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Many diseases are caused by the faulty function of various different cell types. In order to understand what can go wrong and how it can be fixed, it is important to know as well as possible how a cell works. The fundamental problem is to understand how the 20- to 30,000 genes in a mammalian cell regulate each other. Depending on how 'active' a gene is, RNA is produced at a certain rate and will eventually be translated into proteins. Protein products of some genes can bind to DNA and regulate activity of other genes (sometimes their own), thus forming an extremely complex gene regulatory network. The interactions within this network are constantly fluctuating strongly. It is thus particularly puzzling how a cell manages to keep control in spite of this background noise. This high complexity posed an insurmountable obstacle until very recently. New developments in experimental technologies are currently revolutionizing research in biology and provide a means to address this problem. These novel technologies are largely based on remarkable advances in sequencing DNA and allow probing in parallel many factors important for gene regulation. A tremendous amount of data is produced by such experiments. This requires extensive computational analyses but makes it possible for the first time to study such a complicated regulatory network and its background noise. A better understanding of this network will provide fascinating new insights into the general molecular mechanisms that control cell function and will open up clinical perspectives for the cases where this function is defective.

Uranium, the heaviest naturally occurring element, is the main component of nuclear waste. In air, and in the environment, it forms dioxide salts called uranyl compounds, which are all based around a doubly charged, linear O=U=O group. These compounds are very soluble and are problematic environmental groundwater contaminants. The U=O bonds are also extraordinarily chemically robust and show little propensity to participate in the myriad of reactions that are characteristic of transition metal dioxide analogues which have chemical and catalytic uses in both biological and industrial environments. Due to relativistic effects, thorium, another component of nuclear waste, and a potential nuclear fuel of interest due to the lower proliferation risk, also does not have straightforward, predictable chemistry, and is a remarkably soft +4 metal ion. The behaviour of its molecular oxides is poorly understood, although tantalising glimpses of what might be possible come from gas phase studies that suggest oxo structures completely unlike the other actinyl ions. Uranium's man-made and highly radioactive neighbour neptunium forms linear O=Np=O dications like uranium, but due to the extra f-electron, shows much more oxygen atom reactivity. In nuclear waste, cation-cation complexes form with U, Np, and Pu when the oxo groups bind to another metal dioxo cation, making the behaviour of the mixtures harder to predict. However, by adding an electron to the uranyl ion, we and others have shown in recent years that the singly reduced uranyl can provide a more oxo-reactive, better model for the heavier actinyls. Since the route for precipitating uranium from groundwater involves an initial one-electron reduction to an aqueous-unstable intermediate, these stable U(V) uranyl complexes are potentially important models for understanding how uranium is precipitated. Our work to uncover actinyl ion reactivity similar to that seen in transition metal oxo chemistry has focused on using a rigid organic ligand framework to expose one of the oxygen atoms. We have most recently reported a smaller, more constrained macrocycle that can bind one or two uranium or thorium cations, so far in the lower oxidation states. This also allowed us to look at covalency in the metal-ligand and metal-metal interactions. We will use the control afforded by these two rigid ligands to make a series of actinide oxo complexes with new geometries. Some, including more chemically esoteric projects, are initially anticipated to be purely of academic interest, and an important part of researcher training. Some of the reactions will have more relevance to environmental and waste-related molecular processes, including proton, electron, and oxo group rearrangement, transfer, and abstraction. Results concerning the reactivity of these new complexes will help us better understand the more complex metal oxo systems found in nuclear wastes and the environment. We will look at hydrocarbon C-H bond cleavage by the most reactive actinide oxo complexes, working on pure hydrocarbon substrates, but recognising the relevance to the destruction of organic pollutants induced by photolysis of uranyl. Working at the EU Joint research centre for transuranic research at the ITU (Karlsruhe), we will also study the neptunium analogues of these complexes. The molecularity of these systems will also make the magnetism of mono- and bimetallic complexes easier to understand and model than solid-state compounds. The experts at the ITU will be able to identify whether the two metals communicate through a central oxo atom or even through ligand pi-systems. We will also provide samples to collaborators at the INE (institute of nuclear waste disposal), Karlsruhe and Los Alamos National Labs, USA, to obtain XAS data that allow the study of the valence orbitals, metal-metal distances/interactions (from the EXAFS) and covalency (from the ligand edge XAS).

