In the UK, musculoskeletal disorders (joint and back problems) affect one in five people long term. While joint replacements are successful, they are challenged by demands of an active and younger population presenting with disorders due to trauma, obesity, or other lifestyle choices. One of the causes for joint and back pain is the deterioration of the different soft tissues acting as cushions in the joints. New surgical interventions are being developed to repair or locally replace those soft tissues in order to delay or prevent a total joint replacement. There is no clear indication yet on which patients benefit the most from them. There is an urgent need to define the type of patients for which new and existing interventions are most beneficial. The local anatomy or level of tissue deterioration differs greatly between patients, and there is currently a lack of biomechanical evidence that takes into account these large variations to help matching patients to interventions. To tackle these issues, this Fellowship, MSKDamage, will develop novel testing methods and tools combining laboratory simulation with computer modelling and imaging. MSKDamage methods will be used to predict the variation in the mechanical performance of a series of treatments at various levels of joint deterioration. This will enable the different interventions to be matched to different patient's characteristics. I will focus on three musculoskeletal disorders and associated repairs: 1. Emerging treatments involving the injection of biomaterials in the intervertebral disc: I will produce realistic testing conditions that can be personalised to a specific patient, assessing each patient's chance of success and identifying areas for treatment optimisation. 2. Evaluation of meniscus repairs in the knee and their interaction with cartilage defects: I will provide new information on the type of cartilage defect that reduces the chances of success of a meniscus replacement in the knee. The research will develop guidance on the type of cartilage defects that need repair for a meniscus replacement to be successful. 3. Optimisation of custom wrist repair: I will help optimise patient-specific wrist repairs so that they reduce the damage in tendons and ligaments in the wrist. MSKDamage builds on my strong track-record in the field and network of industry, clinical and academic collaborators, as well as my recent work that demonstrates the specific information which need to be included in models of degraded tissues in the spine and the knee. MSKDamage aims to (1) develop a methodology to test interventions for a specific patient and its specific tissue degradation, (2) carry out a series of case studies which demonstrate the capacity to test a range tissues disorders and repairs. This work is a particularly suitable for a Fellowship, as it will allow me to develop fundamental engineering tools and methods while engaging with end users for significant economic and societal impact. I will also develop as a leader in the field, leading a growing research group and taking actions for the research community, directly related to the research, with advocacy on sharing more research outcomes openly for creation of more impact, and indirectly related to act as an ambassador for public and patient involvement for research related to computer simulations in healthcare.

Heat engines form one of the cornerstones of classical thermodynamics. By converting heat into mechanical work they powered the industrial revolution in the 19th century. Molecular heat engines have the potential to convert thermal energy to electrical power and vice versa with efficiency close to the thermodynamic limit. The topic of single-molecule thermoelectricity is therefore of fundamental importance for the development of on-chip cooling and heat-to-electricity energy harvesting technologies that could power the quantum revolution of the 21st century. The key challenge in harnessing the thermoelectric energy conversion capabilities of single molecules is gaining a better understanding of the quantum mechanical interactions between molecular electronic and vibrational degrees of freedom, which could prove transformative for experiments in the research area of open quantum systems. These experiments will deliver impact in two ways: by exploring new science and by laying the foundation for new technologies. New science: Molecular heat engines form an ideal platform for exploring the dialogue between quantum mechanics and thermodynamics. While some theoretical efforts have been undertaken towards this end, many predictions remain to be verified by experiments. New insights into thermodynamics on the molecular scale will also raise further questions: Does quantum coherence boost the thermoelectric efficiency of single-molecule heat engines? What happens if the Born-Oppenheimer approximation breaks down? Can molecular vibrational modes be electrically cooled to their ground state? New technologies: Thermoelectrics have a long history of providing simple, reliable power generation. Yet, the use of thermoelectric materials to recover waste heat has remained limited due to their scarcity and toxicity, and the unfortunate fact that the properties that determine their efficiency - the electrical conductance, the thermal conductance, and the Seebeck coefficient - are contra-indicated, meaning that an improvement to one will deteriorate another. Quantum effects in single-molecule heat engines lift the link between these contra-indicated properties, thereby opening up the possibility for highly efficient thermoelectric generators that could provide a low-cost, environmentally-friendly means of scavenging waste heat that would drastically decrease global energy consumption. This proposal seeks to develop the instrumentation and experimental methodology to investigate controlled thermoelectric heat-to-energy conversion in a single molecule, where the emphasis is on controlling the molecular interactions. This control will be achieved by using two-dimensional networks of nanoparticles linked via molecular junctions. Building on recent ground-breaking experiments, I will use electric-field control to tune the molecular energy level alignment with respect of the Fermi level of the substrate, while simultaneously controlling the tunnel coupling and applied bias voltage. A local heater will drive a thermally generated flow of electrons through a single molecule, which I will be able to optimize thanks to the unprecedented degree of tunability in the system. By probing the thermoelectric efficiency over a wide parameter space, I will establish the intrinsic thermodynamic limits to single-molecule energy conversion.

