• 2013-2022close
• UK Research and Innovation close
• 2014 close
• 2017 close

Mechanical ventilation in the intensive care unit (ICU) is often a life-saving intervention for patients suffering from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). However, in recent years, it has become clear that mechanical ventilation can exacerbate lung damage and may even be the primary factor in lung injury e.g. ventilator-induced lung injury (VILI) and ventilator associated pneumonia (VAP). Consequently, lung protective ventilation (LPV) strategies have been developed, including positive end expiratory pressure (PEEP) and high frequency oscillatory ventilation (HFOV). Despite the use of LPV, the mortality associated with ARDS and ALI is still great, with reported rates between 33 and 55%. Thoracic electrical impedance tomography (EIT) has emerged as a promising new imaging tool for bedside use. It is a non-invasive technique which provides the internal conductivity distribution based on electrical measurements on the skin. Existing research and commercial EIT systems have typically arranged measurement electrodes in rings around the thorax and produced two-dimensional image slices based on over-simplified two-dimensional generic shapes e.g. circular or elliptical cross-sections. Unfortunately, such an approach creates significant image artefacts and poor levels of repeatability. In order to eliminate this problem, EIT measurements and image reconstruction must be treated as a fully three-dimensional problem, taking into account the electrode positions and the body shape of the patient. One of the aims of this project is to provide reliable and robust three-dimensional EIT image reconstruction based on 3D informed body shape acquired from other modalities such as magnetic resonance imaging (MRI) and x-ray computed tomography. Currently, there exists no consensus amongst clinicians on how to optimize PEEP ventilator settings. Improved knowledge about the distribution of ventilation will enable clinicians to set more appropriate ventilation parameters in order to reduce the potential occurrence of VILI. In particular, the value of bedside EIT monitoring for determining the effect of PEEP in comparison with traditional indirect methods, such as arterial oxygenation or global tidal volumes, is still largely unknown. Additionally, despite the clear link between lung mechanics and regional ventilation, ventilator settings are normally based on blood gases and pressure-volume curves rather than measurements of lung mechanics. A significant aim of this project is to provide clinicians with robust image-based lung mechanics models which will further aid the validation of EIT in the ICU. Previous clinical EIT studies have generally utilized EIT instruments operating at relatively slow frame rates, inflexible drive and measurement strategies along with limited number of electrodes. In this project, we will develop a state-of-the-art fast 3D EIT system using advanced measurement techniques which have not yet had a significant impact in the clinical environment. In fact, there has never been a substantial investigation of EIT in the ICU which has drawn together the unique combination of high quality EIT measurements, three-dimensional image reconstruction and the validation of lung mechanics modelling. We propose to establish a world-leading capability in the measurement and imaging by EIT in the ICU. This project builds upon the substantial expertise in EIT at the University of Manchester (UoM) and the UK's leading clinical group in applied thoracic EIT at Kings College London and Guy's and St Thomas' NHS Trust. We will also build upon the world-leading capability at UoM in modelling and dynamic MRI acquisition including oxygen-enhanced and dynamic contrast-enhanced MRI. The proposed project registers strongly on the EPSRC research theme of healthcare technologies.

