2274747Investigating the role of interoceptive mechanisms in the development of biobehavioural markers of drug addiction.ClosedStudentshipCOVIDPsychologyThe role of interoception, the ability to sense the internal state of the body, in adaptive and maladaptive behaviour remains elusive. The purpose of the present research project, is better to understand the role of the peripheral opiate systems in interoception and its role in maladaptive behaviours, such as those observed in compulsivity, a disease model of which is drug addiction. Thus, an under-investigated characteristic of addiction is the dysfunction in interoception and the associated impairment in insight, manifested at several levels of integration of the brain, from sensory processing to emotion regulation and meta-cognition. Drug addicts display deficits in cost-benefit decision making tasks which rely on interoceptive mechanisms and its neural correlate, the insular cortex. Furthermore lesions of the insular cortex in smokers have led to an increased likelihood of cessation of smoking. In preclinical rodent models, cocaine methiodide (an analogue of cocaine that does not reach the brain) has been shown to maintain instrumental responses initially reinforced by cocaine demonstrating that the interoceptive properties of cocaine acquire reinforcing properties in individuals with a history of cocaine self-administration. Despite the compelling evidence showing that interoception and its neural substrate, the insular cortex, contribute to the development of behavioural characteristics of drug addiction, evidence is poor on the underlying molecular and cellular mechanisms. The extent to which central versus peripheral (hence interoceptive) opioidergic mechanisms of opiates contribute to the formation of interoceptive cues and development of addiction-related behaviours for opiates remains to be established. The aim of this project is to investigate the role of the peripheral opiate system in interoception and its contribution to the individual vulnerability to develop drug addiction. We will combine rodent models of drug addiction developed and refined in the Belin lab with correlational and causal interrogation of neural networks in behaving rats and post-mortem investigations of molecular correlates at the neural and circuit level. We will initially investigate if rats can discriminate heroin from a vehicle with or without the presence of a peripheral opioid antagonist in a drug discrimination task. This will indicate the role peripheral opioid receptors play in the relaying of interoceptive information of heroin. Subsequently, using a self-administration paradigm, we will test if the blockade of peripheral opioid receptors affects the reinforcing properties of heroin. This will mean pre-treating rats with injections of selective antagonists of peripheral opioid receptors and looking at their effects on acquisition of self-administration and loss of control over heroin intake. Furthermore we will employ more complex self-administration paradigms to look at facets of drug-preparatory behaviour such as compulsive seeking. Next we plan to use fibre photometry to investigate the cellular dynamics in the insular cortex during heroin-seeking behaviour; thus establishing neural correlates complementing the behavioural experiments. Furthermore, we aim to selectively manipulate neural circuits using optogenetics to functionally study the circuits and potentially investigate synaptic mechanisms. This will enable us to identify biobehavioural markers of the vulnerability to the abuse potential of drugs and better understand the role interoception plays in this process.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedEP/Y004663/2Quantum Algorithms for Nonlinear Differential Equations - QuANDiEClosedResearch GrantEPSRCSchool of EngineeringAbstracts 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.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedEP/F069103/1Stereospecific arylation of organolithiums: synthetic, mechanistic and structural investigationClosedResearch GrantEPSRCChemistryThe discovery of new small molecules for use as drugs, agrochemicals, fragrances etc. relies on the availability of simple precursors that can be incorporated into more complex target molecules. The research we propose will lead to a simple and efficient way of making some classes of molecule currently considered difficult or even impossible to obtain, a limitation which means that some groups of potential targets are currently unavailable. It seeks to develop a transformation in which an aromatic ring becomes bonded to a lithium-bearing carbon atom in such a way that the shape of the starting material is remembered in the product. The products have the common feature of a highly hindered carbon atom carrying an O, N or S substituent - a feature difficult to construct by existing methods. The proposed reactions proceed by a remarkable mechanism, and by joint investigation involving both synthetic organic and structural inorganic chemists we propose to understand why the reaction works the way it does and to use this understanding to develop further related transformations.17FABAB0-878A-49C2-8D3D-6B8F62B1A2F0Chemical synthesis10023B3EB33-7332-4E38-81A1-3B9348723526Biological & Medicinal Chem.20062ADC54-54DC-4D30-8D45-E6BCB95D1FF2Asymmetric Chemistry2035D9E755-0524-4F1F-8127-C728E8287E55Chemical Synthetic Methodology602785447Past, present and future benefits from marine biogenic shellfish reef habitats (4463)ClosedStudentshipNERCBiosciencesBiogenic shellfish reefs are complex seafloor habitats created by the presence of species such as oysters and mussels. They promote high biodiversity and provide important benefits to humans including improved water quality, food provision and cultural services such as recreational diving and fishing. These habitats were once