There is immense interest at present in targeting the action of a class of compounds, termed cannabinoids, in the treatment of obesity and metabolic-related disorders. Cannabinoids are present in cannabis, but our bodies naturally create cannabinoid-like chemicals, known as endocannabinoids that lock-on to protein molecules found on the surface of cells called cannabinoid receptors (i.e. CB1 and CB2). During obesity, diabetes and, as we have recently discovered, during ageing the CB1 is notably over-activated by endocannabinoids produced by the body resulting in impaired insulin action and dysregulation of energy balance in metabolically important tissues such as muscle, fat and liver. CB1 over-activation has been linked strongly with development of insulin resistance and increased adiposity. In contrast, emerging data indicates that CB2 may confer a protective physiological effect. In line with this idea, we find that CB2 inhibitors (antagonists) augment the insulin-desensitising effects of the endocannabinoid, anandamide (AEA) in muscle cells, whereas CB2 activators (agonists) ameliorate the loss in insulin signalling. Moreover, it is noteworthy that whilst CB1 expression is enhanced in ageing muscle that of CB2 is significantly decreased, consistent with the reduced insulin sensitivity that prevails in ageing skeletal muscle. Intriguingly, CB1 antagonists (e.g. rimonabant) promote glucose tolerance, stimulate energy expenditure and reduce body weight in obese animals by mechanisms independent of their appetite-reducing effect. Consistent with such findings, we find rimonabant ameliorates age-related tissue insulin resistance and fat mass gain in older animals. Precisely how CB1 antagonism elicits these beneficial effects is unclear, but our recent work indicates that CB1 blockade induces activation of AMPK - a molecule that not only senses cellular energy but promotes the breakdown and burning of fat in mitochondria (the cell's energy factory). The molecular events linking CB1 blockade to AMPK activation and the effect of the latter on enzymes involved in fat breakdown/burning and mitochondrial dynamics remain poorly understood. The proposed studies will utilise cultured muscle and fat cells to understand how CB1 inhibition or CB2 activation impacts upon molecules implicated in insulin action, energy balance and mitochondrial function and integrity. Our molecular analyses will involve biochemical and state-of-the-art imaging techniques for visualising mitochondrial staining in muscle and fat cells. These cell-based studies will be complemented with analysis of tissues from young and old mice genetically deficient in CB2 or experiments in young and aged mice administered a pharmacologically active dose of a CB1 antagonist or CB2 agonist for two weeks. During this period we will monitor food intake, glucose tolerance, energy expenditure, physical activity and fat mass before sampling blood/tissue for experimental analyses designed to dissect the mechanisms by which CB1 blockade or CB2 activation improves the metabolic status of aged animals. We also aim to test the effects of exercise in aged animals given that physical activity is known to help sustain tissue sensitivity to anabolic hormones such as insulin and preserve tissue functionality during aging. These studies will help unveil whether exercise curtails age-related changes in tissue CB1 and CB2 expression and, if so, whether these correlate favourably with measures of whole body energetics (i.e. body fat, glucose tolerance and energy expenditure). The proposed research will specifically expand our fundamental understanding of how modulating peripheral CB receptor activity influences energy balance and insulin action. The findings that will emerge will advance our knowledge of these key issues and prove invaluable in designing therapies that selectively target the peripheral ECS for treatment of age and obesity-related metabolic disorders.

From mystical experiences brought about through trance or psychedelic drug use, to film fantasies such as The Matrix, Avatar and Surrogates people have long been fascinated with the idea of projecting the self outside of the body, or into a different body, or even into a radically different world. In history and in literature, such an experience is often described as a life-transforming event-through transcending corporal limits, or leaving your own body entirely, perhaps to temporarily inhabit another, you might come to see and understand yourself in new and more enlightened ways. With the development of next generation virtual reality and telepresence technologies, the possibility of experiencing the world from a point-of-view other than that from behind our own eyes is becoming a possibility for all of us. Fully immersive technologies, through which you have the compelling feeling of being in another place or body, are on the near horizon, and scientists and technologists are everyday discovering new ways to directly manipulate your experience of where, what, or even who, you are. As more-and-more people devote time and energy to life in virtual or 'cyber' realities-with different degrees of immersion-our cyberselves, the people who we become in these virtual worlds, could become as important to us as our 'real' selves. Since the technologies are advancing so rapidly, there has been little time to consider the transformative effects that widespread access to deep and prolonged immersion could have on people, their relationships, and our societies (both real and virtual); for example, the idea that the virtual world is less 'authentic' than the physical one is being challenged by people for whom their cyber-relationships are more important than those happening in 'real' life. The "Cyberselves in Immersive Technologies" project considers it imperative that we examine the transforming impact of immersive technologies on our societies and cultures. To do so effectively, a multi-disciplinary approach is required that embraces methods from both the humanities and sciences. Our project includes philosophers and cultural theorists, working alongside psychologists, technologists, and cognitive scientists. We seek to explore and understand the notion of immersion both in its historical and cultural contexts, and in the 'here and now'-examining how immersive technology operates and how it effects our brains on bodies. We plan to draw from these analyses conclusions about the cultural perception and likely social impact of this technology near- and long-term. Our project will involve experimental studies using a virtual reality environment, and the comparison of immersion in this virtual world with that of experiencing the real world through telepresence (remote presence) interfaces to an advanced humanoid robot. We will use state-of-the-art motion capture, virtual reality and robotics equipment already operating at the Sheffield Centre for Robotics and the University of Pompeu Fabra, Barcelona to explore objective and subjective aspects of the immersive experience and to understand how our conceptions of our bodies may be transformed by such experience. By collaborating across disciplines and by combining this approach with cultural and ethical analyses we expect to (i) generate an improved understanding of the cultural, historical and ideological constructions around the notion of virtual reality and the projected self; (ii) transform the way that cognitive scientists investigate immersive and virtual reality technologies as a way of discovering more about the nature of the self; (iii) identify critical cultural anxieties and future societal challenges raised by immersive technologies; and (iv) promote a scientifically- and culturally- informed debate about the potential benefits and risks of living more of our lives as cyberselves.

