This project uses bioinformatics protocols to explore the impacts of non-synonymous mutations (nsSNPs) in proteins associated with diseases, including germline, rare diseases and somatic diseases such as cancer. New approaches were explored for determining the impacts of disease-associated mutations on protein structure and function. Whilst this work has mainly concentrated on the analysis of cancer mutations, the methods developed are generic and could be applied to analysing other types of disease mutations. Different types of disease-causing mutations have been studied including germline diseases, somatic cancer mutations in oncogenes and tumour-suppressors, along with known activating and inactivating mutations in kinases. The proximity of disease-associated mutations has been analysed with respect to known functional sites reported by CSA, IBIS, along with predicted functional sites derived from the CATH classification of domain structure superfamilies. The latter are called FunSites, and are highly conserved residues within a CATH functional family (FunFam) – which is a functionally coherent subset of a CATH superfamily. Such sites include key catalytic residues as well as specificity determining residues and interface residues. Clear differences were found between oncogenes, tumour suppressor and germ-line mutations with oncogene mutations more likely to locate close to FunSites. Functional families that are highly enriched in disease mutations were identified and exploited structural data to identify clusters within proteins in these families that are enriched in mutations (using our MutClust program). We examined the tendencies of these clusters to lie close to the functional sites discussed above. For selected genes, the stability effects of disease mutations in cancer have also been investigated with a particular focus on activating mutations in FGFR3. These studies, which were supported by experimental validation, showed that activating mutations implicated in cancer tend to cause stabilisation of the active FGFR3 form, leading to its abnormal activity and oncogenesis. Mutationally enriched CATH FunFams were also used in the identification of cancer driver genes, which were then subjected to pathway and GO biological process analysis.

Developing scalable nanomaterial production methods is necessary for realising nanomaterial commercialisation. In principle, production via Liquid Phase Exfoliation satisfies this need. However, techniques reliant on energy input damage the material via mechanical stress, yielding suspensions of multi-layer stacks, stable only for days, and necessitating centrifugation for manipulation. An alternative, emerging technique relies upon the charging of material to allow spontaneous dissolution of pristine 2d nanomaterials. Here this is explored for pnictogen chalcogenide layered materials, focusing on unanswered questions relating to the practicality of the method. In this thesis, ion intercalated Bi2Te3 and Sb2Te3 were dissolved within the aprotic solvents: N-methyl-2-pyrrolidone (NMP) and dimethylformamide (DMF). Successful exfoliation of undamaged, hexagonal 2d nanomaterials was confirmed. A range of complementary experimental techniques were used including TEM, AFM, and SAXS. From the analysis of thousands of nanosheets it was found that gradual diffusion of nanosheets, as a result of their spontaneous exfoliation, lead to fractionation of nanosheets of differing lateral width throughout the liquid volume without need for centrifugation. Nanosheet lateral dimension was also controlled by stoichiometry of the intercalant metal, with an optimum intercalant stoichiometry of 0.1 < x < 1.5 for Kx. Bi2Te3 for production of pristine nanomaterial. The chemical stability of the solution was investigated in relation to exposure to air, water, and heating, with a focus on tellurium impurities. Using SEM and TEM it was shown that tellurium impurities resulted from the presence of alkali metal polytellurides, which could be minimised by optimising the Kx. Bi2Te3 stoichiometry. However, the existence of nanosheets in a 16 month old solution demonstrates stability of these liquids when handled under inert conditions. Together these results demonstrate that this scalable method allows material manipulation and tailoring of nanosheet dimensions, whilst also giving weight to the argument that the liquids can be described as true thermodynamic solutions.

The work presented in this thesis focuses on developing compression techniques to exploit fully the constraining power of high-order statistics when applied to the cosmological observable of interest. We present four different methods in the three-point (3pt) case. The mathematical theoretical framework is first de- veloped and then followed, for all the methods, by application on real data. In particular we use data from the CMASS sample of the Sloan Digital Sky Survey III BOSS Data Releases 11 and 12. Our compression results are compared to those obtained via standard analysis, for example Markov chain Monte Carlo (MCMC) sampling. First, we consider the three-point auto-correlation function as an integrated compressed version of the standard correlation one. We derive analytic expres- sions including corrections for the Primordial non-Gaussianity. We then test the model on data to constrain cosmological parameters. Secondly, we explore two methods of compressing the redshift-space galaxy power spectrum and bispectrum with respect to a chosen set of cosmological parameters. Both methods transform the original data-vector into a compressed one with dimension equal to the number of model parameters considered using the Multiple Optimised Parameter Estimation and Data compression algorithm (MOPED) algorithm. Analytic expressions for the covariance matrix are derived in order both to compress the data-vector and to test the compression perfor- mance by comparing with standard MCMC sampling on the full data-vector. Finally, we apply our compression methods to the galaxy power spectrum monopole, quadrupole and bispectrum monopole measurements from the BOSS DR12 CMASS sample. We derive an analytic expression for the covariance ma- trix of the new data-vector. We show that compression allows a much longer data-vector to be used, returning tighter constraints on the cosmological param- eters of interest.