highly abundant around the United Kingdom but were subsequently severely depleted. Because of the multiple benefits they provide to humans and marine biodiversity, biogenic reefs are of high conservation and restoration interest. However, we lack an understanding of the scale of past loss, the benefits they once provided and what benefits they could provide in the future if they were to be restored. We also need to understand who will benefit from restoration activities and what trade-offs will have to be made to keep these habitats healthy while coastal habitats continue to be heavily used. To fill these knowledge gaps, this PhD will investigate the past, present and future of ecosystem service provision in biogenic shellfish reefs at a site in the South West of England, the Fal Estuary. A case study approach will allow for in-depth analysis and practical application. It will also develop methodological approaches and generate lessons for wider research and management. This PhD will work closely with stakeholders and adopt natural and social scientific approaches to understand the implications of past loss and future regeneration of these habitats, and how the benefits and trade-offs of restoration action will be distributed across society. Supervised by experts based at the University of Exeter, Plymouth Marine Laboratory and Natural England, the student will develop a deep knowledge of the challenges facing marine managers while generating an interdisciplinary understanding of approaches to tackle these challenges head-on. Recent governmental commitments in the 25 Year Environment Plan & Fisheries Act to an ecosystem approach to management, and commitment to a Net Gain approach to biodiversity, means this project has great potential to inform policy and management for biogenic reefs. The successful student will gain the ability to delve into ecological, historical and social science approaches to gain interdisciplinary research skills that they can build on in their future careers in academia, government or industry.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedMC_PC_14099University of Dundee - Confidence in Concept 2014ClosedPartnership and ContributionMRCMRC Protein Phosphorylation and Ubiquitylation UnitAbstracts 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.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedBB/V002007/1Probing the structure and function of a super-rogue photosystem II complex involved in chlorophyll f synthesisClosedResearch GrantBBSRCLife SciencesThere is an urgent need to develop new strategies to improve crop yield to feed the ever-growing global population. Crop plants grow because they use the energy of sunlight to drive the conversion of atmospheric carbon dioxide into biomass. This process of photosynthesis is relatively inefficient with much less than 1% of the incident solar energy converted into stored chemical energy. One straightforward way to improve photosynthetic efficiency is to capture more of the sunlight in the first place. Plants rely on chlorophyll pigments (as well as some accessory pigments) to absorb light to drive photosynthesis. The chemical nature of the chlorophyll pigments found in plants necessarily means that photosynthesis is restricted to the visible region of the solar spectrum. In recent years, however, several strains of cyanobacteria, which perform plant-like photosynthesis, have been discovered that make modified forms of chlorophyll that absorb light in the far-red region of the spectrum. If these far-red chlorophylls could be made in plants and assembled correctly in the photosynthetic apparatus, the number of photons of light that could be used to drive photosynthesis could be increased by up to 19%, a considerable increase in efficiency. One of the far-red absorbing chlorophylls is chlorophyll f (Chl f). In order to make Chl f in plants, an important first step is to identify and characterise the cyanobacterial enzyme that synthesises Chl f. In a recent breakthrough, Don Bryant and colleagues in the USA showed that Chl f synthesis was dependent on the ChlF protein subunit which, somewhat surprisingly, was found to be related to one of the proteins present in the well-studied photosystem II complex which catalyses the light-driven oxidation of water to oxygen characteristic of plant photosynthesis. In follow-up work, we have discovered that ChlF does not act alone, as was originally thought, but is part of a new type of PSII complex, which we term the super-rogue PSII complex. The super-rogue PSII complex shows clear similarities to regular PSII but has evolved to make Chl f rather than split water into oxygen. Chl f is made from the Chl a pigment through an oxidation reaction involving molecular oxygen; but the chemistry involved in this process is currently unknown. In this application, we propose to study the structure and mechanism of the newly identified super-rogue PSII complex in unprecedented detail. We aim to investigate whether the super-rogue complex is photochemically active and will test the hypothesis that the super-rogue PSII complex activates molecular oxygen into a reactive form that oxidises a Chl a molecule bound to a specific site in the super-rogue PSII complex. The project involves a team of scientists with skills in microbiology, molecular biology, biochemistry and spectroscopy. Our experimental approaches are diverse and involve working on biochemically pure protein complexes as well studying cyanobacterial mutants expressing Chl f. Ultimately our studies will provide important new knowledge on a new type of photosystem II complex that will underpin future work producing Chl f in crop plants.Synthesis of chlorophyll f (Chl f) in cyanobacteria requires the expression of the ChlF subunit, a paralogue of the D1 subunit of oxygen-evolving photosystem II, but the mechanism remains unclear. In background