Delivering sustainable food production in the face of climate change with reduced fertilizer and pesticide input requires a revolution in crop improvement. Meanwhile, modern crops are becoming increasingly depleted in gene biodiversity. Extending crop biodiversity and supporting future crop improvements can be achieved by 'mining' allelic variants of genes from ancestral wild germplasm. Novel strategies to utilize multi-parental breeding populations and apply the genomics revolution offer a promising route towards exploitation of exotic germplasm for breeding. We will test both approaches using wild barley (Hordeum vulgare ssp. spontaneum) as a model to improve agronomic performance of cultivated barley under abiotic and biotic stress conditions. For this, we will explore a nested association mapping (NAM) approach using the first cereal NAM population HEB-25 ('Halle Exotic Barley') to simultaneously test 25 wild barley accessions for beneficial gene effects. HEB-25 consists of 1,420 BC1S3 lines, each of which carrying ca. 25% of wild barley genome from one of 25 exotic donors on a 75% genetic background of the recipient spring barley cultivar Barke. First, the HEB-25 lines will be assessed for allele content, employing state-of-the-art Exome Capture with Next Generation Sequencing (EC-Seq) to discover single nucleotide polymorphisms (SNP) for 21,643 genes in each of the 1,420 HEB-25 lines. We expect to map roughly 400,000 SNPs, giving several SNPs per gene with the goal to distinguish any wild barley allele from the recipient Barke allele. Second, the HEB-25 lines will be cultivated in field trials in Germany, Scotland and Israel, to assess phenotypic stress performance under either nitrogen deficiency, drought or pathogen attack. Morphologic, agronomic, and nutrient content traits will be scored, as well as resistances against the important barley diseases leaf rust, yellow rust and net blotch. In addition, agronomic performance will be modeled in Israel by up-to-date remote sensing technology, to establish non-invasive phenotype prediction models. Third, the collected data sets will be archived and further processed in a central data warehouse at Halle, built around a custom web-accessible relational database, enabling universal access to the project outputs. Fourth, the resulting genotypic and phenotypic data sets will be combined in a Genome-Wide Association Scan (GWAS) to identify wild barley alleles that improve plant performance under stress. Because the gene resolution is extremely high this study will yield individual high confidence candidate alleles that putatively regulate the studied traits. Fifth, to validate the identified trait-improving exotic alleles in follow up studies, high-resolution offspring populations derived from the originally studied HEB-25 lines will be developed in Halle by backcrossing. The expected outcome of the BARLEY-NAM project will be beneficial in two directions. On one hand, the molecular regulation of new HEB properties will be studied in detail using the developed backcross lines. On the other hand, trait improving exotic alleles will be used in future breeding programs. This will ultimately lead to new elite barley cultivars with improved properties and, simultaneously, extend the biodiversity of our modern elite barley gene pool due to the incorporation of wild barley germplasm.

In recent years it has become clear that there are many more lymphocytes resident in non-lymphoid tissues than previously thought and that tissue resident cells may be crucial for protection against pathogens, but many questions remain to be resolved. For example: 1. What is the importance of local versus systemic immunity in different infections and species? 2. Does protection of a host animal also prevent transmission? 3. How a correct balance of local and systemic protective immunity best be induced and maintained in different diseases? 4. What is the role of the innate immune system and signals from pathogen associated molecular patterns in initiating protection? 5. How does the microbiota of the host influence development of systemic and local immunity? We shall ask these questions initially in pigs using influenza virus as a model. We shall use different routes of infection and methods of immunisation to establish the hallmarks of protective local and systemic immune responses. Using different vaccine vectors, adjuvants and formulations, we shall dissect the essential innate and adaptive components of a protective response. Furthermore we shall determine whether these hallmarks are reflected in prevention of transmission. Using antibiotic treatment, diet or administration of defined commensal organisms, we shall manipulate the microbiota and define their effect on protective immune responses. The mechanisms will be further analysed in mouse transgenic or homologous recombinant (knockout) models. These studies will help us understand the role of local and systemic immunity in protection against pathogens and to identify in which circumstances it will be essential to recruit local immunity to achieve successful protective immunity by vaccination

This research seeks to answer the question: To what extent do education and peacebuilding interventions in the two countries promote teacher agency and capacity to build peace and reduce inequalities? The proposed study is anchored within the third of the overarching questions of this call, and aimed at understanding the conditions under which education interventions focused on teachers can promote peace, and mitigate and reduce violence with a view to identifying measures and processes that can increase the effectiveness of such programmes in conflict-affected situations. The research seeks to critically evaluate a series of programme interventions aimed at improving and enhancing the peacebuilding role of teachers through a multi-scalar, mixed method study that seeks to link the everyday practices of teachers in conflict affected contexts with the local, national and global actors and factors that shape their practices and behaviour. South Africa and Rwanda have been selected because both countries have emerged peacefully out of intense and violent conflict in the 1990s and now have two decades of postconflict experience to draw from. Secondly, they have been important sites for a range of postconflict interventions in the education sector, and in particular on teacher related interventions. Thirdly, they allow for a comparison of similar interventions across two countries which have since 1994 has put in place important policy interventions to promote peace and social cohesion which warrant close scrutiny. Fourthly, both countries enable examination of the complex interrelationship between inequality and peace and social cohesion in education. The overarching aim of the study is to identify elements of education policy interventions that have enabled teachers to become active agents of peacebuilding in postconflict countries and that may inform future interventions. These objectives will be achieved through an empirically grounded evaluation of the nature, implementation, and impact of large-scale interventions that are designed to support teachers as peace-builders in schools in postconflict contexts. We will look at specifically at interventions focusing on teachers, found in both South Africa and Rwanda, including interventions related to 1) Teacher training 2) Teacher recruitment, deployment and management 3) Teacher performance and practices 4) Curriculum and textbook reform. Research will include a political economy analysis of the context of these interventions in each country in order to critically embed the research in the local context, and will draw upon a realist evaluation approach (Pawson, 2005) which seeks to understand the underpinning programme theory of each of the interventions, as well as the challenges and outcomes. Research will also include a global mapping of peacebuilding interventions aimed at teachers, interviews and focus groups with key stakeholders in each country, and detailed classroom observations in three key sites in each country. The research is linked to, and supported by, a UNICEF 4 year $160 million Education, Peacebuilding and Advocacy Programme (2012-2016), which will ensure its relevance, influence and impact in practitioner, policy and academic domains. It will feed into debates related to the role of education in peacebuilding with the opportunity to both improve the quality of UNICEF 's and international agencies' peacebuilding and education programmes and to influence a broader United Nations debate on education's place in postconflict peacebuilding interventions. The research team comprises an internationally diverse and interdisciplinary team of experts from the UK, South Africa, and Rwanda with expertise in teacher education, peacebuilding and conflict studies. The research team will work closely with UNICEF in order to maximise, local, national and global impact and build knowledge and capacity in this important field

