Cells are enveloped by a membrane barrier composed of lipids and proteins that keep useful materials inside the cell and exclude harmful, toxic compounds from entering. Some of the proteins that residue in the membrane have evolved to function as transport machines, shuttling essential nutrients into the cell and exporting waste products. Understanding how these transport proteins (transporters) function is of major biotechnological and medical significance, as many of these proteins function abnormally in diseases such as cancer, which require cells to take up many more nutrients than surrounding tissue. Proteins adopt a variety of different states which enable them to carry out their specific tasks in cells. However, to date the biomedical science community has largely focused their efforts on determining the three-dimensional structure of transporters using the well-established technique of X-ray protein crystallography. The structures represent static snapshots but fail to provide information on the dynamics of these proteins. Our research project aims at addressing a major conceptual gap in the field, by understanding the dynamics of transport and how lipids present in the membrane impact on the structure and function of transporters. We will use the latest techniques in biological spectroscopy to map out the variety of structural states adopted by an important family of nutrient transporters responsible for the uptake of peptides into the cell. Our methodology will be to label these proteins at selected positions and to measure the distance between the labels in native lipid environments. Using the crystal structures we have already obtained, and new ones to be resolved here, we will measure the changes in these distances as the proteins move peptides across the membrane. We will be able to model the structural changes taking place during function, to understand in much more detail how nutrients and small molecules can be selectively transported into the cell for further use in metabolism and cell function. This work has significant implications for not only metabolic processes, especially in disease conditions, of which there are many, but also in the use of these proteins to deliver drugs into a cell as well as use these proteins in biotechnological ways to allow cells to make selected compounds for use in industry and pharamacology, which are long term aims.

The bodily fluids of the mammalian organism are in a constant state of flux. Even in the absence of challenges such as dehydration, haemorrhage or starvation, salt and water are constantly being lost as a consequence of normal, obligatory renal excretory functions, and by the processes of respiration and perspiration. The body has two mechanisms that function to control the consumption and the excretion of water and salt, in order to maintain the optimal bodily content required for good health. The first mechanism involves the production by a part of the brain paraventricular nucleus (PVN) of a hormone called vasopressin that tells the kidney to conserve water. The second mechanism is behavioural, and involves the instincts of thirst and salt appetite that emotionally drive the organism to correct its fluid balance. These mechanisms can go wrong resulting in ill-health. For example, disorders of fluid balance are evident in a substantial proportion of elderly patients admitted to hospital, and dehydration is a frequent cause of morbidity and mortality in old people. An age-related decline in the response to a variety of dehydrating challenges has been reported in humans, and this seems to involve a reduction in thirst and salt appetite, as well as dysregulation of vasopressin production. Another way that disorders of fluid balance can affect wellbeing is as a consequence of an excessive intake of dietary sodium, which is associated with the development of several chronic degenerative diseases, such as cardiovascular disorders, including hypertension. These medical conditions, which are becoming more prevalent as a result of increased life expectancy, progressively decrease life quality and increase the need for medical and social assistance. Epidemiological and experimental studies have suggested that events occurring in utero and during lactation can result in long-term consequences in adult life. Interestingly, both excessive salt intake and dehydration during pregnancy provoke increased salt appetite in adult offspring, which may then impact on long-term health and wellbeing. We have recently produced exciting new evidence that suggests that the PVN is not only involved in the production of vasopressin, but also has a central role in generating the instincts that control the consumption of salt. We thus hypothesise: i) that the PVN integrates hormonal and behavioural responses to salt and imbalance. ii) that these integrative functions are perturbed in old age, resulting in decreased thirst perception, reduced sodium appetite, and altered activity of AVP neurones. iii) that these integrative functions are perturbed by foetal exposure to high salt, resulting in a reprogramming of the set point for adult salt consumption. Or aims are now to decipher the molecular mechanisms by which the PVN controls behavioural (thirst and sodium appetite) and hormonal (AVP synthesis and secretion) mechanisms of salt and water homeostasis. Further, we will find out how these mechanisms go wrong in old age and following foetal programming.

Brazil

Rare earth elements (REE) are the headline of the critical metals security of supply agenda. All the REE were defined as critical by the European Union in 2010, and in subsequent analysis in 2014. Similar projects in the UK and USA have highlighted 'heavy' REE (HREE - europium through to lutetium) as the metals most likely to be at risk of supply disruption and in short supply in the near future. The REE are ubiquitous within modern technologies, including computers and low energy lighting, energy storage devices, large wind turbines and smart materials, making their supply vital to UK society. The challenge is to develop new environmentally friendly and economically viable, neodymium (Nd) and HREE deposits so that use of REE in new and green technologies can continue to expand. The principal aims of this project are to understand the mobility and concentration of Nd and HREE in natural systems and to investigate new processes that will lower the environmental impact of REE extraction and recovery. By concentrating on the critical REE, the research will be wide ranging in the deposits and processing techniques considered. It gives NERC and the UK a world-leading research consortium on critical REE, concentrating on deposit types identified in the catalyst phase as most likely to have low environmental impact, and on research that bridges the two goals of the SoS programme. The project brings together two groups from the preceding catalyst projects (GEM-CRE, MM-FREE) to form a new interdisciplinary team, including the UK's leading experts in REE geology and metallurgy, together with materials science, high/low temperature fluid geochemistry, computational simulation/mineral physics, geomicrobiology and bioprocessing. The team brings substantial background IP and the key skills required. The research responds to the needs of industry partners and involves substantive international collaboration as well as a wider international and UK network across the REE value chain. The work programme has two strands. The first centres on conventional deposits, which comprise all of the REE mines outside China and the majority of active exploration and development projects. The aim is to make a step change in the understanding of the mobility of REE in these natural deposits via mineralogical analysis, experiments and computational simulation. Then, based on this research, the aim is to optimise the most relevant extraction methods. The second strand looks to the future to develop a sustainable new method of REE extraction. The focus will be the ion adsorption deposits, which could be exploited with the lowest environmental impact of any of the main ore types using a well-controlled in-situ leaching operation. Impact will be immediate through our industry partners engaged in REE exploration and development projects, who will gain improved deposit models and better and more efficient, and therefore more environmentally friendly, extraction techniques. There will be wider benefits for researchers in other international teams and companies as we publish our results. Security of REE supply is a major international issue and the challenges tackled in this research will be relevant to practically all REE deposits. Despite the UK not having world class REE deposits itself, the economy is reliant on REE (e.g. the functional materials and devices industry is worth ~£3 Bn p.a.) and therefore the UK must lead research into the extraction process. Manufacturers who use REE will also benefit from the research by receiving up to date information on prospects for future Nd and HREE supply. This will help plan their longer term product development, as well as shorter term purchasing strategy. Likewise, the results will be useful to inform national and European level policy and to interest, entertain and educate the wider community about the natural characters and importance of the REE.