What Works Scotland will be a collaborative centre bringing together staff from the Universities of Glasgow and Edinburgh, other academics and key non-academic partners. Its aim is to support the use of evidence to plan and deliver sustained and transformative change based on agreed outcomes at all levels with a particular focus on the local. There is a particular focus on promoting the systematic use of evidence in the design, reform and delivery of public services. Examination of what works and what does not will take place in the context of the Scottish model, an approach to policy development that, while not unique, differs considerably from elsewhere in the UK. The team has adopted a demand led and collaborative approach and will work with a range of third sector organisations, different levels of central and local government and with Community Planning Partnerships to generate an evidence culture involving feedback, improvement methodology and expert support. The Christie Commission identified a range of problems facing Scotland including demographic change, economic and fiscal challenges, inter-institutional relationships and endemic long-term 'wicked issues'. It has also been estimated that in Scotland over 40 per cent of public service expenditure is the result of preventable issues. The Scottish model of public service delivery aims to ensure that services are designed for and with communities. This 'deliberative public policy analysis' demands that communities and those who design services are aware of best practice and evidence. The Community Planning Partnerships (CPPs) are key to the delivery of these services with a focus on 'voice' through participatory, collective, decision-making, planning and delivery in the context of targets set by National Government. A key challenge for each CPP is to articulate its Single Outcome Agreement and relate this to both the outcomes set out in the National Performance Framework. However, a common criticism of the CPPs is that the implementation of the model so far has been limited and patchy. The focus of WWS will on the four key questions identified in the call: - How can we take what we know from individual projects and interventions and translate this into system-wide change? - What is working (or not working), and why, at the different levels of delivery and reform and at the interface between those levels? How do we identify actions which can be taken in communities, at CPP and the national levels to improve impact? - What does the evidence (including international) say about large-scale reform programmes that have succeeded or failed and the impact they had in a system-wide context? - Why do results vary geographically and between communities, and how can we balance local approaches with ensuring spread of what works? A wide range of methods - qualitative and qualitative - will be employed. The capabilities approach will provide the overarching framework. Originally developed by Amartya Sen, capabilities are in widespread use across the globe and underpin the work of a variety of organisations. It is a useful corrective to top down economic evaluations and fits well with the Scottish deliberative approach. We will develop the Capabilities framework and combine it with the outcomes-based National Performance Framework, ensuring that the Scottish model is intellectually grounded and contributes to broader international debates on these matters. We will have 3 workstreams: evidence into action; outcomes and capabilities; and spread, sustainability and scaling up. We will employ a range of methodologies including case studies collaborative action research, contribution analysis, elite interviews and content analysis, cost effectiveness and evaluation. WWS will focus on four case studies of key CPPS and work with them to help them change their core business processes within priority areas in four CPPs and will aim to achieve lasting impact.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Diagnosis of developmental disorders such as autism and attention deficit hyperactivity disorder (ADHD) rarely occurs prior to 3 years. Thus, there is very little known about the emergence of these disorders during infancy. It is important to identify the earliest symptoms of these conditions for three reasons: (1) as it allows us to see symptoms in their original "pure" form before a child's difficulties becomes compounded by years of atypical development, (2) it enables us to discover early risk signs suggesting the infant's development needs close monitoring, and (3) it allows us to potentially intervene in the course of development before the onset of the full syndrome - a strategy that some believe may be more effective than waiting until a disorder is fully established. This grant addresses these issues in three parts. In the first Part (A) we will expand on our current studies of infants at-risk for a later diagnosis of autism to also include infants at-risk for ADHD (by virtue of being the younger brother or sister of an older child already diagnosed with ADHD). We will compare the development of brain and cognitive functions in typical (low-risk) infants, and those at-risk for autism and ADHD, using a variety of baby-friendly methods such as MRI (Magnetic Resonance Imaging) while in natural sleep, EEG (electroencephalography), eye-tracking, and parent-infant interaction. We have chosen to compare autism and ADHD risk for several reasons. One of these is to determine how specific the early warning signs are for particular later