Walking (or cycling) around an area helps people to keep physically active in their daily life, reducing the risks of obesity and depression. Streets that are pleasant to walk along also provide opportunities for people to meet and chat with friends and acquaintances. This both enhances the quality of life and is good for health. Busy roads can deter people from going outside their home to socialise, walk or cycle because of noise or fear of injury. This can also lead to people deciding to avoid making trips, particularly if the alternative to crossing a busy road (e.g. an underpass) increases distances or is considered inaccessible, unsafe or unpleasant. People living on streets with heavy traffic know fewer neighbours and have fewer local friends than people living on streets with less traffic; people with fewer social contacts have worse physical and mental health and die younger. When people do not even try to cross roads because of traffic, they often cannot reach shops, health facilities, services, friends or family easily. This is called community severance (CS). All these effects are worse in older and other vulnerable groups, for whom mobility and social ties are fundamental to good health. This severance increases social inequalities and exclusion, leading to various economic and social costs. CS probably affects people's physical and mental health and wellbeing too, but this has not been studied very much. Studying health effects of community severance is challenging, as there are no agreed measurement methods that can be used easily and because this is a complex subject, crossing several areas of expertise. We will first study two residential areas to develop an in-depth understanding and measure of CS. We will ask local residents what is important to them. We will observe what happens in practice when older people try to walk around their neighbourhood. We will consider all this information in the context of the whole area, the levels and composition of road traffic and the way streets connect to each other. We will use the information we collect to develop ways to measure CS in three ways: (i) questions to individuals to assess the effects on them, (ii) how they value these impacts, and (iii) a measuring tool to estimate the extent of community severance due to particular types of roads or road layouts. We will then test these tools in two different residential areas. The main methods we will use are: community engagement, to explore perceptions and measures of CS and potential solutions; household-based surveys of travel behaviour, social networks, health and wellbeing; computerised surveys to elicit residents' values for severance and mitigation; on-street surveys of travel behaviour; measurement of traffic and road characteristics; space syntax methods, to study how the network of streets affect accessibility and mobility; and analyses integrating these discipline-specific methods. The final stage will be to test the impacts on CS - and thus on mobility and wellbeing - of proposed interventions to reduce CS. By the end of this project, we will have developed and tested three tools. The first two will be for local government to use, to model and to value levels of CS in their area. The third will be a set of questions that can be asked in surveys to find out whether and how severance affects local people. The survey can then be used by local communities, providing information they can use in discussions with local councillors and staff. The tools can be used by local government to test proposed transport policies, development plans and interventions to assess whether they will affect severance. They can also be used by researchers to find out whether and how CS affects people's mobility, social isolation, and short- and long-term health and wellbeing. The survey can also be used in national surveys so that a more complete picture of this problem is obtained across the UK.