work we have discovered that ChlF is able to substitute for D1 to form a modified PSII complex with a role in Chl f synthesis rather than water oxidation. We have named this complex the super-rogue PSII complex (or sr-PSII). We have also identified a QD sequence motif in ChlF that is important for Chl f synthesis and possibly the binding of Chl f. To clarify the role of sr-PSII in Chl f synthesis, we propose to: (1) determine the co-factor composition of the sr-PSII complex; (2) use time-resolved absorbance and fluorescence spectroscopies to characterize its photochemical activity; (3) probe the presence of the potential Chl f-binding site by monitoring changes in the optical properties of variant sr-PSII complexes in which the axial His ligand or the QD residues that are predicted to H-bond to the formyl group are mutated; (4) test the possible involvement of reactive oxygen species in Chl f synthesis (5) establish an in vitro system for Chl f synthesis using either the isolated sr-PSII complex or membranes containing sr-PSII to help assess catalytic parameters of the enzyme and (6) test whether heterologous production of Chl f is enhanced by expressing the native 'far-red' PSII subunits of Chroococcidiopsis thermalis which are known to bind Chl f. In parallel we will (7) isolate FLAG-tagged sr-PSII from C.thermalis to assess whether the native system contains additional protein components and then use mutagenesis to confirm the importance of the QD motif in the native system. Overall this work will provide new insights into the synthesis of Chl f which will be important for future work aiming to introduce Chl f into the photosynthetic apparatus of plants as a strategy to enhance photosynthetic efficiency.Understanding the details of Chl f synthesis might in the long-term lead to the development of microalgae and plants with more efficient photosynthesis, especially in far-red enriched environments, such as the lower regions of the canopy, or in dense cultures of algae. In the agricultural sector, beneficiaries could include: companies involved in modifying or selecting plants to maintain and or improve crop yields; farmers who wish to develop new practices for similar reasons; governments and policy-makers interested in developing novel strategies to achieve food security; and the public who will benefit from food security. In the biotechnology sector, beneficiaries include companies who wish to develop microalgae and other related photosynthetic organisms as solar biorefineries for the sustainable production of green chemicals and high-value products. In the bioenergy sector, beneficiaries include: companies wishing to develop alternatives to fossil fuels; governments and policy makers who are interested in new routes to energy security and for new energy sources for developing countries; the military who are looking for alternative fuels for specific and niche uses; environmentalists who need to focus on rational long-term alternatives to fossil fuels. In the environmental and ecological sector, beneficiaries include those wishing to understand more about the role of chl f-producing cyanobacteria in a changing environment. In the education sector, in museums and in the media, there will be benefits from publicising new advances in photosynthesis, one of the most fundamental biological processes and one that has been taught at secondary school and so readily familiar to the general public. Staff hired for the project will obtain training in cutting edge research in world-leading research centres. Peter Nixon and James Murray are members of the Photosynthesis Research Lab at Imperial College which includes world leading experts in Photosynthesis including Bill Rutherford FRS and Jasper van Thor, with expertise ranging from femtosecond spectroscopy to cyanobacterial physiology. The PDRA and technical staff will be in an excellent position to progress their careers. They will have the benefit of the excellent intellectual environment of a leading university with a tradition of close ties with engineers and industry.2D9083F0-05FA-4726-9EB2-3FCC293CAAF9Biomolecules & biochemistry484CCA4C04-0C28-41BE-8869-FA6391A7F005Microbial sciences2452C19A61-0A59-4643-A8D3-583E9A7F811APlant & crop science246997E843-AD07-4064-B67D-D4A928309DB4Biochemistry & physiology4819F550D7-1AE6-4B86-87B9-2C2934306C34Environmental Physiology243D51C146-5AFC-42C5-93BB-17CC751DE0DABioenergetics24BBS/E/I/00001302Role of avian dendritic cellsClosedInstitute ProjectBBSRCAbstracts 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 UK poultry industry faces many challenges to remain sustainable, including moves to more extensive rearing systems; withdrawal of antibiotics and other drugs such as anti-coccidials; resistance and residue problems with anti-helminthics. These will all impact on poultry health, but also the potential to impact on human health. Increased incidence of zoonotic pathogens in chickens, such as avian influenza, could lead to an increase in these diseases in man. One approach to these challenges is to develop novel and more effective vaccines. For this to be a realistic and sustainable approach, we need a better understanding of host-pathogen interactions in chickens. This proposal seeks to build on our unique capability to grow dendritic cells (DC) in a non-mammalian species. DC in mammals are professional antigen presenting cells, providing a link between innate and adaptive immune responses, driving the adaptive response to that necessary to clear infection with a particular pathogen. In mammals, antigen presentation takes place primarily in lymph nodes (LN). The chicken, like most non-mammalian vertebrates, lacks LN but antigen presentation still occurs. This proposal forms part of our efforts to understand antigen presentation in a species lacking LN. This proposal aims to understand DC biology in the chicken