New World primates live in the tropical regions of Central and South America, and include such well-known and charismatic species as spider monkeys, howler monkeys, marmosets and capuchins. Today, there are more than 170 species known in five families, which collectively exhibit a broad range of different body sizes, diets and activity. Remarkably, all this diversity originated from a single common ancestor that reached South America from Africa 35-45 million years ago, probably by being transported over sea on a raft of vegetation. Why and how did this ancestor give rise to all the varied species that make up modern New World primate radiation? What were the drivers leading to the diversification of the different families? Were abiotic factors like changes in climate, the uplift of the Andes mountains, and the development of the Amazon river, or were biotic factors (competition with other mammals) more important in driving diversification? Can we identify when and why there were changes in body size, diet and activity pattern in different New World primate groups? Our proposed project will attempt to answer these questions. To do so, we will combine two very different, but complementary, types of data: genomic data, which provides detailed information on living species, and fossil data, which provides (often very incomplete) information on past diversity. Previous studies have usually used either genomic data or fossil data, but ours will combine the two, to take advantage of their different strengths and to compensate for each other's weaknesses. Firstly, we will examine the genomes of different New World primate species to see if we can identify genes relating to traits like diet, body size and activity pattern. By doing so, we will be able to infer how these traits have changed through time in the different New World primate groups. Secondly we will produce a new evolutionary tree (phylogeny) of all the living New World primate species, using large amounts of genomic data and sophisticated methods to produce the most complete and accurate phylogeny of the group, and we will use "molecular clocks" to infer divergence times for when different lineages split from one another. With our new phylogeny and divergence times, we will examine how the rate of diversification has varied through time, and whether very high or low rates of diversification coincide with periods of environmental change. We will also identify previously unrecognised species and reassess the taxonomy of all known species. This information will be key to conservation efforts, by helping identify the species most in need of protection to conserve maximum biodiversity. Thirdly, we will use data from the fossil record to model how living and extinct lineages of New World primates have diversified through time. This data can be compared with the pattern of diversification indicated by the phylogeny of living New World primates, to see if they are broadly similar. If they show major differences, this suggests that extinction has played a key role in New World primate evolution. We will also use the fossil record to test the hypothesis that New World primates outcompeted superficially "primate-like" mammals (actually, relatives of modern marsupials) that were already present in South America when the New World primate ancestor arrived from Africa. Our project will massively increase our understanding of New World primate evolution, shed new light on diversification and evolutionary processes in general, and help identify those New World primates most vulnerable to extinction. In doing so our findings will be of interest to a wide range of scientists, including evolutionary biologists, genomicists, ecologists and palaeontologists. Because our project, by rigorously clarifying NWP species numbers and boundaries, our results will also have broader practical utility for conservation practitioners and policy makers in governmental and non-governmental agencies.

