With increasing recognition of the importance of insects, there are growing concerns that insect biodiversity has declined globally, with serious consequences for ecosystem function and services. Yet, gaps in knowledge limit progress in understanding the magnitude and direction of change. Information about insect trends is fragmented, and time-series data are restricted and unrepresentative, both taxonomically and spatially. Moreover, causal links between insect trends and anthropogenic pressures are not well-established. It is, therefore, difficult to evaluate stories about "insectageddon", to understand the ecosystem consequences, to devise mitigation strategies, or predict future trends. To address the shortfalls, we will bring together diverse sources of information, such as meta-analyses, correlative relationships and expert judgement. GLiTRS will collate these diverse lines of evidence on how insect biodiversity has changed in response to anthropogenic pressures, how responses vary according to functional traits, over space, and across biodiversity metrics (e.g. species abundance, occupancy, richness and biomass), and how insect trends drive further changes (e.g. mediated by interaction networks). We will integrate these lines of evidence into a Threat-Response model describing trends in insect biodiversity across the globe. The model will be represented in the form of a series of probabilistic statements (a Bayesian belief network) describing relationships between insect biodiversity and anthropogenic pressures. By challenging this "Threat-Response model" to predict trends for taxa and places where high-quality time series data exist, we will identify insect groups and regions for which indirect data sources are a) sufficient for predicting recent trends, b) inadequate, or c) too uncertain. Knowledge about the predictability of threat-response relationships will allow projections - with uncertainty estimates - of how insect biodiversity has changed globally, across all major taxa, functional groups and biomes. This global perspective on recent trends will provide the basis for an exploration of the consequences of insect decline for a range of ecosystem functions and services, as well as how biodiversity and ecosystem properties might be affected by plausible scenarios of future environmental change. GLiTRS is an ambitious and innovative research program: two features are particularly ground-breaking. First, the collation of multiple forms of evidence will permit a truly global perspective on insect declines that is unachievable using conventional approaches. Second, by validating "prior knowledge" (from evidence synthesis) with recent trends, we will assess the degree to which insect declines are predictable, and at what scales.

After fertilization, a single zygote proceeds through a series of cleavage steps to develop into a multicellular embryo, called a blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in a dish as pluripotent embryonic stem cells (ESCs). ESCs have become invaluable tools in regenerative medicine and to study development itself. With 1 in 8 couples experiencing infertility in the UK, it is ever more important to understand the factors contributing to healthy embryo development. Transposable elements (TEs) are parts of our DNA that are currently or historically mobile, -i.e. having the capacity to 'paste' themselves into new places in the genome. Many TE sequences used to be thought of as simply 'junk DNA'; however, we are beginning to understand that TEs have evolved to play new and unexpected roles in development and disease. For example, uncontrolled TE activity has been implicated in neurodegeneration and cancer. However, the expression of many TEs is also high in normal development, suggesting that they may also have beneficial roles in cells. This proposal focuses on exploring the function and regulation of a particular TE, called mouse endogenous retrovirus type L, MERVL. MERVL is the earliest expressed TE, and is transiently upregulated in mouse embryos at the 2-cell stage. This stage, conserved in human in 4-8 cell embryos, encompasses an essential process called Zygotic Genome Activation, when the embryo begins to turn on its own genes for the first time. These embryos are also considered "totipotent", meaning that they can not only generate embryonic tissues but also extra-embryonic tissues (like placenta). Interestingly, a small proportion of ESCs transiently become "2C-like" in normal culture, also possessing enhanced developmental potency. Here, we will use mouse ESCs and mouse embryos to investigate how and why MERVL regulation is important in early development. Using these tools, we will identify and characterize key factors required to activate and repress MERVL. In turn, we will investigate how these factors regulate the 2-cell stage, and affect ZGA and totipotency. To understand how MERVL and other TEs are directly regulated, we will combine genome-editing systems, called CRISPR/Cas9, with recent biochemical tools to pull out sets of proteins that bind MERVL. Lastly, we will explore the conservation of MERVL function and regulation in human cells, where a similar TE, HERVL, is known to play a conserved role. We aim to a) understand how HERVL regulates the 4-8 cell stage and human ZGA b) investigate how new HERVL regulators might contribute to specific cases of disease. These studies will significantly increase our understanding of how TEs contribute to early development, and will shed insight on how such processes are perturbed in disease.