in more depth. Firstly, we wish to define the phenotype of DC, both immature DC and those matured in vitro under different conditions, in more depth. In mammals and presumably in the chicken, DC travel to the site of infection, and thence to the site of antigen presentation, under the influence of chemokines. We intend to determine which chemokines have functional effects on chicken DC. Preliminary data suggests that DC can be matured to either a Th1 or TH2 phenotype. We will determine if DC can bias T cells to a Th1 or Th2 phenotype in vitro. We then want to characterise ex vivo-isolated DC, and finally begin to analyse chicken DC migration in vivo.unavailable6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedES/I004823/1Disruption to the development of maternal sensitivity: the impact of depression and alcohol use during pregnancy on mother-infant interactions.ClosedResearch GrantESRCCommunity-Based MedicineAbstracts 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.57835945-1CF3-4554-A46B-1504261EB208Psychology10057835945-1CF3-4554-A46B-1504261EB208Psychology1002629596Development of a modelling and simulation framework to optimize layered bearing architecturesClosedStudentshipEPSRCFaculty of Engineering and the EnvironmentPlain half shell journal bearings are used in a wide range of turbomachinery shaft applications, including marine, automotive and power generation applications. These bearings have to be conformable and fatigue resistant under quite complex service loading conditions. Complex layered architectures may offer a tuneable approach to optimizing fatigue performance in terms of controlling initiation behavior and growth behavior (sometimes these two effects may play out in opposing ways). Currently a somewhat empirical approach is employed by manufacturers to identify the number, thickness and type of the different layers in the thin overlay coating. Work at Southampton University has now identified a consistent way in which to track the initiation and early stages of fatigue growth (using thermography techniques) and provided a detailed assessment of crack initiation and growth in the various layered constructions provided to date (using FIB and other advanced microscopy techniques). A follow-on PhD is now planned to apply these newly developed and validated techniques (mechanical testing, strain analysis, thermography and advanced microcopy characterization) to a systematic set of variations in overlay coating architecture (spacing, thickness, separation etc of hard and soft layers). These will be produced by the student via electroplating approaches at the sponsor company's new purpose built laboratory and they will then evaluate this systematic set of parametric explorations in terms of how this controls fatigue behavior. An important component of the PhD will be to develop and validate a materials modeling and simulation framework based on these findings to investigate optimization of the layered architecture for fatigue performance.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified2934080Investigating the Regulation and Replication of R-loops at TelomeresActiveStudentshipMRCEukaryotic chromosomes are capped at each end by specialised nucleoprotein structures called telomeres, which are mutated or altered in essentially all incidences of cancer. Telomeres are transcribed into a non-coding RNA called TERRA, which forms a three-stranded R-loop structure in which the RNA remains bound to the template. R-loops are particularly prevalent at telomeres in ALT-type cancer cells, where they are thought to prevent efficient replication of the chromosome end. This project will identify novel R-loop regulating factors at telomeres and examine how TERRA-based R-loops regulate and influence the telomere replication process.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedMR/W000830/1A CELL ATLAS OF THE DEVELOPING HUMAN SENSORY NERVOUS SYSTEM: INVESTIGATING DEVELOPMENT TO UNDERSTAND DISEASEClosedFellowshipMRCContext of the research: Pain is the main reason that diseases of the muscles and joints lead to disability. In particular, for the tens of millions of individuals who suffer from Osteoarthritis (OA) , pain can be debilitating at end stages and be present even at rest, preventing the use of joints in the hand, hip and knees. Around the world, this tremendous societal and monetary burden is set to rise alongside an aging population. Currently, there is no cure for osteoarthritis and end stage disease is treated with joint replacement, a costly and major operation. Importantly, we lack effective pain-relief medications for OA. Until recently, it was thought that wear-and-tear of the protective lining of the joint, and increased bone-to-bone contact is what leads to pain in disease. Interestingly, recent studies from various research groups have shown that new nerves sprout into the joint surface as part of the disease process of OA. These nerves appear to be present in individuals with painful OA, but is absent in those with less painful OA. In adulthood, nerves normally have limited capacity to grow, so this leads us to think that disease nerves are driven by processes similar to those that are active when we our nervous system begins to develop while an embryo in the womb. The objective of this project is therefore to apply cutting edge technology to investigate the development of the human sensory nervous, comparing it to what happens in disease, with the aim of identifying novel ways of interfering with it, in order to treat pain. Aims and objectives: First, we aim to understand how the sensory nervous system forms in the developing human. To achieve this, we will use single-cell sequencing technologies. This will allow us to detect what drives different types of developing nerves, one by one. We aim to form a classification system for these nerves, sorting them by their