University of Oxford

We are currently in the midst of a global epidemic of metabolic disease that includes obesity and type 2 diabetes. These conditions are frequently associated with fat deposition in the liver, so-called non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disease that extends from simple fat accumulation through to inflammation (non-alcoholic steatohepatitis, NASH) which can progress to fibrosis and scarring and eventually lead to cirrhosis of the liver which may require a liver transplant. In addition, it significantly increases your risk of developing primary liver cancer (hepatocellular cancer, HCC). Within 5 years, this will become the commonest cause of liver transplantation. The condition is also associated with an increased risk of heart attacks and strokes as well as problems directly related to the liver. There are currently no specific treatments that are licenced for the treatment of NAFLD and the gold-standard test to diagnose the stage and severity of the condition (liver biopsy) is associated with significant complications. As part of this proposal, we will measure natural steroid hormone metabolites in urine samples from patients with NAFLD (as identified on liver biopsy) as well as HCC to see if this can provide an alternative way to diagnose and stage the severity of the disease without the need for a liver biopsy. This approach will be compared against standard blood tests as well as scans including magnetic resonance imaging. The data that we have generated leading up to this proposal have suggested that we can very effectively diagnose the most extreme ends of the NAFLD spectrum and this has helped to identify one specific steroid metabolizing enzyme (AKR1D1) that we believe to be crucial in the progression and development of NAFLD. We have already generated a mouse model with deletion of AKR1D1 and the female mice do not put on weight with a high fat diet and are protected from diabetes. Within this proposal we will further characterize the metabolism of these animals looking at food consumption, energy expenditure as well as using different dietary regimens to replicate all the stages of NAFLD to see if they are protected from the development of NAFLD and HCC. Finally, we will also begin to develop drugs that are specific inhibitors of AKR1D1 to see if these may represent potential treatments for NAFLD and metabolic liver disease in the future.

This is a continuation of the grant ref ST/J002216/1 (UK Programme for the European Extremely Large Telescope). The continutation will cover the E-ELT Project Science work in the period 1/4/2013 - 31/3/2015. The Summary below is taken from that of the original grant. We propose a programme to enable the UK to take a leading role in the construction of the first generation of instruments for the world's largest optical and infrared telescope - the European Extremely Large Telescope. Previously funded STFC programmes have been used to develop technology and instrument concepts to put the UK in a position to take the PI role in one of the two 'first light' instruments for the E-ELT and to take significant roles in three of the instruments expected to closely follow. Strong involvement in a programme of instruments will give the UK considerable science return through direct influence on the scientific priorities of these instruments and early science through guaranteed time return to the UK. There will also be important industrial return to the UK in terms of direct contracts and technology transfer. The European Extremely Large Telescope (E-ELT) project aims to provide European astronomers with the largest optical-infrared telescope in the world. With a diameter of 42m and being fully adaptive from the start by incorporating a large deformable mirror, the E-ELT will be more than one hundred times more sensitive than the present-day largest optical telescopes. The E-ELT will vastly advance astrophysical knowledge by enabling detailed studies of planets around other stars, the first galaxies in the Universe, black holes, and the nature of the Universe's dark matter and dark energy. The E-ELT has now completed its Phase B study, led by ESO with strong involvement of European Industry, and a fully-costed construction proposal is now undergoing international review before to be put to ESO Council in December 2010. A series of instruments has gone through detailed Phase A studies with strong UK involvement. Out of this process, ESO has developed an instrument plan which has two instruments selected for 'first light' and a pool of six other instruments in competition to form a sequence in the first generation. The ESO E-ELT Science Working Group (SWG) and the Scientific and Technical Committee (STC) have both recommended that the first light complement at the E-ELT should comprise a "HARMONI-like" spectrograph (ELT-IFU) and a "MICADO-like" imager (ELT-CAM). This first light complement is part of the instrumentation plan embedded in the E-ELT construction proposal. The outcome of the ESO selection process places the UK in the unique position of being one of only two European countries leading the development of an E-ELT first light instrument. Given the enormous discovery potential of the E-ELT, this provides UK astrophysicists with an unprecedented opportunity to exploit the power of the world's largest ground based optical/near-IR telescope.