In this project we will investigate how to make sense from sound data, focussing on how to convert these recordings into understandable and actionable information: specifically how to allow people to search, browse and interact with sounds. Increasing quantities of sound data are now being gathered in archives such as sound and audiovisual archives, through sound sensors such as city soundscape monitoring and as soundtracks on user-generated content. For example, the British Library (BL) Sound Archive has over a million discs and thousands of tapes; the BBC has some 1 million hours of digitized content; smart cities such as Santander (Spain) and Assen (Netherlands) are beginning to wire themselves up with a large number of distributed sensors; and 100 hours of video (with sound) are uploaded you YouTube every minute. However, the ability to understand and interact with all this sound data is hampered by a lack of tools allowing people to "make sense of sounds" based on the audio content. For example, in a sound map, users may be able to search for sound clips by geographical location, but not by "similar sounds". In broadcast archives, users must typically know which programme to look for, and listen through to find the section they need. Manually-entered textual metadata may allow text-based searching, but these typically only refer to the entire clip or programme, can often be ambiguous, and are hard to scale to large datasets. In addition, browsing sound data collections is a time-consuming process: without the help of e.g. key frame images available from video clips, each sound clip has to be "auditioned" (listened to) to find what is needed, and where the point of interest can be found. Radio programme producers currently have to train themselves to listen to audio clips at up to double speed to save time in the production process. Clearly better tools are needed. To do this, we will investigate and develop new signal processing methods to analyse sound and audiovisual files, new interaction methods to search and browse through sets of sound files, and new methods to explore and understand the criteria searchers use when searching, selecting and interacting with sounds. The perceptual aspect will also investigate people's emotional response to sounds and soundscapes, assisting sound designers or producers to find audio samples with the effect they want to create, and informing the development of public policy on urban soundscapes and their impact on people. There are a wide range of potential beneficiaries for the research and tools that will be produced in this project, including both professional users and the general public. Archivists who are digitizing content into sound and audiovisual archives will benefit from new ways to visualize and tag archive material. Radio or television programme makers will benefit from new ways to search through recorded programme material and databases of sound effects to reuse, and new tools to visualize and repurpose archive material once identified. Sound artists and musicians will benefit from new ways to find interesting sound objects, or collections of sounds, for them to use as part of compositions or installations. Educators will benefit from new ways to find material on particular topics (machines, wildlife) based on their sound properties rather than metadata. Urban planners and policy makers will benefit from new tools to understand the urban sound environment, and people living in those urban environments will benefit through improved city sound policies and better designed soundscapes, making the urban environment more pleasant. For the general public, many people are now building their own archives of recordings, in the form of videos with soundtracks, and may in future include photographs with associated sounds (audiophotographs). This research will help people make sense of the sounds that surround us, and the associations and memories that they bring.

The question - whether we should think of the world as consisting of entities statically defined by essential properties (i.e. in philosophical jargon, "substances"), or as processes, that undergo and persist precisely because of change - is a fundamental metaphysical dichotomy, debated since the pre-Socratics. Since the rise of atomism in the seventeenth century the substance view has dominated scientifically grounded philosophy. John Dupré's ERC-funded project, A Process Ontology for Contemporary Biology, develops the thesis that for biology, at least, this has been a profound mistake (Dupré 2012: Nicholson and Dupré, in press). Dupré argues that living systems are always dynamic at multiple spatial and temporal scales and their persistence, far from being merely the continued possession of essential properties, is the result of the finely articulated interplay of multiple processes. Visual representation is essential both to the practice and the communication of science. However, whereas drawing in the past played a central role in fields such as morphology and embryology, the rise of photographic and digital technologies and the growing emphasis on molecules as opposed to whole organisms have increasingly marginalized drawing practices. A serious problem faced in the development of a fully processual biology is that most visual representation strongly suggests a realm of static things. For example, the presentation of an organism will be of a particular developmental 'stage', typically the mature adult, which confounds the fact that this is a momentary temporal stage of the developmental process. Even where representation of something as plainly dynamic as metabolism, for example, will include arrows representing time, the natural reading will be of transitions between a fixed array of things (instances of chemical kinds). Moreover, while visual images or 'visual explanations' (Tufte 1997) in science depend on a variety of graphic devices ranging from the use of video, and photography to the use of computational graphic software, simulation and hand-drawing, these means of making images largely depend on mechanistic models (for, or of, their objects) which are already intertwined with their methods of production. The decline of drawing in scientific practice is epitomised by Wakefield's research field, cell division and mitosis. Whereas 20 years ago, as a PhD student, his learning was centred around direct participation, through microscope-based observation and drawing of cells, his own PhD students are now further removed, watching 2D representations of cells on computer screens and printing out screen-shots. For the last 5 years, his interest in this distinction has grown, leading to an exploratory collaboration with the PI and, through this application, the Co-I. Anderson's work over a number of years has highlighted the epistemic costs of the decline of graphic skills in the Life Sciences. She has researched the ways in which scientists have used drawing as a way of developing deep insights into their subject matters, and in her own practice, under the rubric of 'Isomorphology', she has developed classificatory methods that highlight formal parallels cutting across the traditional boundaries of animal, mineral and vegetable. This work has been carried out in collaboration with a variety of scientists and museum curators and has resulted in residencies, exhibitions, talks and workshops.Building on the Isomorphology project, her more recent work, guided in part by extensive discussions with Dupré, has begun to explore ways of representing biological process, under the new rubric of Isomorphogenesis. In line with the growing interest in process-centred understandings of biology, the present project will address the need for novel image-making practices to provide more intuitively dynamic representations of living systems through an innovative collaboration between art, biology and philosophy.