function, for example, some nerves may sense touch and others may sense pain, and they might be driven by different signals to grow. Secondly, we will map the distribution of these developing nerves in space, using a type of technology known as spatial transcriptomics. This will form an atlas of the nerves throughout the body and allow us to understand how nerves are queued to grow towards their destination during development. Then, we will map nerves in the diseased human osteoarthritic knee joint in adulthood. We will apply innovative technologies to first identify areas where nerves are present, and then sequence the genes activated within these areas. This will allow us to understand whether nerves growing in disease are similar or different to nerves that grow during development.Lastly, we will use computational programs to compare developmental nerves to disease-nerves. This will allow us to decide how to target the disease-nerves. Potential applications and benefits: We will be the first group to perform single-cell sequencing on the developing nervous system in human. This will allow discovery of new cell-types, and create an atlas for them throughout the human body. These findings will further our understanding of all painful conditions. In the case of osteoarthritis, it may allow us to identify targets that can be exploited to allow depletion of the pain-associated nerves described above. We aim to disseminate our findings to allow public access by the research community. This will lead to improved understanding of other diseases, such as in cancer, where nerves can also sprout during the disease process. In the long term, our findings can also be applied to help improve models of nerves grown in the laboratory, and potentially also inform ways of promoting nerves to regenerate in the body.I aim to test the hypothesis that the process of neo-innervation of the adult osteoarthritic joint by pain-associated nerve afferents recapitulates transcriptional profiles that are active in the developing human fetal sensory nervous system, with a view to obtain mechanistic insight, and identify potential therapeutic targets for pain. First, I will create the first human cell atlas (HCA) of the developing sensory nervous system. Secondly, I will identify the transcriptional profiles of adult osteoarthritic joint cartilage that is innervated by pathogenic nociceptive afferents (absent in the osteochondral junction in health). Finally, I will compare the transcriptional profiles in these states to test our hypothesis, and additionally prioritise potential treatment targets. Single-cell RNA sequencing(scRNAseq) will be applied to human dorsal root ganglia samples between the fetal ages of 6 to 20 weeks, with 1-2 sample(s) each gestational week. To create a spatial atlas, single-nuclei RNAseq and Visium RNAseq (10X genomics) will be applied to sequential slices of the same tissue sample at ages of 6-7 weeks and 18 weeks. In adult osteoarthritis tissue, multiplex in situ hybridization will be used to identify regions of interest by neuronal markers followed by the use of Nanostring GeoMx for targeted sequencing. Finally, computational integration will be applied to reveal reciprocal matches in cell states between development and disease. Potential treatment targets will be tested in further projects through in vitro and in vivo experiments. The study will create the first HCA of the developing nervous system and transcriptional profiles of disease, the findings will provide new insights into normal human development as well as disease, with therapeutic implications. The developmental dataset can also be studied to understand nerve regeneration in adulthood, with implications in regenerative medicine, and in generating in vitro models of sensory nerves.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified2775728Grey Milk and Lost Kin: Re-sounding, Re-visioning, and Re-membering Trauma in the Scottish Gypsy Traveller ArchivesClosedStudentshipAHRCResearch Management"We have no right to any form of writing, that is our curse," proclaimed a 1950s Gypsy Queen (Lecouteux 2016, p.6). This research transforms the curse of "internalised oppression" (Davis 1981) as my ancestors incite an uprising by way of the archives. My practice-based research aims to retrieve and revalue "subjugated knowledge" (Foucault 1980) through critical archival interventions, place-based approaches, experimental filmmaking and literary practices. I will interrogate the absence and rupture of 'knowing' caused by forced assimilation and cultural dispossession, exploring the sociocultural impacts of knowledge suppression and its far reaching mechanisms of denial. Grounded in lived experience, this study adds to urgent scholarly work seeking to transform the cultural ramifications of colonial legacies which actively erase Indigenous and Local knowledge systems, their cultural heritage, and collective identity. My family avoided persecution by keeping our genealogy secret and disavowing our Scottish Gypsy Traveller ancestry.From the mid twentieth century onwards, vast institutional archives were amassed in Scotland of the travelling peoples' oral traditions. Newly accessible online since the pandemic, I will subvert these archives to activate the affective, cultural and experiential injuries of "racial capitalism", drawing out the traumatic traces of invisibility and exclusion (Gordon 2008). I will then reframe and valorise the Gypsy Travellers' knowledge system, building power relations through "re-citation" with other subjugated cosmologies. Finally, I will undertake an intersectional exploration emphasising the feminist and decolonising interventions of re-sounding, re-visioning and re-remembering, mobilising solidarity and liberatory consciousness to counteract "epistemic violence" (Galván-Álvarez 2010).Thus, I will create a body of work, including film, art and audio works, that act as "a counter-archive of knowledge"-underpinned by Indigenous narrative and listening strategies (Horavoka 2017). In this way, my research will contribute to experimental sonic and cinematic techniques and methodologies, whilst generating critical pathways that pluralise knowledge systems more widely.