In a series of pioneering works in the early 1970's, John Kosterlitz and David Thouless first connected the concept of topology to the physics of solids. The basis of this framework is the discrete topological unit, an object defined by its resistance to being smoothly deformed into a continuous background, in the way a disk cannot be smoothly deformed into a ring or torus. Kosterlitz and Thouless showed that the most favourable configurations of the systems they explored must host these topological units. They then went on to predict a material phase transition without symmetry breaking based on these objects, violating all known theories and observations at the time. This so-called topological phase transition has subsequently been used to describe transitions in thin-film superconductors, liquid crystals, and two-dimensional magnets. For this work, Kosterlitz and Thouless shared the 2016 Nobel Prize. Yet, despite the groundbreaking nature of these findings and their subsequent wide-ranging experimental support, the topological units originally predicted have never been observed at the single unit level. In this programme of work, we will use highly advanced microscopy techniques to "see" each of these topological objects for the first time. The unparalleled resolution of these microscopes can be further used to map the interior of the objects all the way down to their atomic building blocks. These experiments, when combined with advanced computational approaches to the original problem considered by Kosterlitz and Thouless, will provide an entirely new microscopic portrait of these topologically protected objects. Yet, this work aims far beyond simply observing the topological units; we will develop and deliver a series of approaches to actively manipulate these objects. The first set of techniques for manipulation will utilize influence from the microscope itself, in much the same way a magnifying glass can be used to start a fire. The second series of approaches will modify the surrounding environment to influence the properties and behaviour of the topological objects. As an individual topological unit cannot be smoothly deformed, it represents an unprecedented opportunity for information technology: using a topological state to store and protect a piece of information. Topologically protected data sidesteps the conventional approaches based on energy to protect information, making them extremely promising for high-density, energy efficient approaches to magnetic information technologies. Ultimately, the set of experiments proposed is designed to inform how we might move from a microscopic topological element toward a fully functional unit of a computer. The insights picked up along the way will answer many more fundamental questions: To what extent does topology protect information? How do these units behave in real, that is defective, materials? What approaches can we take to influence the fundamental behaviour of these objects?

Molecular imaging is one of the key tools for non-invasive clinical diagnosis and opens up the possibility of personalising patient treatment. Positron Emission Tomography (PET) in particular is expanding rapidly and new PET imaging centres are currently being installed across the UK. Biomedical research provides increasing numbers of active molecules that target disease sites in the body and thus could in principle function as imaging agents by labeling with a positron emitting isotope. However, 18-F-FDG is currently the only routinely used PET tracer in the clinic, despite the wide availability of the 18-F radionuclide. This is mainly due to the complexity of the multistep-procedures requiring specialized equipment to make the 18-F labeled imaging agents. The current labeling methods also can be harmful to sensitive biomolecules and thus a small precursor molecule is often labeled that is then attached to an active biomolecule to create the imaging agent. This project will develop a new 18-F-labeling method for sensitive biomolecules which uses the metal aluminium to bind fluoride, rather than carbon-fluorine bond formation which has been the main approach adopted hitherto. The one step labeling procedure will allow clinicians to add the 18-F-fluoride directly into a prepared kit containing the biomolecule in order to prepare the imaging agent. The use of special polymer beads in the labeling has the potential of achieving a higher ratio of labeled to unlabeled precursor than conventional solution methods. This has the advantage of giving better contrast in-vivo and reducing the problems of patient reaction caused by the presence of unlabelled excess biomolecule. The chemistry involved requires no specialised equipment and the faster, kit-based method helps to minimise the exposure of radiation workers to the radionuclide. To achieve our aim, we are designing metal binding sites for fluoride that will allow radiolabeling under conditions that do not harm sensitive biomolecules and proteins. We also propose to combine this approach with methods to attach biomolecules of interest in a way that preserves their ability to reach the target site in the body. Additionally, the compounds we propose are intrinsically fluorescent, so that the potential imaging agents can also be evaluated in living cells using fluorescence microscopy, since PET imaging on its own does not have the resolution necessary to observe the behaviour of the complexes in something as small as a cell. By offering much improved labeling, our new system will facilitate the discovery of new potent biomolecules and facilitate the adoption of Positron Emission Tomography in the clinic without the need for expensive, specialized equipment. A final benefit of the ligand chemistry involved for aluminium is that it also has the potential to be used with other metallic PET radionuclides.