outcomes. Another reason is that we know that there is some shared genetic risk between these disorders, and that they quite commonly co-occur in the same children. Part A is embedded within national and international collaborative networks in order to increase the number of babies studied on some key measures, and correspondingly increase our ability to detect effects. While in Part A we search for the earliest appearing markers and symptoms, in Part B we will initiate work on potential early interventions. Specifically, we will build on our recent study on improving attention skills in typical (low-risk) infants by engaging them in eye-tracker controlled "games" in which they track moving objects on a screen. We will extend this work in several ways to make the training programme more suitable as a potential intervention for infants at-risk for ADHD, e.g. by greatly extending the period of training, and by taking advantage of new technology to allow for some training sessions to take place in the infant's home. In Part C we plan a new line of basic research that can also be extended to infants at-risk in the future. While we know much about the early development of vision and auditory processing, very little research has been done on the sense of touch. Touch is important to study for many reasons, including that it is a primary mode of sensory interaction with parents. We will use several imaging methods to learn about the development of brain regions important for basic aspects of touch, social touch, and the infants emerging multi-sensory perception of its own body.

Ion imaging, first demonstrated just 25 years ago, is already having a major impact on the way we explore molecular change (the very essence of chemistry) in many gas phase systems. The technique has features in common with mass spectrometry (MS). Both start by removing an electron from the target species, generating ions, i.e. charged molecules or fragments, which are then 'sorted' by their mass. In traditional MS, the species of interest is characterised by its spectrum of ion yield versus mass. Electron removal in most ion imaging experiments is induced by a short pulse of laser light; the resulting ions are then accelerated towards a time and position sensitive detector. Heavier ions travel more slowly, so one can image ions of just one particular mass by ensuring that the detector is only 'on' at the appropriate time. The spatial pattern of ion impacts that builds up on the detector when the experiment is repeated many times is visually intuitive, and provides quantitative energetic information about the reaction(s) that yields the monitored product. However, the read out time of current ion imaging detectors is too slow to allow imaging of ions with different mass formed in the same laser shot, and many species are not readily amenable to ionisation in current ion imaging schemes. Imaging all products from a given reaction is therefore time consuming (at best) and, at worst, impossible. We seek to solve both these limitations. Two of the team have already demonstrated new, much faster, time and position sensitive sensors capable of imaging multiple masses in a single shot experiment. This multimass imaging capability will be developed further and rolled-out for use and refinement across the team. We also propose new multiphoton ionization schemes as well as 'universal' ion formation methods based on use of shorter laser wavelengths or short duration pulses of energy selected electrons. The following over-arching scientific ambitions will proceed in parallel, and exploit the foregoing advances in ion imaging technology at the earliest possible opportunity: (i) We will use the latest ion imaging methods to explore molecular change in the gas phase, focusing on key families of (photo)chemical reactions: addition, dissociation, cyclisation and ring opening reactions of organic molecules, and metal-ligand and metal-cluster interactions. These choices reflect the importance of such reactions in synthesis, catalysis, etc., their amenability to complementary high level theory, and our ability to explore the same reactions in solution (using a new ultrafast pump-probe laser spectroscopy facility). Determining the extent to which the mechanisms and energetics of reactions established through exquisitely detailed gas phase studies can inform our understanding of reactivity in the condensed phase is a current 'hot' issue in chemical science, which the team is ideally placed to address. (ii) We will develop and exploit new multi-dimensional analytical methods with combined mass, structural and spatial resolution. Mass spectra usually show many peaks attributable to fragment ions, but the paths by which these are formed are often unclear. Imaging MS is proposed as a novel means of unravelling different routes to forming a given fragment ion; distinguishing and characterising such pathways can offer new insights into, for example, peptide structure. Yet more ambitious, we propose to combine multimass and spatial map imaging with existing laser desorption/ionisation methods to enable spatially resolved compositional analysis of surfaces and of samples on surfaces. Such a capability will offer new opportunities in diverse activities like tissue imaging (e.g. detection of metal ions within tissue specimens of relevance to understanding the failure of some metal-on-metal hip implants), forensic analysis (e.g. 'chemical' imaging of fingerprints, inks, dyes, pollens, etc) and parallel mass spectrometric sampling (e.g. of blood samples).