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified2642845Medical diagnosis through the application of Artificial IntelligenceClosedStudentshipOther NPIFSchool of ComputingThis project will look at some aspect of medical diagnosis through the application of Artificial Intelligence which will be determined in more detail by the end of year one6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified1907672DNA methylation age acceleration: examining the role of socioeconomic position and dietClosedStudentshipESRCEpidemiology and Public HealthThis project proposes to investigate whether socioeconomic position is associated with DNA methylation in the MRC National Survey of Health and Development (1946 birth cohort), and whether indicators of diet might mediate any associations found.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassifiedBB/K002341/1Exploiting natural product assembly line genomics and synthetic biology for discovery and optimisation of novel agrochemicalsClosedResearch GrantBBSRCChemistryMicroorganisms including bacteria and fungi are everywhere in the environment. Although a few microorganisms have roles in causing disease, most microorganisms are harmless, and many of them actually produce medicines and chemicals useful to man. A good example is penicillin which is produced by a fungus and used as an effective antibiotic in human and animal medicine. Other compounds include anticancer drugs, drugs which allow organ transplants by suppressing the immune system and anticholesterol drugs. Many microbes also produce compounds of huge importance in agriculture which can be used as insecticides, herbicides and fungicides. It is estimated that around 40% of current world food productivity would be lost without these. As the world population grows and as climate change takes hold efficient food production and food security will become more important and the roles of these naturally occurring compounds will increase yet further. Penicillins came into use during the 1940s, and for around half a century research provided a steady stream of newly discovered natural products. However, traditional approaches began to fail as more and more compounds were discovered because the available methods kept finding the same known compounds. This led companies to try other avenues to provide new compounds for use as medicines and agrochemicals - however fully synthetic compounds have not proven as successful as natural products. Over the past decade academic research, much funded in the UK by BBSRC, but also an international effort, has led to the understanding that most microbes have the capacity to produce very many more compounds than observed - perhaps only 10% of a given organism's potential has been collected to-date. Genome sequencing has revealed that the biosynthetic potential of known organisms is huge - and new organisms are continually being found. If the 90% of unused genes in just the known organisms could be activated there could be a strong flow of new compounds for testing as medicines and agrochemicals - this flow could be increased to a flood if a generic technology could exploit all the as-yet undiscovered microbes. In parallel with the genome sequencing efforts huge progress has also been made in understanding the genes, enzymes and chemistry involved in the microbial synthesis of secondary metabolites. This now allows the pathways responsible for the synthesis of secondary metabolites in microbes to be engineered to produce yet more compounds. The confluence of cheap whole genome sequencing and the ability to engineer microbial pathways underpins this research proposal. The project will be a collaboration between 6 partners: the Challis group at Warwick, expert in microbial genome analysis; the Leadlay group at Cambridge, expert in bacterial polyketide biosynthesis; the Micklefield group in Manchester, expert in bacterial peptide production; the Cox group in Bristol expert in fungal biosynthesis; and Syngenta and Biotica, UK companies with major interest in secondary metabolites. We will obtain the genome sequences of bacteria and fungi known to produce agrochemically useful compounds. We will find the genes responsible for their production and recombine and engineer them to make higher amounts of these compounds, and then libraries of related compounds for testing. We will work with partners in the international agrochemical company Syngenta to develop these as new herbicides, insecticides and fungicides, while partners at the Biotechnology company Biotica will focus on compounds with use in human medicine. Overall we aim to develop a platform technology which can exploit the potential of microbes for the production of useful compounds for use in agriculture and medicine. We will also disseminate our results widely and undertake outreach activities to increase public awareness of industrial biotechnology and the role of genetic engineering and microbiology in ensuring future food security.This project will exploit a major opportunity which has arisen due to three factors: the dramatic lowering in cost of microbial full genome sequencing; the recent advances in rational engineering of microbial metabolic pathways; and the re-emergence of interest in natural products as new agrochemicals and drugs by international companies. The project will bring together 6 partners: the Challis group at Warwick, expert in genomics-based natural product discovery; the Leadlay group at Cambridge, expert in bacterial polyketide biosynthesis; the