Molecular imaging is one of the key tools for non-invasive clinical diagnosis and opens up the possibility of personalising patient treatment. Positron Emission Tomography (PET) in particular is expanding rapidly and new PET imaging centres are currently being installed across the UK. Biomedical research provides increasing numbers of active molecules that target disease sites in the body and thus could in principle function as imaging agents by labeling with a positron emitting isotope. However, 18-F-FDG is currently the only routinely used PET tracer in the clinic, despite the wide availability of the 18-F radionuclide. This is mainly due to the complexity of the multistep-procedures requiring specialized equipment to make the 18-F labeled imaging agents. The current labeling methods also can be harmful to sensitive biomolecules and thus a small precursor molecule is often labeled that is then attached to an active biomolecule to create the imaging agent. This project will develop a new 18-F-labeling method for sensitive biomolecules which uses the metal aluminium to bind fluoride, rather than carbon-fluorine bond formation which has been the main approach adopted hitherto. The one step labeling procedure will allow clinicians to add the 18-F-fluoride directly into a prepared kit containing the biomolecule in order to prepare the imaging agent. The use of special polymer beads in the labeling has the potential of achieving a higher ratio of labeled to unlabeled precursor than conventional solution methods. This has the advantage of giving better contrast in-vivo and reducing the problems of patient reaction caused by the presence of unlabelled excess biomolecule. The chemistry involved requires no specialised equipment and the faster, kit-based method helps to minimise the exposure of radiation workers to the radionuclide. To achieve our aim, we are designing metal binding sites for fluoride that will allow radiolabeling under conditions that do not harm sensitive biomolecules and proteins. We also propose to combine this approach with methods to attach biomolecules of interest in a way that preserves their ability to reach the target site in the body. Additionally, the compounds we propose are intrinsically fluorescent, so that the potential imaging agents can also be evaluated in living cells using fluorescence microscopy, since PET imaging on its own does not have the resolution necessary to observe the behaviour of the complexes in something as small as a cell. By offering much improved labeling, our new system will facilitate the discovery of new potent biomolecules and facilitate the adoption of Positron Emission Tomography in the clinic without the need for expensive, specialized equipment. A final benefit of the ligand chemistry involved for aluminium is that it also has the potential to be used with other metallic PET radionuclides.

The proposed research will develop a novel in vitro model of wound healing within the skin. We will employ state-of-the-art micro-fabrication techniques to create engineered substrates for culturing human keratinocytes. This technology will allow us to precisely control multiple parameters of the wound environment. Specifically, we will determine how the composition, geometry, and stiffness of the wound influence cell behaviour. In addition, we will examine the molecular signalling pathways that regulate the cellular responses to these different environments. This project has the potential to provide significant insights into how human skin cells sense and respond to extrinsic signals during the wound healing process. Moreover, this model system may be a powerful tool for future cell biology studies, drug screening, and other types of translational research.

The Paris agreement commits nations to pursuing efforts to limit the global temperature rise to 1.5 degrees. This represents a level of transformation of the socio-economic and energy systems that substantially exceeds the scenarios that have been found using conventional integrated assessment models (IAMs). Such models generally ignore economic disequilibrium effects such as unemployment, which could become important under conditions of radical economic transformation, and neglect key dynamic processes that control the rate of uptake of new technologies. Rapid reductions in greenhouse gas emissions also potentially violate the simple scaling assumptions used to derive environmental impacts in IAMs because of the slow response of some parts of the climate system such as the ocean, as compared to the land. We plan to develop a set of more realistic dynamic pathways to reach the 1.5 degree target using a new, fully dynamic IAM that does not rely on equilibrium or pattern scaling assumptions. The assessment will identify policy options and the degree of negative emissions required and will quantify the resulting spatial patterns of climate change and the associated uncertainty resulting from incomplete knowledge of climate, carbon-cycle and socio-economic parameters.