This proposal identifies an opportunity to bring together leading international experts to consider the dispersal and impacts of volcanic ash. A key theme emerging from one of our existing research project (STREVA) is the role that volcanic ash plays in disrupting lives and livelihoods across all scales: from major disruption of international air traffic to the destruction of individual livelihoods via irreparable damage to crops and livestock or health problems. Another (VANAHEIM) is uncovering new insights into the ash loading and subsequent dispersal from eruptive columns. Globally other researchers have started to systematically examine the impacts of ash fall-out on critical infrastructure, buildings, communication, vegetation, soil and human or animal health However we currently do not fully understand several things: (i) localised variance in ash dispersal on the kilometre scale and regional (cross-border) dispersal; (ii) thresholds and timings of the ways in which soils and plants are impacted by ash concentrations; (iii) the impact of ash on human and animal health over both short and long time-scales; and (iv) the role that ash concentration plays in disrupting transportation and communication networks during an acute volcanic crisis. Even more importantly, the impact of these processes on communities affected by eruptions lies in their cumulative effects and interacting processes. We want to consider how to tackle this more effectively, by developing andapplying the very best scientific approaches. Through this International Opportunities Fund we will establish a new team of experts to start to tackle these problems with a multi-disciplinary approach which engages key stakeholders and end users, and paves the way for future long-term collaborations. We are taking a 'problem-based' approach to this issue and will focus on one particular island, but use it to consider general problems. This will help us to focus on the most critical scientific issues and provide a new group of researchers with a common problem on which to build an analysis of future research need. The information from the specific setting (St. Vincent) can be immediately applied in disaster planning and regional contingencies for ash disruption. The network built by this project intends to not only report on its findings relevant to St. Vincent but to use these to apply for research finding that enables a diverse group of experts to make real progress in understanding, anticipating and mitigating against the risks from ash fall.

Cryptology has developed out of mathematics and theoretical computer science and is often discussed in purely theoretical and abstract terms. However cryptographic algorithms are a vital part of all modern communication systems. Clearly, this demands additional practical considerations. This realisation has come slowly but steadily over the last decade and lead to a whole new field in cryptography called side channel analysis. Side channels silently leak information about confidential data (e.g. cryptographic keys, user data, etc.) and are hence a serious threat to the trustworthiness of information systems. This fellowship intends to establish a centre of excellence, in which we aim to scrutinize the theory of side channels, the methods used to analyse and exploit them, and the impact of such information leakage on systems used by the wider public.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is an outstanding method of chemical analysis, used extensively in academia and industry to characterise complex samples in 2D/3D. Application areas include materials science, biology, healthcare, energy etc. In the analysis the high-energy 'primary' ion projectile impact on a sample surface, causes ejection of 'secondary' molecular ions which are analysed by a mass spectrometer to provide chemically-rich material characterisation. Scanning the primary beam across the sample provides 2D surface imaging (>100 nm lateral resolution) and by sequentially collecting images while the sample is eroded, 3D sub-surface imaging (>3 nm depth resolution). This unique combination of analytical capabilities means ToF-SIMS is unmatched in its potential to determine, in a single analysis, the composition and detailed distribution of multiple, chemicals in complex samples. Importantly, this technology supports 'discovery mode' research, where the analysis is not biased towards pre-selected, labelled compounds, and therefore leads to hypothesis generation. The analysis is highly-multiplexed and comprehensive - hundreds of species can be potentially detected in a single measurement, limited only by the sensitivity of the process, which here we seek to enhance 100-fold. This proposal addresses critical challenges from next-generation samples demanding greater sensitivity, broader chemical coverage and reliable quantification to address issues including sub-cellular drug localisation and nanoscale molecular materials. It builds on our internationally-leading reputation for innovative ToF-SIMS instrumentation. The characteristics of the primary ion are fundamental in determining impact dynamics at the sample surface and the success of the resulting measurement. The challenge of producing intact secondary molecules from the sample has been largely solved using polyatomic cluster projectiles e.g. C60 and Ar2000 which produce ~100 sputtered molecules per impact. However, only ~0.001-0.1% of these molecules are produced as charged ions, which is necessary for their detection. Clearly there is huge room for improvement in the ionisation efficiency. The principle of projectile-initiated chemical reactions promoting ionisation of sputtered species has recently been firmly established by our work and that of others. We must now build on this knowledge and develop complementary approaches to meet the ionisation challenge and deliver quantitative compositional information. We have assembled a multidisciplinary team of international experts from academia and industry, which is uniquely positioned to pursue this important project. Building on >20 years' experience in innovation of SIMS instrumentation, enabled through EPSRC support and close collaboration with UK Industry, we will develop next-generation reactive ion beams and analytical methodology. This will deliver further transformative gains in performance which are critical to meet future application needs. Our novel results will be framed within the context of emerging theory to understand mechanisms of enhanced ionisation and to underpin the optimisation of projectile parameters. They will stimulate further development of theoretical models of the physical processes underlying SIMS and related techniques. The project is highly-adventurous, providing beyond state-of-the-art analytical capability underpinned with new fundamental understanding. We are ideally placed to exploit this through the interdisciplinary research collaborations at the Manchester Institute of Biotechnology and the Sir Henry Royce Institute for Advanced Materials. The vastly increased quality of data will result in new understanding in a wide range of applications spanning many areas of science and technology.