Micklefield group in Manchester, expert in bacterial nonribosomal peptide bioengineering; the Cox group in Bristol expert in fungal biosynthesis; and Syngenta and Biotica, UK companies with major interest in secondary metabolites. The collaboration will allow the 6 partners to embark on an ambitious programme to rapidly sequence the genomes of 40 microorganisms with the known ability to produce compounds with potential in the agrochemical arena. New bioinformatic methods will be used to rapidly identify biosynthetic gene clusters and link them to the synthesis of particular compounds. Engineering will then be employed to increase titres and activate 'silent' gene clusters with potential to produce bioactive compounds. Focussed libraries of target compounds will be made by biosynthetic engineering and the libraries used for SAR by Syngenta. Compound activity will then be maximised by a combination of biosynthetic engineering and synthetic chemistry. The partners will also engage in dissemination, training and outreach activities designed to maximise the impact of the project in the academic, industrial and public communities.Short term: The project will have high impact with the directly involved partners. For the companies involved it will allow them to gain access to and exploit the significant pool of knowledge and experience within the UK academic community in the area of biosynthetic engineering and synthetic biology. In particular this will help give Syngenta a competitive advantage and maintain their significant research and employment base in the UK. It will have a significant impact for the 4 academic groups involved because it will allow them to collaborate and disseminate best practice in complementary areas of research - this is likely to lead to more publications and publications of higher impact and thus help maintain the UK's competitivity in this area. It will help the academic groups focus their efforts on the development of new products and bring knowledge and experience from commerce into the academic arena. This in turn will enable the academic groups to form new and effective collaborations. Medium term: The research has a good likelihood of leading to the development of new products with utility in the agrochemicals sphere which will underpin improvements in food security internationally. The project will train at least 8 PDRAs and up to 4 students in the area of synthetic biology as applied to industrial biotechnology. These people will form a core of expertise which will benefit both academia and industry. Long term: The development of a platform technology for the systematic exploitation of microbes for the development of new medicines and agrochemicals will form the basis for the development of new technologies using synthetic biology. For example it is likely that similar methodology will underpin the development of new materials, new fine chemicals and processes, new methods to access biofuels and new methods to access foodstuffs.2D9083F0-05FA-4726-9EB2-3FCC293CAAF9Biomolecules & biochemistry604CCA4C04-0C28-41BE-8869-FA6391A7F005Microbial sciences406D0F40FF-D03E-4429-A764-185BC521A840Catalysis & enzymology606997E843-AD07-4064-B67D-D4A928309DB4Biochemistry & physiology40AH/G015198/1EGOR: Environmental Guidelines: Opportunities and RisksClosedResearch GrantAHRCThis research cluster will bring together a team of key professionals, academic researchers representing AHRC/EPSRC disciplines as well as heritage practitioners to appraise the costs and risks of current environmental guidelines for cultural heritage in response to a changing climate. This theme has a national and international dimension since climate change, energy consumption, visitation and pressures for greater access to collections will continue to make considerable demand on cultural heritage in the 21st century globally. The scale and pace of these changes are posing unique challenges to managing the long-term preservation of material culture and are the focus of discussion amongst professional communities both nationally and internationally.This research cluster will inform this debate.\n\nCurrent environmental parameters and tolerances set out in national and international guidelines and standards as well as Governmental Sustainable Development Targets play a critical role in shaping practices in the cultural heritage sector such as building construction, and environmental management. This includes the control of temperature, moisture, light and pollution - the main factors affecting the conservation of material culture. Environmental guidelines impact significantly on how collections are stored, accessed, loaned and displayed. \n\nEqually, the cultural heritage sector is not immune from the challenges posed by global responsibility: reducing reliance on fossil fuels, changing behaviours in favour of re-use and alternative energy sources, for example. It is within this context the appropriateness of current environmental guidelines designed to meet an agreed standard for managing material culture change, enable visitors to access and experience collections to a seasonal standard of comfort, and provide access to collections both locally and internationally is being questioned as the 'costs' of this are being realised. Unfortunately, there are no easy or headline-grabbing answers to this problem: the risks need to be identified, the costs understood, the options appraised. \n\nEGOR will provide the necessary framework to develop thinking in this area in order to realise an intellectual step change in understanding the risks and uncertainties of current environmental guidelines, standards and targets in a changing climate. Consideration will be largely focused on indoor environments, collections and the people who engage with and work in the cultural heritage arena, and will build on foundations established by other research projects e.g. Noah's Ark (EU), Engineering our Futures (EPSRC), Living with Environmental Change (NERC) largely focused on climate impacts outdoors. This will be achieved through 5 sequential activities: \n1. An inaugural meeting of the steering group which includes professional leaders, and named investigators to shape thinking and initiate cross fertilisation of ideas and perspectives;\n2. 