The ability to detect structural changes in interacting biological macromolecules underpins the quest to understand complex biological systems, both for its inherent scientific value and to enable exploitation for biotechnological and medical purposes. Currently, this involves several spectroscopic techniques; NMR, circular dichroism (CD) and infra red (FTIR). However, their success relies on selectively observing signals from only one macromolecular component (as in NMR) or from signal deconvolution. The latter presumes that the spectrum of each component is not affected by its contact with the other. While protein-oligosaccharide interactions are widely studied by NMR, those between proteins and biologically relevant polysaccharides cannot be, because of polysaccharide immobility and line broadening. Furthermore, many biologically important polysaccharides e.g. glycosaminoglycans (GAGs); hyaluronate, chondroitin, heparan sulfate and heparin contain groups which contribute to the spectrum in those spectral regions used for the analysis of protein secondary structure. Their spectral features change depending on their environment and cannot be subtracted or de-convoluted. During a recent BBSRC funded project (BB/D020794/1) we showed for the first time that, uniquely, VCD (vibrational CD; CD in the infra-red) selectively detects protein secondary structural changes in solution complexes of GAG polysaccharides. Experiments were conducted on a laboratory FTIR instrument using a conventional IR light source. The factor limiting the widespread application of VCD to a host of other interactions is the weaknesses of the VCD signal (1-10 % that of CD) requiring large amounts of protein. We will develop a bench-top light source based on established plasma technology, suitable for the generation of broad band IR of a considerably higher intensity than conventional light sources, which could also be exploited in other applications (e.g. CD in the vacuum UV). The project involves a collaboration between the University of Liverpool and a Midlands based precision engineering firm, M.I.Engineering, who are seeking to diversify into the scientific instrument market. The principle behind the light source design (J.Phys.Chem. 1984, 88, 488-490; Appl.Optics 46, (2007) 4948-4953), as well as the use of VCD to detect selectively protein structural changes in complexes (JACS 130, (2008) 2138) are already established, thereby minimising the risk. In addition, the company has also committed time to discussions and provided a full set of engineering drawings. The project will entail the construction and assembly of a working VCD instrument involving marrying the source with a commercial VCD instrument and establishing benchmarks for its performance before making the first experimental measurements on amyloid:GAG complexes. The long term business aim is to create a marketable product and several subsequent applications for the technology are envisaged. The instrument will enable the selective detection of currently refractory complexes and has applications in proteomics, glycomics and systems biology. The CASE award will provide the student with periods of training at the interface of science and engineering, covering the entire instrument building process, installation, benchmarking, operational optimization, making the first experimental measurements and investigating protein structure in complexes. The student will receive extensive multidisciplinary training in both the academic environment and the industrial and commercial operations including project management, business strategy, gain an appreciation of the scientific instrument market and drivers, as well as wider industrial applications, market analysis, financial aspects including process, development costs and cash-flow dynamics and will emerge equipped with multidisciplinary transferable skills and broad understanding of how to optimize future academic-industrial collaborations.

The interaction between proteins and cell-surface ligands underpin many biological processes such as cell growth, homeostasis, apoptosis and the ability of pathogens to invade host cells. One important family of cell surface ligands are the carbohydrate family of glycosaminoglycans (GAGs) found on the surface of almost all mammalian cells. Analysis of the sequence of the linear block-like arrangement of these GAGs is a significant technical challenge due to only miniscule quantities of pure material being (readily) available, poor chemistries and insensitive detection equipment. This research aims to develop and test a new method for sequencing these GAG polysaccharides utilising recent fundamental improvements made by the applicant. These developments include the exploitation of the opposite end of the molecule than is conventionally used (non-reducing end), with a vastly improved labelling mechanism and an advanced detection system for the conventional end of the molecule (reducing end). This approach will provide a powerful and sensitive sequencing technique capable of employing both ends of the GAG saccharide for characterization. The information gained from GAG sequencing will enable researchers to study previously elusive structures and processes that are biologically and medically significant.