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Organ failure and tissue loss are challenging health issues due to widespread aging population, injury, the lack of organs for transplantation and limitations of conventional artificial implants. There is a fast growing need in surgery to replace and repair soft tissues such as blood vessels, stent, trachea, skin, or even entire organs, such as bladder, kidney, heart, facial organs etc. The high demand for new artificial implants for long-term repair and substantially improved clinical outcome still remains .Our well-publicised successes in using tissue-engineering to replace hollow organs in cases of compassionate need have shown the world that an engineering approach to hollow organ replacement is feasible, as well as serving to highlight those areas where more work is required to provide bespoke manufactured tissue scaffolds for routine clinical use Being able to replicate a functional part of one's body as an exact match and therefore to be able to replace it 'as good as before' is familiar in science fiction. Most implants will share limitations that are associated with either the materials used or the traditional way in which they have been made. With the advancement of additive manufacturing technology, 3D printing, biomaterials and cell production, printing an artificial organs is becoming a science and engineering fact and understandably can save lives and enhance quality of life through surgical transplantation of such printed organs produced on-demand, specifically for the individual of interest. The project seeks to addresses the unmet need in traditional implants by exploiting our proprietary polymer nanocomposites developed at UCL and advanced digital additive manufacturing with surgical practice. we aim to develop a 3D advanced digital bio-printing system for polymer nanocomposites in order to manufacture a new-generation of synthetic soft organs 'on-demand' and bespoke to the patient's particular needs. Our extensive preclinical and on-going preclinical study on the nanocomposite-based organs will ensure the construct is able to induce angiogenesis and to perform function of an epithelium. Here we take these experiences in the compassionate case, and take trachea as an exemplar to develop a manufacturing method of producing bespoke tubular organs for transplantation with nanocomposite material. This proposal will allow us to develop; a) a customer made 3D bioprinter with multi-printing heads and an environmental chamber which can print 'live' soft organs/scaffolds with seeded cells to meet the individual patients needs; b) a series of polymer nanocomposites suitable for 3D printingorgan constructs/host scaffolds; c) a formulations of bio-inks for printing cells, proteins and biomolecules. d) a printed artificial tracheal constructs using their radiographic images with optimised biochemical, biophysical and mechanical properties. e) Establishment of in-vivo feasibility data through observation of restoration of respiratory function and normal tissue integration of pig models which will be surgically transplanted

The proposed UK Consortium on Turbulent Reacting Flows will perform high-fidelity computational simulations (i.e. Reynolds Averaged Navier-Stokes simulations (RANS), Large Eddy Simulation (LES) and Direct Numerical Simulations (DNS)) by utilising national High Performance Computing (HPC) resources to address the challenges related to energy through the fundamental physical understanding and modelling of turbulent reacting flows. Engineering applications range from the formulation of reliable fire-safety measures to the design of energy-efficient and environmentally-friendly internal combustion engines and gas turbines. The consortium will serve as a platform to collaborate and share HPC expertise within the research community and to help UK computational reacting flow research to remain internationally competitive. The proposed research of the consortium is divided into a number of broad work packages, which will be continued throughout the duration of the consortium and which will be reinforced by other Research Council and industrial grants secured by the consortium members. The consortium will also support both externally funded (e.g. EU and industrial) and internal (e.g. university PhD) projects, which do not have dedicated HPC support of their own. The consortium will not only have huge intellectual impact in terms of fundamental physical understanding and modelling of turbulent reacting flows, but will also have considerable long-term societal impact in terms of energy efficiency and environmental friendliness. Moreover, the cutting edge computational tools developed by the consortium will aid UK based manufacturers (e.g. Rolls Royce and Siemens) to design safe, reliable, energy-efficient and environmentally-friendly combustion devices to exploit the expanding world-wide energy market and boost the UK economy. Last but not least, the proposed collaborative research lays great importance on the development of highly-skilled man-power in the form of Research Associates (RAs) and PhD students of the consortium members, who in turn are expected to contribute positively to the UK economy and UK reacting flow research for many years to come.

