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Every year countless drug products fail to make it through the discovery and approval process required for commercialisation and widespread patient use. This failure is often due to issues with poor efficacy and side effects. Drug delivery systems based upon nanotechnology are currently at the forefront of drug discovery research and boast the ability to greatly improve treatment capabilities. However, a general lack of understanding of drug delivery and distribution at the cellular and subcellular levels, is ultimately making the widespread use of these systems an uphill battle. Current 'go to' techniques for in vitro and in vivo quantification primarily revolve around using fluorescent labels and/or processes which cause sample destruction. Both of these are less than ideal. Raman spectroscopy is a non-invasive and label-free technique that can provide molecular information on a wide variety of sample types, ranging from drug formulations to cell and tissue samples. When coupled with microscopy, Raman is able to generate vibrationally, and often chemically, specific images of samples. This thesis examines the use of microscopies utilising the process of Raman scattering, to gain insight into drug delivery systems. A novel methodology is presented using Raman spectral unmixing achieved through multivariate curve resolution alternating least squares analysis to quantify non-ionic surfactant vesicle formulations in terms of drug loading and vesicle component concentration. The method presented was able to accurately quantify a series of calibration samples before providing invaluable insight into vesicle component concentrations. Drug loading calculated using the technique showed similar results to those seen with fluorimetry. Investigation into the intracellular response of cell cultures treated with vesicular drug delivery systems was also completed. Analysis using microscopies based upon the multiphoton techniques of coherent anti-Stokes Raman scattering and two-photon excited fluorescence allowed for complementary label-free and label-based imaging. A cellular response was observed upon treatment. The source of this response was investigated further, quantified and a dose-response relationship identified. Extent of drug delivery from vesicles was also quantified and compared to that of delivery from drug free in solution. The research outlined in this thesis demonstrates the excellent versatility and quantitative power of Raman spectroscopy to further elucidate the role drug delivery systems can play in improving therapeutic treatments.

The basic premise of the thesis is challenging Schmitt's statement "Sovereign is he who decides on the exception" (Schmitt 2005 pg.1). Schmitt's presumption is that the sovereign can be found via the process of finding who makes the decision. This presumption is made on the basis of Schmitt's belief of the inherent nature of the decision to the application of legal and political orders. This thesis hopes to unpack this claim in its entirety and examine the claim that the sovereign is the one who makes the exception. This is not to deny that sovereigns do make decisions but rather the thesis' aim is to question and unpick the claim that the decision is the defining feature of sovereignty. Indeed, the thesis argues the decision is not the defining feature of sovereignty but can paradoxically lead to the undoing of state sovereignty when it is applied. The undoing of sovereignty in this case is not the downfall of the regime as some may suppose. Rather, the undoing as sovereignty can be seen as challenging Schmitt's own terms i.e., unity and homogeneity crystallised by the decision. The undoing of sovereignty in this regard can be witnessed in the illustrations themselves. Whilst the regimes of Bahrain, Egypt, and Syria have not fallen we have witnessed significant challenges to their claims of sovereignty from below. These challenges expose the failure of sovereignty within these regimes illuminating the limitations of Schmittian decisionism.

The Channel Plain Region, now largely submerged by high sea-level, incorporates the UK Crown dependencies of the Channel Islands, Northern France (specifically Brittany and Normandy), and southern Britain. La Cotte de St Brelade sits within this landscape, and is pivotal in understanding the Early Middle Palaeolithic Neanderthal occupations of the area. This research presents a series of new palaeogeographic models, new analysis of the lithic assemblages of the lower, Saalian deposits at La Cotte, and chronostratigraphic and technological relationship(s) across the region. This includes sites such as Piégu, Menez-Dregan, Grainfollet and Les Gastines. Overall, this provides an up-to-date synthesis of Neanderthal behaviour between c. 220 – 160 kya within North Western Europe. Specifically, continuities and changes in behaviour over the period in question are highlighted, including changes in lithic acquisition practices related to climate and landscape changes. Finally, this research adds to the recent re-analysis of the upper “bone heap” assemblages (Pope et al. 2012; Scott et al. 2014; Smith 2015; Shaw et al. 2016), within the later Saalian (>160 kya), and the upper Weichselian deposits (Wragg Sykes 2011; Bates et al. 2013; Scott et al. 2014; Shaw et al. 2016), at La Cotte de St. Brelade.