Studies performed in Canada, Australia, USA and in Europe have shown that long combination vehicles (LCVs), with two or more trailers can significantly reduce road congestion, improve safety, improve transportation cost efficiency, reduce fuel use and greenhouse gas emissions and significantly reduce road surface wear. Unfortunately three major practical barriers prevent adoption of LCVs in the UK: (i) poor manoeuvrability; (ii) poor high speed stability; and (iii) poor reversibility.(i) Many of the roundabouts and narrow roads in the UK's freight transportation network would be impossible for conventional LCVs to negotiate. One way to improve the low speed manoeuvrability of an LCV would be to steer the trailer and/or tractor drive axles. Simple 'passive' steering systems have been developed for rigid trucks and tractor/semi-trailers. Such systems set the road wheel steer angles in a fixed relationship to the geometry of the vehicle: the angles do not change with speed. Recent studies have shown that passive steering systems substantially improve the low-speed manoeuvrability of tractor/semi-trailer combinations by reducing cut-in. They also significantly reduce lateral tyre forces / leading to lower tyre wear and reduced road surface damage. This is important for transporting goods in urban areas where vehicles need to negotiate sharp corners and small diameter roundabouts, at low speeds.(ii) High speed stability is also a problem for many conventional LCVs since lateral accelerations are amplified with each successive trailer. This can lead to premature roll-over during evasive manoeuvres. While passive steering would improve the low speed manoeuvrability of LCVs, the applicants have recently shown that such systems reduce high-speed yaw stability, increase rearward amplification and degrade handling. Consequently fitting a passive steering system to an LCV is likely to further degrade its already poor high-speed stability. To overcome these problems at high speeds an active steering system could be used instead of passive steering. In an active system the steering relationship is varied while the vehicle is in motion to achieve optimal performance at all speeds. While such systems have yet to be developed for heavy vehicles, they have been successfully employed on cars and SUV's: eg Delphi's 'Quadrasteer' system fitted to GMC SUV's. Quadrasteer increases manoeuvrability at low speeds and improves handling and stability at high speeds. Similar benefits could be gained by using active steering on HGVs in general and LCVs in particular.(iii) Finally, the poor reversibility of conventional LCVs would severely restrict the use of existing freight terminals and loading dock infrastructure in the UK. However active steering could be designed to assist drivers to reverse complex multi-unit vehicles. Preliminary research by the applicants has shown that active steering can improve the reversibility of tractor/full trailer combinations, however, algorithms to suit other vehicle combinations, such as tractor/semi-trailers and LCVs, still need to be developed.The main research challenges to be addressed in this project are therefore to develop active steering technologies for LCVs. Once prototype technologies have been developed and tested it will be possible to assess the costs and benefits of implementing active-steering on LCVs in the UK.The research will build on previous work on active steering systems for lorries performed in Cambridge University Engineering Department. It will involve theoretical control system development; field testing of control concepts using existing experimental heavy goods vehicle units; prototype actuator hardware development and laboratory testing; and a detailed cost/benefit analysis. The research will be performed by two postdoctoral researchers in the university, working in collaboration with engineers from a consortium of companies in the heavy vehicle industry.

The Innovative Manufacturing and Construction Research Centre (IMCRC) will undertake a wide variety of work in the Manufacturing, Construction and product design areas. The work will be contained within 5 programmes:1. Transforming Organisations / Providing individuals, organisations, sectors and regions with the dynamic and innovative capability to thrive in a complex and uncertain future2. High Value Assets / Delivering tools, techniques and designs to maximise the through-life value of high capital cost, long life physical assets3. Healthy & Secure Future / Meeting the growing need for products & environments that promote health, safety and security4. Next Generation Technologies / The future materials, processes, production and information systems to deliver products to the customer5. Customised Products / The design and optimisation techniques to deliver customer specific products.Academics within the Loughborough IMCRC have an internationally leading track record in these areas and a history of strong collaborations to gear IMCRC capabilities with the complementary strengths of external groups.Innovative activities are increasingly distributed across the value chain. The impressive scope of the IMCRC helps us mirror this industrial reality, and enhances knowledge transfer. This advantage of the size and diversity of activities within the IMCRC compared with other smaller UK centres gives the Loughborough IMCRC a leading role in this technology and value chain integration area. Loughborough IMCRC as by far the biggest IMRC (in terms of number of academics, researchers and in funding) can take a more holistic approach and has the skills to generate, identify and integrate expertise from elsewhere as required. Therefore, a large proportion of the Centre funding (approximately 50%) will be allocated to Integration projects or Grand Challenges that cover a spectrum of expertise.The Centre covers a wide range of activities from Concept to Creation.The activities of the Centre will take place in collaboration with the world's best researchers in the UK and abroad. The academics within the Centre will be organised into 3 Research Units so that they can be co-ordinated effectively and can cooperate on Programmes.