The outer surface of human skin has cells that produce a complex mixture of water insoluble lipids including cholesterol. These molecules serve a variety of functions, including producing the water-resistant barrier of skin and contributing to its antimicrobial properties by limiting the types of bacteria which can persist. One of the major groups of bacteria found on skin are members of the genus Staphylococcus, including abundant species such as S. epidermidis and S. hominis. Some species that colonise more intermittently, such as S. aureus are widely known for their association with human diseases, notably MRSA. There are still many unanswered questions regarding the success of staphylococcal colonisation of human skin and our experimental plans are aimed at increasing our understanding of skin survival mechanisms. By examining the response of the staphylococci to components of the lipid matrix, which is proposed to restrict the numbers of colonising bacteria, we have begun to question how staphylococci respond to individual lipids. The response of staphylococci to the lipid cholesterol has received little attention previously and our data leading to this application suggests it has a major effect on Staphylococcus aureus membranes. S. aureus is named after the golden colour of its colonies when grown in the laboratory and we have shown that addition of cholesterol at concentrations found on skin cause the bacterium to stop producing the pigment and become colourless. The pigment has been demonstrated to be important for membrane stability and it protects the cell from oxidising agents. The described research study will investigate the response of S. aureus to cholesterol to answer key questions: Why does cholesterol reduce the presence of the golden pigment in its membrane? What effect does cholesterol have if it does enter the S. aureus membrane? What are the consequences of not having the pigment and it is replaced by cholesterol? If we add the purified pigment to S. aureus does it have similar effects to adding cholesterol i.e. do they have similar roles? We will examine the consequences of cholesterol challenge on S. aureus membrane composition to examine if it changes. We have identified several gene mutants that have increased survival in the presence of cholesterol and we will investigate why survival is altered to help determine the effect of cholesterol on the cell. We will generate gene expression datasets from three species of staphylococci (S. epidermidis, S. hominis and S. aureus) that are know to differ in their abundance on skin and their production of membrane staphyloxanthin. The datasets that are generated will be compared to analyse cross-species similarities and differences in gene expression to build a picture of their mechanisms and responses to skin lipids. By identifying differences between staphylococci considered normal skin residents and disease-causing species, this study could generate fundamental data leading to the design of new cosmetics for underarm odour or dandruff, which are important research areas for the project partner Unilever Plc. Similarly the data could lead to target identification for future design of novel therapeutics, including antibiotics.

In order to understand living systems, biologists have taken to generating predictive models of the system, allowing them to run computational experiments that reduce the number of more traditional, lab-based experiments that would previously be necessary to gain such an understanding. This approach follows that which is now commonplace in engineering, in which, for instance, aeronautical engineers will develop sophisticated models of aircraft and test safety aspects of the proposed design in a computer, long before developing the aircraft itself (or even putting it in a wind tunnel). This biological modelling approach is named "systems biology" and has been employed successfully in a number of areas. The focus of this proposal is in modelling metabolism. Metabolism is the collection of interconnected chemical reactions that allow cells to extract energy and material from the nutrients that they consume and to grow. All free-living organisms necessarily have such metabolic systems. Thus, modelling human metabolism will allow us to understand the human body's healthy state, for instance as a function of ageing, and aid in the design of chemicals (whether nutrients or drugs) that can maintain human health. In a similar vein, metabolic modelling is also being used in the development of cell factories, which are able to produce industrially relevant chemicals, which are commonly produced by the chemical industry through more traditional means, and often involve the use of oil as a feedstock. This approach (known as fermentation or "industrial biotechnology") is not new - we have been fermenting yeast cells to produce alcohol for thousands of years - but traditional fermentation improvements, lasting decades in the case of penicillins, involved random mutation and selection, often coupled to the incorporation of harmful 'passenger' mutations. However, recent research has shown that metabolic network modelling methods provide a rational approach, both for mature fermentations and for new ones such as bio-isoprene for sustainable car tyre production. Thus, these methods have great value for the sustainable bioproduction of important substances, such as biofuels and fine chemicals. Metabolic modelling therefore has much promise for health and environmental sustainability in this coming century. However, much of the information necessary for the building of these models is held in textbooks, patents and scientific journals, and large teams of researchers are required to search for, judge and extract this information before including it in the models. Thus, the traditional development of such models currently follows (and requires) a time consuming and expensive manual process. Modern methods allow this to be automated. This process of extracting information from the literature can be greatly facilitated by the application of the methods of text mining. Text mining applies sophisticated algorithms to recognise relevant terms and sentences buried in text, and can be trained to recognise those passages of text within a large number of documents that may be relevant to a given application. In this work, we will utilise text mining to extract information necessary for the construction of metabolic network models from the large number of scientific articles that are published daily. The results of these analyses will be presented to model developers, who will judge and extract this information to develop existing metabolic models further. A specific easy-to-use web application will be developed in order to allow a multiple users to contribute towards this model building process, irrespective of their background and previous experience of computational model building. The results of this work will be more complete metabolic models, which will allow researchers to improve understanding of metabolism in a range of organisms, and therefore use this increased knowledge in applications of health and environmental sustainability.

