The project investigates automatic verification of computer security protocols by using formal tools and techniques drawn from the areas of multi-agent systems, automatic verification and formal logic. Upon succesful completion of the project, a range of security protocols will be verified automatically by computer tools.

In many tissues (epithelia, muscle, neurons), electrical or neurohormonal signals activate metabolism at times of heightened demand to ensure efficient use of resources. These cues are typically lost in cancers, but resource-efficiency remains important, particularly when oncogenic mutations instruct a programme of rapid growth that could lead to self-limiting depletion of tumour resources. Sustainable use of resources may be implemented through rationing, whereby cohorts of cancer cells take turns to engage in energy-intensive activities (e.g. biomass growth, division). We believe this explains the emergence of metabolic heterogeneity. However, time-dependent phenomena evade discovery pipelines based on steady-state measurements of gene expression, protein abundance, or metabolite levels. We developed a method for sorting cells by a surrogate of fermentative flux, as opposed to steady-state metabolite concentrations which do not predict rates. Applying this to rapidly-growing pancreatic ductal adenocarcinoma (PDAC) cells, we described a signalling cascade that alternates metabolic state between basal and activated1. Operating as a delayed negative feedback circuit (akin to pacemakers, e.g. circadian), the cascade is triggered by interleukin 6 (IL6) receptors activating STAT3, which stimulates fermentation and respiration alongside transcription of its negative regulator SOCS3. Such a system can produce metabolic rhythms independently of cell-cycling. Since it is not hardwired, a population of such metabolic oscillators maintains dynamic heterogeneity, without drifting. We propose that our mechanism rations resources for energy-efficient PDAC expansion, and that its inactivation would eventually deplete resources, i.e. have therapeutic value. This project will: Screen a panel of PDAC lines for energy-efficiency of growth using real-time measurements of fermentative/respiratory fluxes and biomass, and relate this to metabolic phenotype and its heterogeneity. We will use single-cell assays and sorting methods developed by our group. Ranking by energy-efficiency will enable correlative discovery. Verify the delayed negative feedback mechanism. Metabolic sub-populations will be tested for IL6-STAT3-SOCS3 markers and oscillator kinetics will be tracked using a fluorescent reporter of STAT3 transcriptional activity after sequential sorting. Oscillator properties will be manipulated, e.g. changes to PEST motif that affect SOCS3 degradation. Identify genetic regulators that enable resource-smart growth using a CRISPR/Cas9 screen under limited resources (closed system), relative to unlimited resources (superfused system). The effect of inactivating candidate-genes on 'resource-smart' growth will be validated using competition assays with wild-type cells. Test vulnerabilities in the rhythm-generator as a therapeutic strategy by growing mouse xenografts comprising efficiency-compromised and wild-type cells.

Doping is the incorporation of chosen atomic impurities to make a material behave better or differently. When Shuji Nakamura developed a method of producing electrically conducting GaN by activating magnesium (Mg) atoms, he continued a tradition fundamental to all modern electronic devices. Mg doping of GaN allowed production of p-n junctions for today's ubiquitous 'white' light-emitting diodes (LED) and won Nakamura a share in the 2014 Physics Nobel prize. In the same way, europium (Eu) doping of oxide phosphors provided the necessary red optical emission in the 'fluorescent' lamps of a previous lighting revolution. We now propose to take the science of Eu-doped GaN beyond the limited goal of improving red III-nitride LEDs. We aim to explore the potential of hysteretic photochromic switching (HPS), recently discovered by us in GaN co-doped with Eu and Mg, to form the basis of a new solid state qubit or quantum bit. First trials of rare earth (RE-) doped semiconductors, carried out in the late 1980's, suggested that materials with a wider band gap would show better high-temperature performance, thus favouring II-VI materials and III-nitrides over conventional semiconductors like silicon. However it was not until the present century that III-N semiconductors, grown as high-quality epitaxial thin films on sapphire, were good enough to test this conjecture; another decade passed before Fujiwara demonstrated an LED based on GaN doped with Eu during growth (2010). Extensive comparative studies of Eu doping methods by the proposer and coworkers in the decade 2001-2011 established that, while such thick GaN:Eu samples could produce brighter overall emission, material produced by ion implantation, followed by annealing, was actually more efficient per dopant ion, by up to 400 times at low temperatures. We also showed that the defect responsible for the GaN:Eu red LED emission was the 'prime' defect, Eu2, consisting of an isolated Eu ion on a Ga lattice site. The commoner Eu1 defect has a more complex emission spectrum, suggesting a Eu atom perturbed by a lattice defect, such as a vacancy or interstitial atom. The total number of such complex centres reported in the GaN:Eu literature is larger than 10. While attempting to improve the light emission advantage further by implanting Eu in p-type or n-type GaN templates, we discovered hysteretic photochromic switching (HPS) in GaN(Mg):Eu: p-type, Mg-doped GaN samples implanted with Eu ions and annealed. The HPS shows itself in the temperature dependence of the photoluminescence spectrum. At room temperature, the dominant emission, due to the centre Eu0, shows a sharp line at 619 nm. For comparison, Eu1 has a peak at 622 nm and Eu2 at 621 nm. On cooling the sample, the Eu0 intensity increases, as expected, until about 230 K, when it appears to saturate. Below 30 K, we observe a surprising rapid decline of Eu0 as the temperature decreases towards the base temperature of the cooling system. At the same time, an Eu1-like spectrum emerges and effectively replaces Eu0 at 11 K. We deduce that Eu0 somehow switches to Eu1 on cooling over a narrow temperature range. This switching does not reverse if the temperature is then increased from 11 K through 30 K. In fact, Eu1 fades rather slowly, allowing Eu0 to reappear only above ~ 100 K; this is hysteresis. Sample emission is maximum at about 200 K and then fades, reversibly, between 230 K and room temperature. The occurrence of photochromic switching near 20 K on cooldown followed by luminescence hysteresis on warming is given the acronym HPS (hysteretic photochromic switching). The surprises continue: for samples cooled in the dark, switching from Eu0 to Eu1 can be seen in the time domain; and a resonance line appears at an intermediate wavelength between Eu0 and Eu1. The proposed project aims to determine if the resonance is an actual superposition of Eu0 and Eu1, promising a novel and simple solid state qubit based on Mg acceptor defects.

