Medical diagnosis and the resulting treatment will improve the results significantly when a more personalized system for health assessment is implemented. This can be achieved by providing detailed information about the metabolic status of individuals. The use of metabolomic data to predict the health trajectories of individuals will require bioinformatic tools and quantitative reference databases. For example protein phosphorylation is probably the most important regulatory event in eukaryotes. Many enzymes and receptors are switched 'on' or 'off' by phosphorylation and dephosphorylation. Antibodies can be used as powerful tools to detect whether a protein is phosphorylated at any particular site. Such antibodies are called phospho-specific antibodies; hundreds of such antibodies are now available. They are becoming critical reagents both for basic research and for clinical diagnosis. Approaches to identify and more importantly quantify phosphorylated proteins, like mass spectrometry-based proteomics, are becoming increasingly important for the systematic analysis of complex phosphorylation networks. However, most of them lack the ability to identify the phosphorylation status rapidly and accurately. Furthermore, other post translational modification such as sulphurylation and the redox status of translational proteins and selenoproteins could give vital information about the metabolic status of an individual. Two challenges lie ahead for the bioanalytical community; the separation of the complex mixtures of metabolites, peptides and proteins and their quantitative determination. Most methods can only cover one of the challenges. Here, with this proposal, we seek funding to complete the world-wide unique set-up the SCOttish Trace element Speciation & Metabolomics Analytical Network (SCOTSMAN), a new combination of chromatography and/or electrophoresis and dual mass spectrometry to develop a rapid separation technique which is capable of online identification and quantification of metabolites and proteins which have been labelled or tagged in a complex matrix of organic compounds which do not contain an hetero-element. Hence, this method is able to pick out the needles in the haystack. This set-up will be able to quantify biomolecules containing a hetero-element such as phosphorous or sulphur or metals and metalloids such as copper, selenium and arsenic. Using element-specific detection coupled with high resolution mass separation, the requested instrument is capable of quantifying the compounds at ultra-trace level which is relevant for background studies and non diseased individuals. Since the instrument response is not dependant on the compound itself, it can be used to quantify the element in the introduced sample without having the exact compound as a standard. If that analyser is now coupled to a separation method online, the unambiguous quantification of the compound carrying the tag or label can be done directly. When identification of certain metabolites is of importance, the second complementary molecular mass analyser (already in place) will provide accurate data on the mass of the molecule simultaneously. This information is vital to deduce molecular formula. Altogether this proposal, supported by the manufacturer and a charity organisation has an extremely good add on value, since the requested instrument will be coupled directly with additional complementary mass analyser with similar calibre to built this unique analytical set-up for biologists, plant physiologists, microbiologists, researcher interested in systems biology and pharmacologists.

New analytical capabilities enabling the analysis of smaller amounts of material lead directly to the development of new avenues of research in earth and environmental science. In-situ techniques such as laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and secondary ion mass spectrometry (SIMS) allow small amounts of material to be analysed (c.1-5ng) directly without the blank contribution from processing reagents which limit traditional dissolution-based methodologies. However, for materials of small size and/or low concentrations of analyte, the signal:noise ratio (SNR) limits the precision of the analysis. This dictates analysis of larger amounts of material to achieve the required precision, even for sensitive in-situ techniques. We intend to develop ground breaking laser ablation acquisition and data handling methods to routinely achieve higher SNR's and enhance precision. These methods will be applied to picogram-nanogram quantities of material, depending on the application. To demonstrate this capability, our primary application will be the uranium isotopic characterization of 1micron uranium oxide (UOx) particles for nuclear forensic investigations. This is an internationally important application with a pressing need to characterize individual micron-sized uranium particles collected during international monitoring operations. Isotope ratios from nuclear materials reveal details about their processing, origin, and purpose. Different degrees of enrichment from natural compositions (238U/235U = 137.88) are required