on a layer of glial cells in the hypothalamus known as tanycytes, as these cells express a receptor for FGF21 known as FGFR1c, and show changes in gene expression and glucose-stimulated calcium signalling in response to stimulation of these receptors. We will test the hypothesis by determining whether administration directly into the brain of FGF21 itself or a closely related compound developed by the pharmaceutical company Eli Lilly changes appetite, energy expenditure and body weight. We will also use imaging of slices of brain derived from rodents to determine whether FGF21 directly affects neurons and glial cells. The overall outcome of this project is that we will understand how the hormone FGF21 is able to produce its beneficial effects of improved glucose dispersal and loss of body fat. We will have identified which tissues respond to FGF21, and will determine if part of its action is in the brain via the control of behaviour and the autonomic nervous system. There are many beneficiaries of this project. The information gained will be important for other academic researchers in universities and in research institutes, and for researchers in the pharmaceutical industry working on obesity. In addition, the project will provide training in advanced imaging and experimental physiology, and the researchers will promote public understanding of research into appetite control and obesity.

Life-End summary Sustainable production of safe chicken is an international priority and preserving bird welfare is a key component of this. Current intensive (broiler) production can compromise bird health and welfare and food safety and there are strong links between poor bird welfare and the Campylobacter public health threat. Campylobacter is the most common cause of bacterial diarrhoea in the EU and despite millions of pounds of research funding it is estimated that contaminated chicken caused ~700000 human campylobacteriosis cases in the UK in 2013 with around 100 deaths. Infection is characterised by severe abdominal pain and acute (sometimes bloody) diarrhoea and costs the UK an estimated £1 billion per year. Campylobacter contamination of chicken takes two forms. First, surface contamination of carcasses leads to cross-contamination in the kitchen. Second, and perhaps of greater importance than currently thought, contamination within muscle and liver tissues, increasing the health risk by facilitating bacterial survival during cooking. Chickens in poor production environments or exposed to stress are more susceptible to Campylobacter and in such birds the bacteria show greater extra-intestinal spread to edible tissues, possibly as a consequence of disturbance to the gut environment. Therefore, improvements in broiler welfare have great potential to improve public health but there is an urgent need for information on the effect of stress to inform targeted interventions to reduce Campylobacter in broiler chickens. One acutely stressful event in the life of broilers, in any production stream, is harvest when birds are removed from the farm for slaughter. We define the process as comprising: food withdrawal, catching, transport and stunning by either gas or electricity. Although there is a growing body of evidence that these stressors can increase Campylobacter growth rates as well as extra-intestinal spread, there is a paucity of data on their relative importance or how they may select for particular types of Campylobacter. By examining the harvest processes using large scale industry-relevant experimental conditions, state-of-the-art genomics, molecular microbiology and mathematical modelling techniques, we will determine the impact of harvest on gut health in broilers. We will combine this with a study to identify bacterial genetic determinants involved in extra-intestinal spread of Campylobacter to edible tissues. We will quantify the relative impact of each stage of harvest on the gut bacterial population and the physiology and immunity of the birds, and investigate the role these play in controlling extra-intestinal spread of Campylobacter. This multidisciplinary research programme will enhance understanding of the influence of the harvest process on bird gut health and Campylobacter. The quantitative information and modelling will be used to provide direct advice to industry about the elements of the harvest processes that provide the best opportunity for interventions that will mitigate the ongoing challenge of Campylobacter contamination in chicken meat.

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.