There has been a global shift towards the use of biomass as a source of fuels and chemicals necessitated by decreasing fossil reserves, increasing oil prices, security of supply and environmental issues. It has also become clear that the manufacturing industry is embracing this change and has clearly stated its aims to develop sustainable and efficient routes to manufacturing products and hence reducing their dependence on fossil feedstocks and environmental impact. To academics, this represents a huge opportunity to generate new scientific advances in the knowledge that their application will have strong industrial support. In addition to be motivated by scientific curiosity, we scientists need to acknowledge our social responsibility to partner with the manufacturing industry to contribute to a better society and more sustainable future. Advances in the development of routes to renewable chemicals have been observed in recent years, however there are still major issues remaining regarding the efficiency and viability of these routes to deliver renewable chemicals economically. Very importantly, many recent advances in biorefinary technologies have been based on feedstocks that compete with food or feed such as starch or vegetable oils. Large-scale implementation of these technologies can have disastrous consequences for food security worldwide. Therefore, it is paramount that new biorefinary technologies are based upon sources of biomass that do not compete with food production. The overarching aim of this proposal is to develop the next generation of structured polymeric materials that will enable to efficiently produce platform chemicals and bio-surfactants from waste biomass, integrating state of the art technologies for biomass activation and separation in one-pot processes. This project is built upon the expertise in green chemistry, biomass activation, catalysis and materials science from the partners in York and Liverpool and their strong engagement with industry. State of the art facilities in high-throughput materials discovery and characterisation will be utilized, and advanced techniques in biomass activation, such as supercritical CO2 (scCO2) extraction, and microwave pyrolysis and hydrolysis reactors up to scales of 100L will be used.

The current global clinical use of nanomedicines benefits patients daily and has considerable market value; global estimates = US$75bn ('11), predicted to be $US160bn by 2015. The decision to develop new nanomedicines balances the needs of patients (are conventional medicinal approaches failing or unable to help?), type of disease/threat to health (is the disease potentially terminal?) and dosing regimes (oral or injectable administration; chronic or acute dosing?). Many therapies require long-term dosing to maintain health over prolonged periods. For example, >33 m people (incl. children) are currently living with HIV/AIDS and the optimised daily dosing (over decades) of highly active antiretroviral therapies helps to prevent progression of HIV to AIDS, and allows a life for many patients that is as close to normal as possible. In contrast, due to the acute nature of cancer (imminent threat to life) short-term interventions, including highly toxic therapies, are required for rapid cure. Cancer research has seen many nanomedicine benefits including the targeting of poorly soluble drugs to solid tumours. Similar contrasts are seen in antiepileptic and cholesterol-lowering therapies (long term health maintenance) versus systemic fungal infections or acute respiratory distress (immediate cure required). Most nanomedicines are enabled by polymer science ranging from polymer-bound drugs through to polymers stabilising drug nanoparticles or forming nanosized drug encapsulants. Nanomedicine expansion to long-term dosage forms and chronic diseases will increase and the behaviour/fate of polymeric materials in the body must be studied to generate safety and toxicology information, to increase the speed-to-clinic (ie patient benefits) and enable decision-making of pharmaceutical companies and regulatory bodies. Currently, the study of low concentrations of polymeric materials in complex environments is extremely difficult. The use of radioactive isotopes for biomedical research is well established with drugs labelled to allow rapid quantification and tracing, however, very few reports describe radiolabelled polymeric components of candidate nanomedicines and facilities for polymer radiochemistry have largely disappeared in UK Universities. The University of Liverpool has created facilities to enable radiomaterials chemistry, providing new academic UK skills and enabling pharmacological studies of polymers used in nanomedicine strategies and other applications. This 3 year programme aims to conduct the first nanomedicine studies that simultaneously monitor drug AND enabling polymeric materials, whilst exploring the synthesis of radiolabelled polymers with the most up-to-date techniques. This will place UK nanomedicine research at the forefront of understanding and provide an engagement platform for global pharmaceutical companies and regulatory bodies as the huge potential for nanomedicine is realised for patients of all ages across multiple disease areas.

The health of the skin has profound effects on both our physical and psychological well-being. Enormous academic and commercial effort is devoted to optimising the health and appearance of skin. The barrier function of skin has been widely studied, but less well studied is its role in providing enough friction to allow us to grip and manipulate objects. Excessive friction can produce undesirable skin conditions such as chaffing and irritation in many scenarios such as wearing a respiration face mask or the skin being in contact with a damp surface. Conversely reduction of skin friction can occur in old age and compound the difficulties experienced by the older population when gripping and manipulating objects. Many potential determinants of friction have been studied, including applied load, skin deformation, skin mechanical properties and surface textures and materials, but the sub-surface behaviour and skin strain has not been investigated as rigorously. Most of these parameters have been investigated statically and although it is known that they will change when the contact is dynamic no quantitative data is available for using in computer models of skin. The aim in this work will be to develop new imaging techniques to allow sub-surface observation of how skin behaves when it is sliding against an object and what influences this the most, for example, skin moisture, applied load, sliding speed etc. The contact area between skin and object will also studied in greater detail than before as this has a major effect on friction and as yet no techniques exist for characterising this in a moving contact. The objectives of the work will initially focus on developing the equipment and techniques needed to observe the surface and sub-surface behaviour. These will then be combined with skin testing apparatus to allow the measurements of friction etc. to be taken in parallel with the sub-surface images. The information from the tests and the techniques themselves will then be applied in three practical case studies to ensure real world impact for the work. The first will involve working with Philips on studying facial masks used by sleep apnea sufferers. Test data will help improve computer models of the contact between facial skin and a mask. The second will be carried out with Unilever and focus on characterising the effects of skin creams and cleansers. The final case study will be on using the new non-invasive imaging technique in clinical studies carried out by dermatologists at The University of Sheffield to replace tape-stripping methods currently used to study skin damage.