Lead zirconate titanate is a ferroelectric material of considerable interest with a wide range of technological applications. It has been the subject of many experimental and theoretical studies yet there are a number of unsolved questions preventing further miniaturisation and optimisation of this and other ferroelectric materials. Exotic ultra-dense domain morphologies, as an example, offer an exciting avenue for the development of novel nanoelectronics. In this work, large scale molecular dynamics is used to construct a strain-temperature phase diagram of the domain morphology of PbTiO3 ultrathin films. By sampling a wide range of strain values over a temperature range up to the Curie temperature, it is found that epitaxial strain induces the formation of a variety of closure- and in-plane domain morphologies. The local strain and ferroelectric-antiferrodistortive coupling at the film surface vary for the strain mediated transition sequence and this could offer a route for experimental observation of the morphologies. Remarkably, a new nanobubble domain morphology is identified that is stable in the high-temperature regime for compressively strained PbTiO3. It is demonstrated that the formation mechanism of the nanobubble domains morphology is related to the wandering of flux closure domain walls, which is characterised using the hypertoroidal moment. Molecular dynamics calculations, supplemented with electrical measurements from collaborators, are used to provide insight into the microscopic switching properties of near-morphotropic PZT. The simulations and experiments exhibit qualitatively similar hysteretic behaviour of the polarisation at different temperatures, showing widening of the Polarisation - Electric field hysteresis loops, and the decrease of the coercive field towards high temperatures. Remarkably, polarisation switching at low temperatures is shown to occur via a polarisation rotation and growth mechanism that is fundamentally different from the high temperature switching, where nucleation is rate limiting. Analysis of B-cation contributions show that nucleation and switching are facilitated by Zr centred unit cells and, by extension, Ti centred unit cells in Zr-rich environments. Ti-rich clusters in morphotropic PZT, at low temperature, are observed to have suppressed ferroelectric displacements which may incorrectly be perceived as ferroelectrically inactive `dead-layers'. Finally, fundamental insight into the microscopic mechanisms of the ageing processes are provided. From simulations of the prototypical ferroelectric material PbTiO3, it is demonstrated that experimentally observed ageing phenomena can be reproduced from intrinsic interactions of defect-dipoles related to dopant-vacancy associates, even in the absence of extrinsic effects. Variation of the dopant concentration is shown to modify the material's hysteretic response, identifying a universal method to reduce loss and tune the electromechanical properties of inexpensive ceramics for efficient technologies.

Metallocenes, discovered at the beginning of the 1950s, were very well studied for their diverse properties in redox reactions, chemical catalysis and easy decomposition of ligands. After the theoretical study by Liping Zhou et al. in 2008 that ferrocene wires possess the ability to generate a nearly 100 % spin polarised current, new interest in ferrocene arose as a potential candidate for spintronic applications. The utilisation of ferrocene itself, however, presents big challenges due to its low sublimation temperature and therefore to our knowledge no ferrocene-based thin films without complex connecting ligands have been reported so far. In the present work it is shown that it is possible to produce thin films of molecules containing two linked ferrocene units on a variety of substrates at substrate temperatures of about 300 K. Structure and morphology of the thin films showed a strong substrate dependence. The intrinsic diamagnetic behaviour of the biferrocene molecules was preserved in the thin film. In order to use biferrocene as an active spin manipulation medium for spintronic devices ferromagnetic or antiferromagnetic behaviour is required. Therefore, the magnetic behaviour of single and double oxidized biferrocene thin films was investigated. The biferrocene was single and double oxidized using tetracyanoquinodimethane (TCNQ) and TCNQ-F4, respectively. The effect of the biferrocene:TCNQ and biferrocene:TCNQ-F4 molecular ratios on the oxidation yield was studied. In both cases the highest oxidation yield was achieved for molecular ratios of 1:4. Single oxidized biferrocene showed paramagnetic behaviour whereas double oxidized biferrocene displayed weak intramolecular antiferromagnetic coupling due to ligand-mediated superexchange. With the aim to achieve stronger antiferromagnetic coupling bis(fulvalene)diiron thin films were studied. Due to the reduced iron-iron separation and the two mediating connecting ligands in the bis(fulvalene)diiron in comparison to the biferrocene three times stronger antiferromagnetic coupling was observed for double oxidized bis(fulvalene)diiron. Furthermore, major differences in the morphology and crystal structure in comparison to biferrocene were observed.