The current FLIP proposal builds upon an existing BBSRC Industrial Partnership Award in collaboration with Skretting (the largest global producer of aquaculture feed). The existing project is based on a novel manipulation of diets that has already been demonstrated to improve the efficiency of converting food into growth by a remarkable 20 % under laboratory conditions. It uses laboratory studies with live fish to assess the energetic costs and health implications of feeding in aquaculture fish, and then to design optimal diet compositions to minimise these costs. It aims to make energetic savings for the fish in particular regarding acid-base and salt balance following a meal, and minimise how these natural disturbances impact upon respiratory gas exchange and excretory processes. The present FLIP proposal will use similar approaches to the above current BBSRC-funded project. However, whereas the current BBSRC-IPA project addresses dietary issues, this FLIP proposal specifically addresses newly discovered water quality changes that are particularly associated with intensive recirculating aquaculture systems (RAS). The present FLIP proposal seeks to use a 2-way interchange between academia and industry to address previously unconsidered factors that can have a major influence on the biology and efficiency of growth in fish. By facilitating an interchange of academic and industrial personnel between their respective sites this project aims to address these non-ideal changes in water chemistry associated with intensive recirculating aquaculture systems (RAS). It aims to establish (and ideally prevent) previously unrecognised energetic costs for fish caused by these water quality issues that can impair health, welfare, growth and ultimately the production efficiency in aquaculture. It is a collaboration with Anglesey Aquaculture Ltd (AAL), the largest marine RAS in Europe and the UK's only farm for seabass, a high value and commercially important fish. This form of land-based aquaculture is increasingly promoted worldwide due to its sustainability in terms of low water use and minimising environmental problems from waste products. However, the intensity of the aquaculture conditions creates water quality problems that must be countered, primarily a consumption of oxygen and excretion of carbon dioxide by the fish. This is compensated by large scale aeration of the recirculating water which effectively restores oxygen, but is often insufficient to removal all the animal's waste carbon dioxide which subsequently acidifies the water. To deal with this pH problem RAS operators added huge amounts of alkali (1-2 tonnes of caustic soda per day) at considerable cost. However, this pH compensation measure is now realised to create further water quality issues, specifically high alkalinity and low calcium within the water. These secondary changes are known to impair the physiology and energetics of fish, and are therefore suspecting of negatively impacting their feeding and growth. By facilitating a 2-way transfer of knowledge and skills (via direct secondments of one academic and one industry interchanger, at each other's site), this FLIP project aims to provide a cost-effective, evidence-based solution(s) to these specific water quality issues. Furthermore, we aim to embed a culture of problem-solving through academic-industrial collaboration into the fabric of both organisations such that future problems associated with sustainable production of fish can be avoided or mitigated in a timely fashion.

Life-End summary Sustainable production of safe chicken is an international priority and preserving bird welfare is a key component of this. Current intensive (broiler) production can compromise bird health and welfare and food safety and there are strong links between poor bird welfare and the Campylobacter public health threat. Campylobacter is the most common cause of bacterial diarrhoea in the EU and despite millions of pounds of research funding it is estimated that contaminated chicken caused ~700000 human campylobacteriosis cases in the UK in 2013 with around 100 deaths. Infection is characterised by severe abdominal pain and acute (sometimes bloody) diarrhoea and costs the UK an estimated £1 billion per year. Campylobacter contamination of chicken takes two forms. First, surface contamination of carcasses leads to cross-contamination in the kitchen. Second, and perhaps of greater importance than currently thought, contamination within muscle and liver tissues, increasing the health risk by facilitating bacterial survival during cooking. Chickens in poor production environments or exposed to stress are more susceptible to Campylobacter and in such birds the bacteria show greater extra-intestinal spread to edible tissues, possibly as a consequence of disturbance to the gut environment. Therefore, improvements in broiler welfare have great potential to improve public health but there is an urgent need for information on the effect of stress to inform targeted interventions to reduce Campylobacter in broiler chickens. One acutely stressful event in the life of broilers, in any production stream, is harvest when birds are removed from the farm for slaughter. We define the process as comprising: food withdrawal, catching, transport and stunning by either gas or electricity. Although there is a growing body of evidence that these stressors can increase Campylobacter growth rates as well as extra-intestinal spread, there is a paucity of data on their relative importance or how they may select for particular types of Campylobacter. By examining the harvest processes using large scale industry-relevant experimental conditions, state-of-the-art genomics, molecular microbiology and mathematical modelling techniques, we will determine the impact of harvest on gut health in broilers. We will combine this with a study to identify bacterial genetic determinants involved in extra-intestinal spread of Campylobacter to edible tissues. We will quantify the relative impact of each stage of harvest on the gut bacterial population and the physiology and immunity of the birds, and investigate the role these play in controlling extra-intestinal spread of Campylobacter. This multidisciplinary research programme will enhance understanding of the influence of the harvest process on bird gut health and Campylobacter. The quantitative information and modelling will be used to provide direct advice to industry about the elements of the harvest processes that provide the best opportunity for interventions that will mitigate the ongoing challenge of Campylobacter contamination in chicken meat.

