The motivation for this proposal is that the global reliance on fossil fuels is set to increase with the rapid growth of Asian economies and major discoveries of shale gas in developed nations. The strategic vision of the IDC is to develop a world-leading Centre for Industrial Doctoral Training focussed on delivering research leaders and next-generation innovators with broad economic, societal and contextual awareness, having strong technical skills and capable of operating in multi-disciplinary teams covering a range of knowledge transfer, deployment and policy roles. They will be able to analyse the overall economic context of projects and be aware of their social and ethical implications. These skills will enable them to contribute to stimulating UK-based industry to develop next-generation technologies to reduce greenhouse gas emissions from fossil fuels and ultimately improve the UK's position globally through increased jobs and exports. The Centre will involve over 50 recognised academics in carbon capture & storage (CCS) and cleaner fossil energy to provide comprehensive supervisory capacity across the theme for 70 doctoral students. It will provide an innovative training programme co-created in collaboration with our industrial partners to meet their advanced skills needs. The industrial letters of support demonstrate a strong need for the proposed Centre in terms of research to be conducted and PhDs that will be produced, with 10 new companies willing to join the proposed Centre including EDF Energy, Siemens, BOC Linde and Caterpillar, together with software companies, such as ANSYS, involved with power plant and CCS simulation. We maintain strong support from our current partners that include Doosan Babcock, Alstom Power, Air Products, the Energy Technologies Institute (ETI), Tata Steel, SSE, RWE npower, Johnson Matthey, E.ON, CPL Industries, Clean Coal Ltd and Innospec, together with the Biomass & Fossil Fuels Research Alliance (BF2RA), a grouping of companies across the power sector. Further, we have engaged SMEs, including CMCL Innovation, 2Co Energy, PSE and C-Capture, that have recently received Department of Energy and Climate Change (DECC)/Technology Strategy Board (TSB)/ETI/EC support for CCS projects. The active involvement companies have in the research projects, make an IDC the most effective form of CDT to directly contribute to the UK maintaining a strong R&D base across the fossil energy power and allied sectors and to meet the aims of the DECC CCS Roadmap in enabling industry to define projects fitting their R&D priorities. The major technical challenges over the next 10-20 years identified by our industrial partners are: (i) implementing new, more flexible and efficient fossil fuel power plant to meet peak demand as recognised by electricity market reform incentives in the Energy Bill, with efficiency improvements involving materials challenges and maximising biomass use in coal-fired plant; (ii) deploying CCS at commercial scale for near-zero emission power plant and developing cost reduction technologies which involves improving first-generation solvent-based capture processes, developing next-generation capture processes, and understanding the impact of impurities on CO2 transport and storage; (iimaximising the potential of unconventional gas, including shale gas, 'tight' gas and syngas produced from underground coal gasification; and (iii) developing technologies for vastly reduced CO2 emissions in other industrial sectors: iron and steel making, cement, refineries, domestic fuels and small-scale diesel power generatort and These challenges match closely those defined in EPSRC's Priority Area of 'CCS and cleaner fossil energy'. Further, they cover biomass firing in conventional plant defined in the Bioenergy Priority Area, where specific issues concern erosion, corrosion, slagging, fouling and overall supply chain economics.