The West Antarctic Ice Sheet contains over 2.2 million cubic kilometers of ice, which if it all melted would raise global sea level by about 5 metres. Over the last few decades West Antarctica has experienced a significant warming. Air temperatures have increased across the surface of the ice sheet, but in addition warmer ocean currents have been melting the ice sheet where it reaches the ocean. The net result has been that some of the ice flowing down to the coast of West Antarctica has been accelerating and thinning so that the coastal area of West Antarctica is now contributing almost 10% to the current rise in global sea level. The climate of West Antarctica is strongly influenced by the storms over the Southern Ocean between the Antarctic Peninsula and the Ross Sea which force warm, maritime air across the ice sheet. There are a large number of storms in this area of the Southern Ocean which are collectively called the Amundsen Sea Low. This is a highly variable feature and is influenced by the ozone 'hole' and climatic conditions across the tropical Pacific Ocean. It is extremely important to know how the climate of West Antarctica will change over the coming century so that we can produce accurate estimates of sea level rise. However, the only tools we have to predict the future are computer models that simulate the atmosphere, ocean and ice across the Earth. These models run as part of initiatives such as the Intergovernmental Panel on Climate Change have a relatively coarse spatial resolution of about 200 km, which is not sufficient to accurately resolve the complex mountainous terrain of areas such as the coast of West Antarctica. For this project we will run a model with a resolution of 10 km through the 21st century to create the most detailed information yet produced of how temperature, snowfall and wind speed/direction will change as greenhouse gas concentrations increase and the ozone hole recovers. Such data will be of value to those modelling the West Antarctic Ice Sheet and enable the production of better predictions of how the ice sheet will change over the coming century and the contribution it will make to sea level rise.

The human immune system plays a vital role in protecting our bodies from disease. It is a complex combination of specialized cells and proteins that recognize and kill bacteria and viruses. It is also extremely effective in recognizing and eliminating normal cells that may be sick or damaged. A key protein that we all have in our blood is called serum amyloid P component (SAP). A closely related protein (CRP) is better known as an inflammatory marker that is routinely tested by doctors in blood samples of patients with suspected infection or inflammation. Much research has been performed to understand the role of SAP in numerous diseases especially protein folding conditions (such as systemic amyloidosis), and amyloid-related diseases that principally affect the brain, such as Creutzfeld-Jacob disease (CJD) and Alzheimer's, however we know very little about the normal function of SAP. A major discovery was that SAP binds to DNA - the component of our cells that contains our genetic information. However, because SAP is normally found in our blood rather than inside cells where the DNA is normally located, it is believed that SAP scavenges DNA that is released into our blood from diseased or damaged cells. This is of critical importance, because it prevents the immune system from attacking our normal DNA, which can have disastrous consequences (such as in the disease systemic lupus erythematosus (SLE)). As well as binding to DNA, the applicant and others have shown that SAP binds to a number of important targets including RNA - another critically important molecule normally found in our cells. Other important binding targets of SAP include bacteria, the extracellular matrix (a supporting scaffold for cells and tissues) and a wide range of immune proteins and cells. The full significance of these other interactions is yet to be determined. The aim of this project is to determine how SAP binds to DNA at the molecular level. The applicant has successfully performed preliminary experiments making initial mutants of SAP in collaboration with the Oxford Protein Production Facility (OPPF). Now, in pilot studies with colleagues in Portsmouth who are experts in DNA-protein interactions, the applicant has determined how tightly SAP binds to DNA sequences and, for the first time, to RNA. We are poised to identify the sections of SAP responsible for binding to the various targets by mutating parts of the SAP molecule. This fundamental research work will help us understand various human conditions linked to ageing. Furthermore, by understanding more about how this protein works, we can determine whether it is a suitable drug target for diseases such as Alzheimer's, SLE and rheumatoid arthritis. Perhaps even more exciting is the possibility that by acting as a DNA scavenger, SAP prevents DNA vaccination working in humans. By understanding more about how SAP recognizes DNA, this work could significantly contribute towards the development of new and safer vaccines.

Marek's disease virus (MDV) is an oncogenic avian herpesvirus that induces malignant T-cell lymphomas and neurological disorders in its natural host, chicken. Although tropism for the central nervous systems is consistently associated with highly virulent MDV strains, the mechanism of MDV-mediated neuropathology is still poorly understood. For the first time, phosphoprotein-14 (pp14), an immediate early protein from MDV1, has been identified as a neurovirulence factor. Furthermore, cAMP Response Element-Binding protein 3 (CREB3) has been identified as a cellular ligand for pp14 through which the viral protein may mediate the neurovirulence. CREB3 is a membrane-bound transcription factor that has recently been shown to be activated in response to DNA and RNA viral infections. Although transcription factors of the CREB3 subfamily are understood to be activated through regulated intra-membrane proteolysis (RIP) the physiological stimuli for proteolytic activation of discrete transcription factors in the CREB3 subfamily and their physiological targets remain to be identified and characterised. The aim of this project is to use a combination of biochemical, reverse genetic and structural approaches to derive new knowledge in pp14-CREB3-mediated neurovirulence.