Diseases of domestic livestock are an ever present threat to the challenge of feeding an increasing global population. African swine fever virus has existed in a natural cycle between warthogs and soft ticks for millennia, but causes a lethal, highly contagious, haemorrhagic fever in domestic swine and wild boar. In 2007, African swine fever was introduced into Georgia, probably through contaminated waste from a ship, and since has spread throughout most of European Russia and has now been reported in Poland, Lithuania, Latvia and Estonia. Effective vaccines against African swine fever are desperately needed. Autophagy is a highly conserved intracellular pathway that has evolved to breakdown and recycle damaged cytoplasmic components by delivering them to lysosomes. Autophagy can also be induced in response to physiological stress, most notably that of starvation (The word autophagy literally means self-eat in Greek). Many important responses to infection are dependent on the autophagy pathway and pathogens have evolved mechanisms to manipulate autophagy for their own benefit. Recent experiments have demonstrated that disrupting the ability of viruses to inhibit autophagy can enhance immune responses. We have shown that African swine fever virus can block part of the autophagy pathway, raising the possibility that deletion of viral proteins that inhibit autophagy may enhance the immunogenicity of a live attenuated ASFV vaccine. The major aims of this project are to further characterise the effect of African swine fever virus infection on the autophagy pathway, identify novel autophagy inhibitors in the African swine fever genome and generate recombinant viruses lacking these genes. The findings from these studies will contribute to the development of safe and effective, live attenuated ASFV vaccine candidates.

Phytoplankton are free-floating plants found in marine and freshwaters that, through their photosynthetic growth, form the base of the aquatic food chain. A small subset of the phytoplankton may be harmful to human health or to human use of the ecosystem. The species that cause harm are now widely referred to as 'Harmful Algae' with the term 'Harmful Algal Bloom' (HAB) commonly being used to describe their occurrence and effects. Some HABs can be harmful to humans through their production of biotoxins that are concentrated in the flesh of filter feeding shellfish, leading to a health risk if the shellfish are consumed by humans. Other HABs can kill farmed fish. HAB events of either type can have serious financial consequences for aquaculture. Early warning of HAB events provides a mechanism to protect human health and minimise business risk for aquaculture. Many important HABs develop offshore. Two of the most important in the UK and worldwide are the genus Dinophysis sp. that causes diarrhetic shellfish poisoning, and the species Karenia mikimotoi that can kill farmed fish. These organisms are transported to coastal aquaculture sites by oceanic currents. For K. mikimotoi we can use satellite remote sensing to identify their offshore blooms, for Dinophysis we know the locations and times of the year that are most high risk. In this project we shall use a combination of satellite remote sensing, in situ measurement (using free floating and moored scientific instruments that measure the properties of the water column) and mathematical modelling of oceanic currents and HABs to get a better understanding of where these harmful blooms develop and under what conditions they will be transported to the coast and subsequently into the fjords where aqaculture is located. Our results will be used to improve risk assessment bulletins that are produced weekly for use by aquaculture practitioners. The new knowledge gained in this project will allow us, for the first time, to interpret modelled ocean current forecasts to provide forecasts of the likelihood of these currents carrying advective HABs to the coast. The work will also allow us to determine if on reaching the coast, water exchange will allow blooms to enter the sheltered fjords within which aquaculture is practiced. This will allow industry to better plan their husbandry and harvesting to minimise HAB risk to business and health.

Astroviruses are of both medical and veterinary importance with vaccines or therapeutics currently unavailable. The molecular biology of these viruses is currently poorly understood and will be important in future control efforts. In common with other viruses Astroviruses must enclose their genome in a protein capsid. To achieve this, other +ssRNA viruses utilise multiple RNA:capsid protein interactions to provide specificity of genome encapsidation and to ensure the correct and efficient assembly of intact mature capsids as a key step in the viral infection cycle. In collaboration between the Pirbright Institute and the Twarock Group at the University of York we wish to establish the molecular basis of genome encapsidation by Avian Nephritis Virus, a member of the Avastrovirus genus. Following on from work performed on other viruses by the Twarock group and collaborators, this studentship will examine the interactions of viral genomic RNAs with their cognate capsid proteins. For this, a variety of molecular and structural techniques will be used to generate molecular and biochemical data to inform computational modelling of the molecular processes underpinning ANV genome encapsidation, which will in turn provide new insights and experimental avenues to pursue to understand this process.

The aim of this project is to identify how environmental factors, notably oxygen tension, affect self-renewal, differentiative plasticity and epigenomic integrity of stem cells. Specifically, this question will be addressed in the context of trophoblast stem (TS) cells. TS cells are the progenitors of key placental cell types and represent the counterpart of embryonic stem (ES) cells. TS cells are of great scientific and potential clinical value. However, their plasticity may be affected by routine culture in ambient oxygen conditions while early development occurs in a low-oxygen environment. Oxygen tension may directly translate into epigenomic changes by regulating novel DNA methylation and demethylation pathways. This project will address the mechanistic aspects of how the epigenome is affected by this environmental effector, which may have important consequences on stem cell plasticity and regenerative capacity of TS cells. As such this project is at the forefront of epigenome regulation and stem cell biology with great relevance on related fields such as cancer epigenetics.