In many tissues (epithelia, muscle, neurons), electrical or neurohormonal signals activate metabolism at times of heightened demand to ensure efficient use of resources. These cues are typically lost in cancers, but resource-efficiency remains important, particularly when oncogenic mutations instruct a programme of rapid growth that could lead to self-limiting depletion of tumour resources. Sustainable use of resources may be implemented through rationing, whereby cohorts of cancer cells take turns to engage in energy-intensive activities (e.g. biomass growth, division). We believe this explains the emergence of metabolic heterogeneity. However, time-dependent phenomena evade discovery pipelines based on steady-state measurements of gene expression, protein abundance, or metabolite levels. We developed a method for sorting cells by a surrogate of fermentative flux, as opposed to steady-state metabolite concentrations which do not predict rates. Applying this to rapidly-growing pancreatic ductal adenocarcinoma (PDAC) cells, we described a signalling cascade that alternates metabolic state between basal and activated1. Operating as a delayed negative feedback circuit (akin to pacemakers, e.g. circadian), the cascade is triggered by interleukin 6 (IL6) receptors activating STAT3, which stimulates fermentation and respiration alongside transcription of its negative regulator SOCS3. Such a system can produce metabolic rhythms independently of cell-cycling. Since it is not hardwired, a population of such metabolic oscillators maintains dynamic heterogeneity, without drifting. We propose that our mechanism rations resources for energy-efficient PDAC expansion, and that its inactivation would eventually deplete resources, i.e. have therapeutic value. This project will: Screen a panel of PDAC lines for energy-efficiency of growth using real-time measurements of fermentative/respiratory fluxes and biomass, and relate this to metabolic phenotype and its heterogeneity. We will use single-cell assays and sorting methods developed by our group. Ranking by energy-efficiency will enable correlative discovery. Verify the delayed negative feedback mechanism. Metabolic sub-populations will be tested for IL6-STAT3-SOCS3 markers and oscillator kinetics will be tracked using a fluorescent reporter of STAT3 transcriptional activity after sequential sorting. Oscillator properties will be manipulated, e.g. changes to PEST motif that affect SOCS3 degradation. Identify genetic regulators that enable resource-smart growth using a CRISPR/Cas9 screen under limited resources (closed system), relative to unlimited resources (superfused system). The effect of inactivating candidate-genes on 'resource-smart' growth will be validated using competition assays with wild-type cells. Test vulnerabilities in the rhythm-generator as a therapeutic strategy by growing mouse xenografts comprising efficiency-compromised and wild-type cells.

The aim of this proposal is to establish a standard digital code for the synthesis of molecules. Like Spotify, which allows the distribution of music in an mp3 (or similar) digital format, the development of a chemical code for synthesis will allow users to share their code as a result of the digitisation 'Chemify' process. The code will be demonstrated both manually and on basic robotic systems available in our laboratory (GU) and with our international collaborators based in the USA (MB), Canada (AAG), Germany (PS), and Poland (BG) who are experts in modular organic scaffold synthesis (MB), computational chemistry and statistics for experimental design (AAG), robotic carbohydrate synthesis (PS), and networks and rules of chemical synthesis (BG). In the long term, the ability to automate the synthesis of molecules will lower the cost of manufacture by enabling the automatic and unbiased exploration of chemical space giving a digital code. Such codes are needed if chemists are to develop systems that ensure reproducibility, and the ability to explore new reactions and statistics driven design of experiments to target unknown molecules. Recently we took a key step to encoding a multi-step synthesis into a digital blueprint,1 but the vision to go from code to molecules represents a gigantic problem. In this proposal, we will aim to develop a chemical ontology for synthetic chemistry that will lead to the first version of a programming language for chemical synthesis. We will then demonstrate the code can be used to synthesise important molecules, already robotically synthesised by us, and examples from our collaborators in the USA, Germany, Canada and Poland on the same universal 'chemputer' synthesise robot.

ChAOS will quantify the effect of changing sea ice cover on organic matter quality, benthic biodiversity, biological transformations of carbon and nutrient pools, and resulting ecosystem function at the Arctic Ocean seafloor. We will achieve this by determining the amount, source, and bioavailability of organic matter (OM) and associated nutrients exported to the Arctic seafloor; its consumption, transformation, and cycling through the benthic food chain; and its eventual burial or recycling back into the water column. We will study these coupled biological and biogeochemical processes by combining (i) a detailed study of representative Arctic shelf sea habitats that intersect the ice edge, with (ii) broad-scale in situ validation studies and shipboard experiments, (iii) manipulative laboratory experiments that will identify causal relationships and mechanisms, (iv) analyses of highly spatially and temporally resolved data obtained by the Canadian, Norwegian and German Arctic programmes to establish generality, and (v) we will integrate new understanding of controls and effects on biodiversity, biogeochemical pathways and nutrient cycles into modelling approaches to explore how changes in Arctic sea ice alter ecosystems at regional scales. We will focus on parts of the Arctic Ocean where drastic changes in sea ice cover are the main environmental control, e.g., the Barents Sea. Common fieldwork campaigns will form