Many inherent problems need to be overcome if we are to approach an energy framework that is both clean and sustainable. Although progress is being made, it is likely that solutions will rely on new concepts in the design of materials rather than improvements to existing materials. This view provides the rationale behind the proposed research: based on preliminary exciting findings, we will extend our studies of a class of materials with unique structural features that have never been fully exploited - nor even fully explored. The research focuses on a mineral, schafarzikite, and our preliminary studies have been directed towards introducing functionality to provide useful properties. This proposal emanates from two highly exciting findings: 1) we have been able to insert anions into channels within the schafarzikite framework; 2) we have discovered a schafarzikite material that contains a low-dimensional copper oxide framework that is ferromagnetic. The first discovery suggests that this structure could make an important contribution to aspects of energy storage, both for new electrode materials and new electrolytes. It is our objective to characterise fully these new materials and screen them for use as advanced materials in these areas. This programme, and possible subsequent commercialisation, will be assisted by a collaboration with Johnson Matthey. The second research finding is of academic interest because ferromagnetic oxides are quite rare. However, added interest attaches to the fact that low dimensional copper oxides provided the basis for the High-Tc superoconducting materials that superconduct at temperatures up to 133 K. However, all these materials have antiferromagnetic parent phases, and this antiferromagnetism is likely to be inportant in the superconductivity mechanism. The chemical manipulation of this particular material to introduce electronic conductivity is therefore a major objective of the programme. We are not aware of any studies that relate to elecronic conduction in copper oxide materials with an inherent ferromagnetic ground state. Materials with the perovskite structure have been studied extensively and their properties have resulted in applications in many areas, including electrodes and electrolytes in electrochemical devices. Although structurally very different from perovskites, functionalising their properties is conceptually similar to that which can be achieved for the perovskite system: cation substitutions at one site can be used to tune the functional properties at the other. However, there has been very little previous research that has focused on this structure. We will therefore be vigilant to recognise other new features that are likely to become apparent during the programme but are not included in the specific targets above. The synthetic aspects of the programme of work will be informed by predictions of suitable chemical targets that have been determined by theoretical calculations relating to the stabilities of possible chemical compositions.

Phosphorus is a key nutrient for plants and needs to be added as fertiliser to facilitate efficient and economic production of agricultural crops. There is no general soil test which can reliably predict how much fertiliser should be added for optimal crop growth. If too much is added it is costly and phosphate can leak into lakes and rivers, causing severe pollution problems known as eutrophication. If too little is added crop yields are poor and uneconomic. The situation is critical because world reserves of usable phosphorus are limited. Liming soils, which generally benefits acidic soils by improving nutrient availability to plants may further complicate the phosphate problem by locking up part of the phosphate so that it cannot be used by plants. A new analytical technique called DGT, which mimics the way that phosphorus in the soil interacts with the plant, provides a good prediction of how much phosphate fertiliser should be added for optimal plant growth. The phosphorus accumulated by DGT during the placement of the DGT device in the soil has until now been measured in the laboratory using conventional procedures, but a new handheld XRF device that can provide an instant readout has become available. This project will first establish that DGT with analysis by portable XRF can used to measure the phosphorus in soils that is available to plants. It will compare the new measurement with established chemical tests and investigate how well it can be used to predict fertiliser requirements for two crop types (a brassica crop and a legume) grown in a range of soils. In a set of experiments where soils are limed, the new method will be used to advance understanding of how liming affects phosphorus availability to plants and of how liming is likely to affect the release of phosphorus to water bodies (due to leaching from the crop rootzone). This work will inform strategies for applying phosphate fertiliser and lime and provide a basis for providing farmers with a fairly rapid and, more importantly, reliable tool for assessing fertiliser requirements. The outcome of the work will provide clear economic benefits to farmers. Environmental gains stemming from reduced loss of phosphorus from agricultural soils into watercourses will benefit the general public and government agencies concerned with the environment, and in some cases water companies by limiting the costs of removing P from drinking water.