Quantum theory can be formulated using a small number of mathematical postulates. These postulates describe how quantum systems interact and evolve as well as describing measurements and probabilities of measurement outcomes. The measurement postulates are logically independent from the other postulates, which are dynamical and compositional in nature. In this thesis we study all theories which have the same dynamical and compositional postulates as quantum theory but different measurement postulates. In the first part we introduce the necessary tools for this task: the operational approach to physical theories (general probabilistic theories) and the representation theory of the unitary group. Following this we introduce a framework which is used to describe theories with modified measurement postulates and we classify all possible alternative measurement postulates using representation theory. We then study informational properties of single systems described by these theories and compare them to quantum systems. Finally we study properties of bi-partite systems in these theories. We show that all bi-partite systems in these theories violate two properties which are met by quantum systems: purification and local tomography.

Colorectal cancer (CRC) is a multistep mutagenic process that provides tumour cells with a growth advantage for clonal expansion. The Wnt signalling pathway is crucial for regulating ISC maintenance and differentiation, whilst aberrant Wnt activation is a hallmark of human CRC. Recent advances in genome-scale analysis of large cohorts of CRCs have uncovered a large number of novel mutations that had not been previously characterised. Interestingly, hierarchical clustering analyses of the related expression data reveals a cluster of differentially expressed genes that is enriched in the previously reported ISC markers, Wnt targets and/or Wnt inhibitors. We hypothesised that some of the genes within the cluster are expressed at the intestinal crypt bottoms to antagonise Wnt signalling to form part of a negative feedback mechanism for ISC homeostasis. The aim of my project was to screen for novel Wnt regulators within this gene cluster. Comprehensive analysis of the cluster identified two potential Wnt regulators: the SH3 domain-binding protein 4 (SH3BP4) and the serine/threonine kinase ZAK/MAP3K20. Here we show that both Sh3bp4 and Zak are expressed at the ISC compartment and are enriched in Apc-mutated tumours. Deletion of Zak enhances radiation-induced intestinal regeneration, suggesting a growth inhibitory role of ZAK in the intestine. Loss of SH3BP4 in vivo exacerbates the Apcmin tumour phenotype by promoting the total number of adenomas and high-grade dysplasia. Mechanistically, ZAK and SH3BP4 suppresses Wnt signalling downstream of -catenin phosporylation. The data revealed novel roles for both ZAK and SH3BP4 in intestinal homeostasis and tumourigenesis via Wnt/-catenin signalling regulation. Taken together, the findings highlight the crucial role that these newly identified genes play in Wnt negative feedback mechanisms in intestinal regeneration and tumourigenesis, which may provide new insights into targeted therapeutic intervention.

In this thesis, I describe x-ray experiments that rst detect the symmetry breaking at magnetic and structural transitions in iridium based transition metal oxides, and then characterise the ensuing state. The magnetic transition in pyrochlore iridates R2Ir2O7, where R = Sm, Nd and Tb, was studied with resonant x-ray scattering at the Ir L3 edge. In all samples, k = 0 magnetic order was discovered below 120 K (Sm), 5 K (Nd) and 78 K (Tb), respectively. It is demonstrated how resonant x-ray scattering can determine the size of the magnetic moment, yielding approximately 0:3 B (Sm) and 0:06 B (Tb). The magnetic dynamics of Sm and Nd pyrochlores could be well described by excitations from an all-in all-out magnetic structure within a minimal nearest-neighbour Hamiltonian of Heisenberg exchange (27 meV) and Dzyaloshinskii-Moriya interactions (5 meV). This provides a consistent description of the magnetic order and excitations, and suggests that a topological Weyl semimetal could be realised in pyrochlore iridates. A structural transition from tetragonal to monoclinic symmetry was discovered in the perovskite iridate Sr3Ir2O7 at 54 GPa using x-ray di raction. The high-pressure phase adopts an altered stacking sequence of perovskite layers, and may coupled to the emergence of a metallic state. X-ray absorption spectroscopy was used to characterise the resulting electronic state at high pressure. Compared to the spin-orbit induced insulating state at ambient conditions, the in uence of spin-orbit coupling in the high-pressure, metallic phase appears diminished.