the core of our research activity. Although our preferred focal region is a N-S transect along 30 degree East in the Barents Sea where ice expansion and retreat are well known and safely accessible, we will also use additional cruises to locations that share similar sediment and water conditions in Norway, retrieving key species for extended laboratory experiments that consider future environmental forcing. Importantly, the design of our campaign is not site specific, allowing our approach to be applied in other areas that share similar regional characteristics. This flexibility maximizes the scope for coordinated activities between all programme consortia (pelagic or benthic) should other areas of the Arctic shelf be preferable once all responses to the Announcement of Opportunity have been evaluated. In support of our field campaign, and informed by the analysis of field samples and data obtained by our international partners (in Norway, Canada, USA, Italy, Poland and Germany), we will conduct a range of well-constrained laboratory experiments, exposing incubated natural sediment to environmental conditions that are most likely to vary in response to the changing sea ice cover, and analysing the response of biology and biogeochemistry to these induced changes in present versus future environments (e.g., ocean acidification, warming). We will use existing complementary data sets provided by international project partners to achieve a wider spatial and temporal coverage of different parts of the Arctic Ocean. The unique combination of expertise (microbiologists, geochemists, ecologists, modellers) and facilities across eight leading UK research institutions will allow us to make new links between the quantity and quality of exported OM as a food source for benthic ecosystems, the response of the biodiversity and ecosystem functioning across the full spectrum of benthic organisms, and the effects on the partitioning of carbon and nutrients between recycled and buried pools. To link the benthic sub-system to the Arctic Ocean as a whole, we will establish close links with complementary projects studying biogeochemical processes in the water column, benthic environment (and their interactions) and across the land-ocean transition. This will provide the combined data sets and process understanding, as well as novel, numerically efficient upscaling tools, required to develop predictive models (e.g., MEDUSA) that allow for a quantitative inclusion seafloor into environmental predictions of the changing Arctic Ocean.

The ocean is undergoing large scale physical, chemical and biological changes which are causing major ecosystem-scale shifts. The impact is clearly evident in shallow continental shelf waters easily accessible to local communities, the fishing industry, and scientists (e.g. increased coral reef bleaching, dwindling fish yields, blooms in nuisance algae and jellyfish). Changes in the deep sea are potentially as dramatic, with equally challenging long-term consequences (e.g. rising temperatures and lowering pH and oxygen levels) especially in the high latitudes. However, these changes are less visible to the general public and are chronically understudied given the logistical challenges of access to the deep sea. Even with increasing recognition of the intrinsic (e.g. biodiversity, blue carbon storage) and economic value (e.g. natural pharmaceuticals, heavy metal resources, fisheries nurseries) of the deep sea, there remain glaring gaps in our understanding of the resilience and vulnerability of the organisms which make up the major habitats of the deep. Particularly important in this regard are the extensive deep-sea habitats formed by calcifying corals. These corals can live for thousands of years and they form vast, diverse habitats in a surprisingly dynamic environment where food supply is controlled by falling particles from the surface and ever-changing currents. However, changes such as ocean acidification, food supply, and declining oxygen levels have the potential to reduce the ability of corals to produce their skeletons effectively. If corals were able to manipulate the composition of their skeletons to be more resilient to these changes, this would represent a key survival strategy in a rapidly changing world. Despite hints that some corals may have this ability, we do not know which taxa, or under what conditions, thus hampering effective marine conservation strategies. In this project we intend to compare three habitat-forming coral taxa which exhibit contrasting modes of skeleton growth likely to dictate their vulnerability to external stress. Scleractinia calcify aragonite and are able to the modify seawater in which they grow so that they can live in low pH waters. Octocorals form their skeletons from calcite, which is more resistant to dissolution than aragonite. Stylasterids have the capacity to form from either aragonite or calcite, and as yet it is not known how they survive in low pH waters. Surprisingly, the phylogenetic tree for these corals is very poorly constrained, making it challenging to assess the relationships between the taxa or even to identify species. Using new genomic and geochemical data, together with a systematic examination of how and where corals grow in the modern ocean, we will be in a unique position to distinguish internal biological controls of coral biomineralization from external influences. We have exceptional access to deep-sea coral collections which will allow us to build the first phylogenomic framework for understanding mineralisation and susceptibility to external pressure in environmentally-critical, habitat-forming deep-sea corals. This will help us understand which deep-sea corals may be vulnerable to current and future climate change, and what environmental parameters are required for coral growth. These data will be used to better protect vulnerable marine ecosystems in the Southern Ocean via input to the Scientific Committee for Antarctic Research which provides objective and independent scientific advice to the Antarctic Treaty Consultative Meetings.