3 working group meetings comprising specialists in art history, engineering, material science and conservation for coherent discussion, and lively debate to understand the implication for current environmental guidelines in a changing climate for people, their values and history, buildings housing collections (often historic structures themselves) and collections. The implications will be considered against a background of global responsibility.\n3. A two-day residential event will conclude this investigative process; the three working groups will present their findings, areas of convergence and divergence will be further debated to determine the risks and uncertainties surrounding environmental guidelines and standards in a changing climate, and the outstanding research needed to fully inform this debate.\n\nA summary of the challenges and user-led research emerging within this theme will be reached at the end of the meeting and presented at the Programme conference in July 2009.2693EEB1-BEF5-45C6-999E-D56488EFFAD7Cultural & museum studies10077E870DC-ED98-44DF-A0C8-06A874EB34A2Cultural Studies & Pop Culture100710397Wittos - Mobile Internet Analytics & Predictive Content Over WiFiClosedGRD Proof of ConceptInnovate UKThe increasing availability and uptake of smart mobile devices offering broadband connectivity has raised demand for a smarter in-store experience, specifically a means for bricks and mortar retailers to connect to and engage with their customers. Whilst analytics of traditional Internet user behaviour has matured, and a myriad of solutions offering insight and engagement have evolved, no comparable solutions exist to offer retailers insight into a customer's online behaviour whilst within their premises. Wittos has developed a breakthrough new solution that offers real-time actionable intelligence and awareness of the customer's in-store intentions. This technology forms the core of the Wittos platform which builds upon a traditional Wireless hotspot offering Internet connectivity. Wittos combines data gathered from the user's online activity, their physical location and path through a venue and uses this to match their actions to a behavioural profile (companion or shopper). This profile can then be matched with products of interest (their online focus) and acted upon to serve the most relevant content to user or improving their instore experience by providing real-time intelligence to staff on the floor. This reactive intelligence offers the retailer a means to increase the customer’s dwell time and increase the chance that an in-store customer transacts. This technology will offer traditional retailers a competitive advantage as relevant alternatives to their purely electronic competitors, a greatly improved in-store customer experience and the ability to match demand and supply in real-time.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified6380BFC8-096F-4D6F-8151-869D08B3288FWITTOS LTDLEAD_PARTICIPANT165589.090461.02444772Post-Translational Modifications Orchestrate Organ SymmetryClosedStudentshipBBSRCPostgraduate Research ServiceA major challenge during morphogenesis includes the establishment of symmetry types, such as radial and bilateral symmetry: a developmental commitment which greatly impacts on organ function. In humans, defects in organ-symmetry establishment leads to malformation and diseases, but despite its importance, our knowledge about symmetry foundation in multicellular organisms is very limited. Less intuitively, organ symmetry establishment is fundamental for plant survival too. Therefore, the aim of this project is to shed light on a new mechanism regulating radial and bilateral symmetry establishment during plant organogenesis, using A.thaliana as a model; investigating how a specific post-translational modifications underpins direct protein interactions between key regulators of plant organ symmetry, which in turn switches on and off gene expression, precisely and quickly, during organ development.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified2434402Random metrics on the CLE carpetClosedStudentshipEPSRCPure Maths and Mathematical StatisticsConformal loop ensembles (CLE) are random collections of loops defined in simply connected domains. They exhibit a fractal structure and arise as conjectured and proved scaling limits of a number of lattice models from Statistical Physics. Since their introduction, connections between CLE, Schramm-Loewner evolution (SLE) curves, and the Gaussian Free Field (GFF) have been shown and categorized. In this project we consider natural random metrics defined on the set of points not surrounded by CLE loops (the CLE carpet) and investigate their properties. A first goal is to build on the relationship between CLE, SLE, and the GFF to show that geodesics in a natural CLE metric are singular with respect to SLE. This disproves a conjecture from 2014 that was based on empirical results.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified750553Safe and Sound - secure and sustainable Cloud3D servicesClosedVouchersInnovate UKSafe and Sound will enable Hao2.eu to research and develop good practise standards and approaches to deliver secure and sustainable Cloud3D services which proactively anticipate and support the needs of vulnerable groups such as people with autism and learning disabilities.6CFA1E1F-F25C-4C23-8FE1-C47AE53E333EUnclassified288A0B86-D107-4599-8CC3-167C05AF1D49HADWEBUTKNOWN LIMITEDLEAD_PARTICIPANT5000.05000.0