Tropical forests hold more species of plant and animal than any other kind of terrestrial environment, and store large amounts of greenhouse gases in their trees and soils. Yet most of us are aware that they are also highly threatened by human activities, with media attention often focussing on deforestation - when forests are replaced with alternative land-uses, such as agriculture and cattle ranching. However, forests are also being modified in other ways, when trees are felled for the commercial extraction of timber, or when forest burn in abnormally dry years. These events are known as forest degradation, and affect a larger area of land than deforestation alone. The widespread nature of forest degradation means it is very important to understand whether these human-modified forests are performing similar roles as intact primary forests. How much carbon and nitrogen do they hold, and are these nutrients cycled between the leaves and the forest floor at similar rates as in primary forests? Can these ecosystem processes by predicted by characteristics of the vegetation itself (such as leaf shape and format, and the rate it carries out photosynthesis). And crucially, what are the implications of these changes for the future of these forests - are they able to resist additional modification? This project will answer these questions in two separate Brazilian biomes, the Atlantic Forests of Sao Paulo and the Amazon forests near the city of Santarem. The data we collect in two years of fieldwork will be used to improve our understanding of forest functioning, and can help develop computer simulations of forests. These simulations can then be used to examine how forests may respond to changes in climate, or other human impacts such as logging or fire. These forests are also crucial for biodiversity conservation, as many rare and endemic species are only found in landscapes where forests have already been heavily modified by humans. It is important to assess to what extent they help conserve these species, and what factors could be managed to improve their conservation value. Tropical forests hold a bewildering number of species, and so many of these species are yet to be described. It is therefore important to focus on groups of species which are well known, making birds and plants are two ideal species groups. The detailed work on forest functioning will take place in a limited number of forest plots, as we are limited by the many precise measures that need to be taken over time. In contrast, biodiversity is much quicker to sample, allowing us to examine much larger areas of around one million hectares in the Amazon and in the Atlantic Forest. As well as examining biodiversity in these landscapes, this project will also assess changes in species traits, which are characteristics that link species to the many tasks they perform in nature. By doing so, we will be able to examine the extent to which human-modified forests are losing key ecosystem processes, such as pollination from long-beaked hummingbirds, or the ability of trees to assimilate and store large quantities of carbon. This will provide us with a much better idea of how the many different kinds of human activity are affecting biodiversity, which is important if we are to design landscapes that help protect the many species of conservation concern. For too long, important scientific knowledge has remained locked away in learned journals, and has failed to inform and influence policies. We are determined not to let this happen with our research, as we believe it will produce important insights that can help us preserve the ecological stability of tropical forests and the biodiversity they contain. To facilitate these impacts, we will make every effort to disseminate our findings. These activities include producing a series of short films for YouTube, linking with local schools, and writing policy briefs.

The activities of many proteins are controlled by the addition of a small highly conserved protein called ubiquitin in a process called ubiquitylation. In particular, protein ubiquitylation plays an important role in controlling cell growth and division and in neurodegeneration. In cell cycle control, key proteins that regulate the cell cycle have to be degraded in a timely fashion to ensure appropriate progression through the replicative cycle. This is done by tagging the proteins with a chain of ubiquitins, linked in a specific fashion,to target them to the proteasome. The proteasome is a multi-protein complex that degrades proteins into short peptides and amino acids. Errors in this control pathway can lead to uncontrolled cell proliferation and ultimately to cancer. In many cases, proteins also have to be destroyed because they have lost their three-dimensional structure and cannot be allowed to accumulate in the cell. This protein damage happens throughout a cell?s lifetime as a result of exposure to certain cellular stresses and chemicals. In various neurodegenerative diseases including Parkinsons there is growing evidence that some of the proteins that are responsible for tagging misfolded proteins with polyubiquitin chains to target them to the proteasome do not function appropriately. This leads to an accumulation of certain misfolded proteins and is a feature of particular degenerate neuronal cell types. Although this research does not bear directly on designing potential therapeutics, it does aim to contribute to a greater understanding of how the polyubiquitin signal is recognised and how polyubiquitylated proteins are subsequently targeted to the proteasome. Our knowledge of these signalling pathways would be greatly assisted by knowing the structures of the ubiquitin-binding proteins and of their receptors at the proteasome in molecular detail. Protein structures can be determined using the techniques of X-ray crystallography and Nuclear Magnetic Resonance spectroscopy (NMR). The aim of the proposed research is to use both these techniques to characterise the regulation of and determine structures for the proteins that control the delivery of ubiquitylated proteins to the proteasome. Ultimately we may be able to exploit this knowledge for the treatment of disease.

Seasonal influenza vaccines are widely used, requiring annual revaccination, but vaccine effectiveness has been low in recent years, especially in older adults who are more likely to experience severe or fatal disease. In the event of an influenza pandemic, a new vaccine will be required, but will not become available in significant quantities until several months after the pandemic starts. At the Jenner Institute at Oxford University we have been working on the development of novel influenza vaccines that will be effective against both seasonal and pandemic influenza viruses, including in older adults, and one of the vaccines is now in a phase II clinical trial. We are now preparing to test further improvements to the vaccine. The first version of the vaccine includes only internal antigens of the influenza virus and boosts T cell responses to them. Multiple studies have demonstrated protection against both seasonal and pandemic influenza in people who have high T cell responses to these antigens, and we have demonstrated that we can boost responses, including in older adults, by vaccination. We will now include a further antigen into the vaccines, to induce antibodies against neuraminidase, which is a protein found on the surface of the influenza virus and is less variable that haemagglutinin which is the major antigen in licensed vaccines. We will also test different routes of vaccine administration. Licensed influenza vaccines are given to adults by intramuscular injection, and are known to increase antibodies to influenza haemagglutinin in the blood. However the virus infects the respiratory tract, and it may be possible to improve protection by delivering the vaccines to the respiratory tract also. The new vaccines will be tested in pigs which have already been exposed to influenza virus, to mimic the effect of vaccinating humans. We will study the induction of immune responses to both the internal antigens and neuraminidase, as well as testing for differences in vaccine efficacy after intramuscular, upper respiratory tract or lower respiratory tract immunisation. Viral vectored influenza vaccines expressing internal antigens have been tested in humans and shown to be safe, and to significantly boost T cell responses. Adding a further antigen and changing the route of vaccine administration may prove highly beneficial in improving vaccine efficacy.