The aim of this proposal is to establish a standard digital code for the synthesis of molecules. Like Spotify, which allows the distribution of music in an mp3 (or similar) digital format, the development of a chemical code for synthesis will allow users to share their code as a result of the digitisation 'Chemify' process. The code will be demonstrated both manually and on basic robotic systems available in our laboratory (GU) and with our international collaborators based in the USA (MB), Canada (AAG), Germany (PS), and Poland (BG) who are experts in modular organic scaffold synthesis (MB), computational chemistry and statistics for experimental design (AAG), robotic carbohydrate synthesis (PS), and networks and rules of chemical synthesis (BG). In the long term, the ability to automate the synthesis of molecules will lower the cost of manufacture by enabling the automatic and unbiased exploration of chemical space giving a digital code. Such codes are needed if chemists are to develop systems that ensure reproducibility, and the ability to explore new reactions and statistics driven design of experiments to target unknown molecules. Recently we took a key step to encoding a multi-step synthesis into a digital blueprint,1 but the vision to go from code to molecules represents a gigantic problem. In this proposal, we will aim to develop a chemical ontology for synthetic chemistry that will lead to the first version of a programming language for chemical synthesis. We will then demonstrate the code can be used to synthesise important molecules, already robotically synthesised by us, and examples from our collaborators in the USA, Germany, Canada and Poland on the same universal 'chemputer' synthesise robot.

This Established Career Fellowship proposal concerns the spatial and time resolved crystallography, structural refinement and functional evolution of one to four atom thick 1D 'Extreme Nanowires' formed inside single walled carbon nanotubes - atomically smooth templates that are thermally robust up to 1130 degrees Centigrade. This is at the practical limit of scalable fabrication, a 'Final Frontier' of materials science and the next and ultimate lowest dimension relative to two-dimensional structures such as graphene or inorganic analogues derived from metal sulphides and similar. It will address the four major aspects of atomically regulated crystal growth deemed to be the most critical in terms of their development: three-dimensional crystallography with atom-by-atom sensitivity; four-dimensional crystallography, addressing the special case of nano-Confined Phase Change Materials, which have potential utility in Non-Volatile Memory; structural refinement based on enhanced information obtained from the forgoing structural studies; and the development of thin film devices, which may be either aligned or misaligned, both for fundamental properties evaluation - including several aspects of Novel Physics - but also for 'Proof of Principle' device creation for potential exploitation in thin film devices including solar cells, chemical sensors, fuel cells, batteries and catalysts, all of which may bring economic benefits. This project is expected to play a significant role in techniques development both in Warwick and through the Project Partner network based in Oxford, Vienna, Warsaw, Pau and Beijing. The 'Ultimate Scale' physical nature of the materials under examination will both test and help improve the most sensitive characterisation methodologies currently available, especially high performance electron microscopy, associated spectroscopic methods, in situ low-temperature imaging, in situ resistance/conductivity measurements, high performance scanning probe microscopies and thin film device fabrication. This project is expected to have in particular a very significant impact on the current rapidly developing field in high-performance electron microscopy in time-resolved 4D studies in which I will exploit ultrafast imaging and diffraction capabilities available in both Oxford/Diamond and Beijing, taking advantage also of the latest developments in Direct Electron Detection in rapid and more quantitative imaging studies. In this regard, the special category of nC-PCMs will provide an ultimate test being literally the smallest scale (i.e. 1 nm) Phase Change Materials ever observed and these experiments will therefore examine reversible and irreversible phase formation at the smallest scale ever likely to be attempted. The new electron diffraction protocol that I have developed will also allow us to 'scale up' phase transformation in bundles and thin films of the template SWNTs enabling resistance and conductivity changes to be measured in situ at the same time as crystalline/glass transformations and to assess their reversibility. Any exploitable physical properties will then be assessed in simple bolometric-type devices that will be used both in further physical testing but also as exploitable 'Proof of Principle' devices. These studies will make use of the many state-of-the-art facilities available at the University of Warwick as the project requires but also more dedicated expertise and information available through a Project Partner network based in the Oxford, Vienna, Warsaw, Pau and Beijing all of whom contribute to and benefit from techniques development, reciprocal characterisation and from developing/expanding their own activities in what will be a unique World-leading enterprise lead from Warwick. The PI will lead these activities from the UK which can then potentially add 1D nanostructures to its dominance in 2D Nanomaterials by pursuing this complementary but 'Beyond Graphene' research.