for nuclear power (238U/235U to c.33) and nuclear weapons (238U/235U c. 1) whilst only minimal (c.0.13%) fractionation occurs in nature. Enrichment processes also produce equally disparate 236U/238U ratios. Uranium isotope ratios can therefore successfully fingerprint the source and ultimate origins of contaminant UOx particles. The challenge is therefore to analyse uranium isotope ratios from individual fine particles. Other techniques such as: alpha and gamma-ray spectrometry, fission-track, conventional thermal ionisation mass spectrometry (TIMS), SIMS and conventional solution multi-collector(MC-)ICP-MS, are either too time consuming and/or expensive, have low precision and/or resolution, or suffer from significant potential background and blank level limitations or interferences. Laser ablation MC-ICP-MS offers a potential solution for all applications requiring the analysis of low amounts of analyte, but only if new methodologies, such as those described here are developed. This proposal details how accurate quantification of isotope ratios in 1micron particles will be achieved using new analytical techniques such as laser ablation in liquid (LASIL), micro-volume ablation cell and torch technology, single pulse acquisition and total signal integration (TSI) data processing techniques. All these methods enhance SNR's and improve spatial resolution in mapping. LASIL combines the sampling benefits of LA with the SNR enhancement of solution mode analysis and offers the exciting possibility of in-drop single-bead post-ablation clean up and accumulation of material (where adequate sample is available) in a single drop to achieve a measureable concentration. The appropriate combination of all these approaches has the potential to successfully analyse 1micron particles and dramatically improve the spatial resolution and utility of LA-ICP-MS applied to environmental sciences. The student will benefit from training at NIGL, a world-class isotope geoscience laboratory, and integration at Loughborough, one of the UK's largest analytical science centres and one specialized in LA-ICP-MS science. The student will attend relevant modules of the MSc programme in Analytical Chemistry and Environmental Science at the University and participate in the graduate school training programme in transferrable and professional skills, also benefiting from annual reporting and progression vivas.

The performance and applications of advanced materials, such as aeroengine turbine blade materials, which need to operate at very high temperatures to achieve high efficiency; new energy materials such as thermal energy storage materials, lithium ion battery materials and next generation battery materials; and healthcare materials, are largely controlled by their microstructures which cover a wide range of length scales from nanometres to millimetres. To exploit existing materials and to develop new materials requires high resolution (so that very fine details can be identified), multi-scale characterisation of the microstructures (so that heterogeneous structure can be revealed) in three dimensions (3D). Developing our capability in materials characterisation is one of the most important areas for materials science and engineering. There are a range of existing 3D materials characterisation techniques including atom probe tomography, transmission electron tomography, FIB slicing and view, X-ray tomography. However there is a noticeable gap, from about 100 um to 1 mm, where current existing techniques are not able to characterise within a practical time frame. This proposal is to develop a unique multi-scale, high-resolution, tri-beam facility for fast machining and 3D characterisation. This new facility will have a femto-second laser beam, a multi-species plasma beam and a high-resolution electron beam. The femto-second laser is able to machine materials 15000 times faster than a conventional FIB. The multi-species ion plasma beam will enable the machining of a wide diversity of materials including materials for healthcare technology applications, energy materials and also aerospace materials. Alongside other detectors, the electron beam will enable high-resolution analysis of the materials prepared by the laser and plasma beams. Therefore the new facility will enable the characterisation of the chemistry, crystallography, morphology and other functional properties of materials from 100 um to 1 mm currently challenging for other characterisation techniques. The integration of a glovebox will facilitate the handling and characterisation of air-sensitive materials including battery materials. Importantly, the inert transfer device will allow transfer of materials from this instrument to other characterisation facilities such as transmission electron microscope where even higher resolution analysis can be performed. This instrument will revolutionise the materials characterisation capability and capacity in the UK leading to accelerated advanced materials and manufacturing development in many important fields including battery materials, aerospace material, energy storage, 3D printing and bio-medical materials.