In 2011, NERC began a scoping exercise to develop a research programme based around deep Earth controls on the habitable planet. The result of this exercise was for NERC to commit substantial funding to support a programme entitled "Volatiles, Geodynamics and Solid Earth Controls on the Habitable Planet". This proposal is a direct response to that call. It is widely and generally accepted that volatiles - in particular water - strongly affect the properties that control the flow of rocks and minerals (their rheological properties). Indeed, experiments on low-pressure minerals such as quartz and olivine show that even small amounts of water can weaken a mineral - allowing it to flow faster - by as much as several orders of magnitude. This effect is known as hydrolytic weakening, and has been used to explain a wide range of fundamental Earth questions - including the origin of plate tectonics and why Earth and Venus are different. The effect of water and volatiles on the properties of mantle rocks and minerals is a central component of this NERC research programme. Indeed it forms the basis for one of the three main questions posed by the UK academic community, and supported by a number of international experts during the scoping process. The question is "What are the feedbacks between volatile fluxes and mantle convection through time?" Intuitively, one expects feedbacks between volatiles and mantle convection. For instance, one might envisage a scenario whereby the more water is subducted into the lower mantle, the more the mantle should weaken, allowing faster convection, which in turn results in even more water passing into the lower mantle, and so on. Of course this is a simplification since faster convection cools the mantle, slowing convection, and also increases the amount of volatiles removed from the mantle at mid-ocean ridges. Nevertheless, one can imagine many important feedbacks, some of which have been examined via simple models. In particular these models indicate a feedback between volatiles and convection that controls the distribution of water between the oceans and the mantle, and the amount topography created by the vertical movement of the mantle (known as dynamic topography). The scientists involved in the scoping exercise recognized this as a major scientific question, and one having potentially far reaching consequences for the Earth's surface and habitability. However, as is discussed in detail in the proposal, our understanding of how mantle rocks deform as a function of water content is remarkably limited, and in fact the effect of water on the majority of mantle minerals has never been measured. The effect of water on the flow properties of most mantle minerals is simply inferred from experiments on low-pressure minerals (olivine, pyroxenes and quartz). As argued in the proposal, one cannot simply extrapolate between different minerals and rocks because different minerals may react quite differently to water. Moreover, current research is now calling into question even the experimental results on olivine, making the issue even more pressing. We propose, therefore, a comprehensive campaign to quantify the effect of water on the rheological properties of all the major mantle minerals and rocks using a combination of new experiments and multi-physics simulation. In conjunction with 3D mantle convection models, this information will allow us to understand how the feedback between volatiles and mantle convection impacts on problems of Earth habitability, such as how ocean volumes and large-scale dynamic topography vary over time. This research thus addresses the aims and ambitions of the research programme head on, and indeed, is required for the success of the entire programme.