This overall aim of this thesis was to develop and optimise the synthesis of superparamagnetic iron oxide nanoparticles (IONPs) as potential magnetic resonance imaging (MRI) contrast agents. Indeed, these nanoparticles offer the possibility of multimodality, surface biofunctionalisation, and can offer better MRI sensitivity than conventional molecular-based contrast agents as long as their magnetic properties are adequate and that they are administered in a sufficient and safe dose. In the initial phases of this project, IONPs were synthesised by the polyol method in various experimental conditions: under inert atmosphere using a Schlenk line, using a microwave reactor and in high pressure high temperature conditions. The impact of these synthetic methods and the reaction variables on the physical and chemical properties of nanoparticles were studied. Iron oxide nanoparticles with low polydispersity were obtained through the polyol synthesis in high pressure high temperature conditions. Iron oxide NPs with a diameter of ca. 8 nm could be obtained in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetisation value (84.5 emu/g). However, poor results were obtained for their stability in aqueous solution. To overcome this, alternative surface functionalisation was investigated, using a variety of ligands in order to improve their stability. The surface of the IONPs could be modified post synthesis with the ligand 3,4-dihydroxyhydrocinnamic acid (DHCA) which provided functionality and long term stability in water and phosphate buffer saline (PBS). Their potential as MRI contrast agents was confirmed as they had an improved r2/r1 ratio by a factor of more than 3 in comparison to FDA-approved nanoparticles for MRI Resovist® and Endorem®, with relaxivity values of r1 = 7.95 mM-1 s-1 and r2 = 185.58 mM-1 s-1 measured at 1.4 T. To assess their biocompatibility, multiparametric high-content imaging analysis was carried out with human mesenchymal stem cells (hMSCs) to evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology. Results demonstrated that hMSCs were minimally affected after labelling with IONP-DHCA. Their cellular uptake was confirmed by transmission electron microscope (TEM) and iron specific Prussian Blue staining and quantified using a colourimetric method. In vivo, IONPs were detected as hypointense regions in the liver by 9.4 T MRI up to two weeks after intravenous administration into six Swiss female mice. These results demonstrate the successful development of novel iron oxide nanoparticles, their biocompatibility with hMSCs, and their potential as MRI contrast agents.

The first two chapters of the thesis are primarily a review of the work in the field. Chapter 1 focusses on optomechanics broadly and chapter 2 on levitated systems, which are of particular interest due to their thermal isolation from the surroundings. Chapters 3, 4 and 5 consist of my own research, much of which was presented in papers published in 2012* and 2013**. * Pender, G. A. T., Barker, P.F., Marquardt, F., Millen, J. and Monteiro, T. S. Phys. Rev. A 85 021802 (2012) ** Monteiro, T. S., Millen, J, Pender, G. A. T., Marquardt, F., Chang, D. and Barker, P. F., New J. Phys. 15, 015001 (2013) Chapter 3 is primarily concerned with determining the conditions for trapping and cooling a dielectric sphere in an optical cavity, with two laser modes. It is found that, by using two symmetric cooling and trapping beams (as opposed to the one-field-trapping-one-field-cooling of Chang et. al.) we predict around twenty times greater level of cooling than previously predicted. Typical experimental parameters are presented in section 3.7. Chapter 4 deals with additional complications and considerations including: beads with a diameter which is a significant proportion of the diving wavelength, the effect of damping, heating and radiometric forces from the background gas, heating by black body radiation and other more realistic assumption. From this I am able to conclude that the dominant source of heating is the background gas and that, despite this heating, ground state cooling would still be possible at realistically low pressure (of less than 10-7 mbar). Chapter 5 discusses how we might observe quantum behaviour in this system. In this chapter I am able to determine that quantum behaviour is observable via a heterodyne detection which allows an asymmetry to be observed in the positional power spectrum of the bead (a classically impossible result).