Zeolites and carbons are rigid sorbents which form the basis of large industries. Metal-organic frameworks have properties complementary to these classical systems. The proposal team have demonstrated the new science that can arise from these properties, in particular through the flexible response of these systems to guests. This proposal exploits two recent advances from our group (the isolation of nanoporous materials based on amino acids and the demonstration that flexible open-framework materials can act as containers for the direct observation of chemical reactions by diffraction) to develop and understand functionalised porous materials for selective sorption and reactivity enhanced or permitted by flexibility.The two new families of materials create linked scientific opportunities. The porous amino acid-based materials have smaller pores than previous chiral open-framework materials but the high density of functional groups lining the pores results in superior enantioselective sorption for guests which have the correct disposition of sites for interaction - 1,3-diols are enantioselectively sorbed whereas 1,2-diols show little resolution. The reactive frameworks (reported in Science 2007) consist of distinct modules with structural and reactive roles, and pre-position two guest molecules involved in an intrapore chemical reaction at distinct sites, suggesting the development of such systems for the control of reactivity and catalysis within the pores.The project will develop these materials towards the long-term target of synthetic materials with properties resembling those of enzymes, by expanding the chemistry and developing an integrated combination of structural, dynamics, and computational approaches to identify the features controlling the behaviour of the new systems. Flexibility-enhanced (host distortion by the guest) and flexibility-permitted (guest not admitted by the rigid host) sorption will be developed. The three strands required to achieve these goals are- a synthesis programme to generate larger pores with enhanced capability to control molecular positioning and generate unusual reactive sites for catalysis (e.g.amino acid protonation to afford Bronsted acid sites). This programme involves complex phase fields and in some cases necessarily small-scale initial synthesis-search reactions, and is thus enabled by the high-throughput facilities in the Centre for Materials Discovery;- a computational methodology which enables understanding of how host flexibility controls the response to guests, and permits the identification of guests which exploit the properties of the new materials. A screening methodology to permit the identification of chiral guests best suited to enantioselective sorption and of hosts which can locate multiple guests and respond flexibly to them will be developed. Detailed understanding of specific sorption processes (distinguished by high ee sorption or unique flexibility) will involve DFT and forcefield-based MD (showing how host dynamics influence guest uptake) to ensure the influence of both charge-based (e.g. hydrogen bonding) and dispersive interactions are identified;- an experimental programme measuring sorption, structure (diffraction, focussing on intra-pore reactivity), dynamics (NMR) and catalysis to both test computational prediction and evaluate the behaviour against an existing set of guests for enantioselective sorption, non-chiral separations and candidate catalytic reactions;- a partner group of industrial research labs to carry out specific evaluations of the materials for separations (ThermoFisher) focussed on specific targets of pharmaceutical interest (Pfizer) and assist development of the modelling approach (Unilever), focussing on flexible guest response by host materials.

The UK chemical manufacturing industry maintains a competitive advantage in high-value products including pharmaceuticals and agrochemicals due to its internationally leading research and development base. New chemicals for these industries are initially developed on a small scale in research laboratories, with process chemistry then being employed to ensure that the reaction is yield-maximized prior to its transfer into commercial chemical manufacture. The optimization of any particular process chemistry stream for an individual chemical product is critically dependent on the identification of any reaction intermediates and bi-products which can reduce the yield of the desired chemical product. Traditional analysis methods are applied to all trial reaction mixtures, but the potential exists to develop faster, more sensitive technologies to provide a step change in the field. If achieved, such an enabling technology has the potential to deliver very considerable competitive advantages to chemical manufacturing industries. Furthermore, it is also important for delivering the best "green" and sustainable industrial practice by maximizing the productive use of chemicals and minimizing chemical wastage. Mass spectrometry is one of the key analytical techniques and is ideal for fast, sensitive analysis of complex mixtures. This makes it ideally suited for application in process chemistry, but its use to date has been limited by the fact that it directly measures only a molecule's mass. This does not define the structure of the molecule unambiguously, since molecules with same mass can have different arrangements of the atoms within the molecule, a situation described as isomerization. This is a very serious problem for small molecule identification, including the agrochemicals and pharmaceuticals encountered in process chemistry, since isomers can display dramatically different chemical properties. Here, we propose a new instrument that will transform the ability of mass spectrometry to rigorously identify unknown molecules, such as those encountered in process chemistry, by combining mass spectrometry with IR spectroscopy in a single instrument. The new instrument will harness the combined sensitivity of mass spectrometry with the structural diagnostic technique of IR spectroscopy to deliver a powerful, new benchtop analytical device. The investigators (Dessent and Fairlamb) bring together unique expertise, and along with their Industrial Partners (Syngenta, Thermo Fisher Solutions, and Photonic Solutions) will work to unlock a next-generation structure determination technique, which can be applied in process analytical technology for sensitive, real-time analysis of complex reaction mixtures to identify a significantly enhanced range of products, side products and reaction intermediates. Through working with our industrial partner Syngenta, our proposal will have immediate impact on the optimization of agrochemical manufacture, with subsequent impact in the pharmaceutical, cosmetic and food product sectors. Longer term, we envisage working with our partner Thermo Fisher Solutions, to rapidly develop the new instrument as a benchtop commercial product (TRL6/7) that can be widely applied in research laboratories and industrial settings.