Ice melting and sea level rise caused by climatic change in turn cause large-scale redistribution of surface water mass. Such large-scale water mass movements alter the Earth's gravity field and deform the Earth's surface, such that the Earth essentially weighs the water load. Measurements of the Earth's gravity field and surface deformation can therefore place constraints on large scale movements of water mass. Conventional hydrological experiments do not have the global coverage to constrain such large-scale water movements, whereas satellite measurements are far better placed in this regard. Despite this, measurement at the largest spatial scales has proved problematic, for example; long term changes in the inter-hemispheric component of this mass motion are as yet unmeasured and present a considerable gap in knowledge. Without this knowledge making accurate measurements of sea level rise will prove difficult. Here we propose to infer large scale water mass movements over the past two decades by developing an integrated observation model using gravity measurements from GRACE and SLR, and measurements of the Earth's shape from GPS. In addition, our results will improve the realisation of the Terrestrial Reference Frame used throughout the Earth Sciences and in particular for altimetric and tide gauge estimates of sea level rise.

In the UK and globally, we are beset by two long-term pandemics: ageing, and metabolic disease. Both are astronomically harmful and costly. As average ages increase, disease prevalence rises, with projected healthcare costs in $trillions. At the same time, one in three adults are now overweight or obese, and recent headlines have highlighted studies predicting 1.3bn diabetic adults by 2050. The devastating health impacts and staggering financial costs provide a very strong motivation to understand the causes of metabolic disease, and how we can promote healthy ageing. Gut microbiota are linked to both metabolic disease and ageing. We see the same effects of microbiota across animals, suggesting causes in fundamental biology. Thus, understanding the biology of host-microbiota interactions in animal models may help us to both fight metabolic disease and promote healthy ageing in humans. Ageing and metabolism are whole-organism processes. The fact that microbiota alter these processes, despite being physically confined to the gut lumen, suggests that microbes exert "remote control" - altering systemic function through long-distance molecular cross-talk. The molecules in play are likely to be hormones and metabolites released from the gut into circulation. We are studying these molecules in fruitflies, which share many aspects of biology with other animals, including humans. Advantages of working in flies are that we have extraordinary control of the microbiota, diet, and the fly's function, allowing us to study mechanisms that occur across animals precisely and rapidly; generating predictions that we expect to generalise across species. We have made two breakthroughs in the first phase of this project. First, we have generated an atlas of metabolic changes that specific microbiota induce in specific tissues, which has indicated regulation of compounds that play fundamental roles throughout animals. Second, we have identified a specific hormone - tachykinin - modulated by specific bacteria, specifically in the gut, which we think signals to a specific receptor in the fly brain. Knocking down this circuit makes flies constitutively long-lived and even dramatically reverses the impact of microbiota on fat storage, indicating a central role as a mediator of microbial effects on ageing and metabolism. This hormone is conserved in humans, and drugs targeting its receptor are already licenced, suggesting we may be able to translate our findings. In the renewal of this project, I will combine both established and new methods to test conclusively whether a tachykinin relay from gut to brain mediates impacts of microbiota on ageing and metabolism. I will use cutting edge technologies to identify specific populations of cells in the fly brain where the tachykinin receptor responds to presence of gut bacteria, depending on gut expression of tachykinin hormone. Finally I will build on my experience of studying ageing and metabolism to investigate how microbiota alters mortality through tachykinin, and how tachykinin appears to induce a metabolic switch in how fat metabolism responds to gut bacteria. This information will lay the foundation for a long-term, large-scale, multi-model research program, characterising biology so fundamental that we anticipate we can target it to promote human health.