The study of supercooled liquids and glasses remains one of the most divisive and divided fields in modern physics. Despite a vast amount of effort and research time invested in this topic, the answers to many central questions remain disputed and incomplete. However, the link between the behaviour of supercooled liquids and their energy landscapes is well established and widely accepted. Understanding this link would be a key step towards resolving many of the mysteries and controversies surrounding the glass transition. Therefore the study of glassy energy landscapes is an important area of research. In this thesis, I report some of the most detailed computational studies of glassy potential energy landscapes ever performed. Using geometry optimisation techniques, I have sampled the local minima and saddle points of the landscapes for several supercooled liquids to analyse their dynamics and thermodynamics. Some of my analysis follows previous work on the binary Lennard-Jones fluid (BLJ), a model atomic liquid. BLJ is a fragile glass former, meaning that its transport coefficients have super-Arrhenius temperature dependence, rather than the more usual Arrhenius behaviour exhibited by strong liquids. The difference in behaviour between these two classes of liquid has previously been attributed to differing degrees of structure in the relevant energy landscapes. I have studied models for both fragile and strong glass formers: the molecular liquid ortho-terphenyl (OTP) and viscous silica (SiO$_{2}$) respectively. My results for OTP agree closely with trends observed for BLJ, suggesting that the same diffusion mechanism is applicable to fragile molecular liquids as well as to atomic. However, the dynamics and energy landscape of OTP are made complicated by the molecular orientational degrees of freedom, making the analysis more challenging for this system. Dynamics of BLJ, OTP and silica are all dominated by cage-breaking events: structural rearrangements in which atoms change their nearest neighbours. I propose a robust and general method to identify cage breaks for small rigid molecules, and compare some properties of cage breaks between strong and fragile systems. The energy landscapes of BLJ and OTP both display hierarchical ordering of potential energy minima into metabasins. These metabasins can be detected by the cage-breaking method. It has previously been suggested that metabasins are responsible for super-Arrhenius behaviour, and are absent from the landscapes of strong liquids such as SiO2. My results indicate that metabasins are present on the silica landscape, but that they each contain fewer minima than metabasins in BLJ or OTP. Metabasins are associated with anticorrelated particle motion, mediated by reversed transitions between minima of the potential energy landscape. I show that accounting for time-correlation of particle displacement vectors is essential to describe super-Arrhenius behaviour in BLJ and OTP, but also required to reproduce strong behaviour in silica. I hypothesise that the difference between strong and fragile liquids arises from a longer correlation timescale in the latter case, and I suggest a number of ways in which this proposition could be tested. I have investigated the effect on the landscape of freezing the positions of some particles in a BLJ fluid. This “pinning” procedure induces a dynamical crossover that has been described as an equilibrium “pinning transition”, related to the hypothetical ideal glass transition. I show that the pinning transition is related to (and probably caused by) a dramatic change in the potential energy landscape. Pinning a large fraction of the particles in a supercooled liquid causes its energy landscape to acquire global structure and hence structure-seeking behaviour, very different from the landscape of a typical supercooled liquid. I provide a detailed description of this change in structure, and investigate the mechanism underlying it. I introduce a new algorithm for identifying hierarchical organisation of a landsape, which uses concepts related to the pinning transition but is applicable to unpinned liquids as well. This definition is complementary to metabasins, but the two methods often identify the same higher-order structures. The new “packings” algorithm offers a route to test thermodynamic theories of the glass transition in the context of the potential energy landscape. Over the course of this thesis, I discuss several different terms and methods to identify higher-order structures in the landscapes of model glass formers, and investigate how this organisation varies between different systems. Although little variation is immediately apparent between most glassy landscapes, deeper analysis reveals a surprising diversity, which has important implications for dynamical behaviour in the vicinity of the glass transition.

Background. Operative stabilisation of paediatric supracondylar elbow fractures is most commonly achieved through the use of percutaneous Kirschner wires. These implants are inert, cheap and simple to use. However, the requirement for removal and the possibility of pin site infection provides opportunity for the development of new techniques that eliminate these drawbacks. Bioabsorbable pins that remain in situ and allow definitive closure of skin at the time of surgery could provide such advantages. However, their ability to maintain fracture reduction and their effect on the growth plate has not been adequately evaluated. Hypotheses. The Acumed® Biotrak Helical Nail (a bioabsorbable fixation implant) has comparable strength to Kirschner wires and does not result in significant disruption of the growth plate or subsequent growth. Studies. Three complementary studies were performed. (1) A retrospective cohort analysis was performed to establish the prevalence of complications related to Kirschner wire fixation of paediatric supracondylar elbow fractures. (2) A saw-bone model was designed to compare the mechanical performance of the Helical Nail and Kirschner wires. (3) An ovine model was designed to assess the in vivo effects of the Helical Nail on limb growth and physeal morphology. The surgical practicalities of the device and its potential for use in the paediatric setting were evaluated. The primary outcome was femoral length six months after Helical Nail insertion. Micro-CT evaluation of growth plate thickness, percentage disruption and bony infiltration was undertaken – the first time this technique has been used in a large animal study. Traditional histopathological techniques complimented the Micro-CT analysis and offered comment on the microscopic appearance of the growth plate immediately adjacent to the bioabsorbable nails. Results. The infection rate within a large tertiary referral centre was 9.6%, which was marginally higher than previous cohort studies. Mechanical testing demonstrated that the Helical Nail had comparable strength in rotation, but inferior resistance to posterior translation, when compared to Kirschner wires. In the ovine model, the Helical Nail disrupted 3.4% of the physis. The nails had no effect on femoral growth during the six month study period. Micro-CT analysis of both the helical nail and Kirschner wire groups demonstrated multiple bony bridges, with two cases of physeal tethering in the Helical Nail group. There was no difference in physeal thickness or bony infiltration of the physis. Histopathology did not reveal any significant inflammatory or foreign body reaction adjacent to the nails. Conclusion. The Helical Nail demonstrated a number of encouraging attributes which indicate its potential. However, in its current state the device is not suitable for use in the stabilisation of paediatric supracondylar elbow fractures.

The question of how to ‘live with difference’ is at the forefront of public debate by policy makers, community organisers and those working in diverse communities. In the UK specifically, recent years of increased migration and rising socio-economic inequalities have prompted those working in diverse communities to cultivate cross-cultural encounters between different groups to improve our capacity to live with difference. This thesis follows one such example of how practitioners working in diverse communities design and implement cross-cultural projects that aim to encourage encounters with difference. The Near Neighbours Programme was set up by the Department of Communities and Local Government (DCLG) and the Church Urban Fund (CUF) to fund small-scale community action projects designed to improve local neighbourhoods and, in doing so, create ‘encounters’ between different ethnic and faith groups. Through 11 months of in-depth ethnographic research into the activities of Near Neighbours and some of their funded projects in West Yorkshire (northern England), this thesis contributes rich insights into: how projects are designed and practiced to shape the conditions of encounter; how people are equipped to engage with difference; the way in which projects are governed; and finally how practitioners reflect on their neighbourhoods through collaborative and participatory research. In doing so, this thesis engages with contemporary debates within Human Geography around inter-cultural encounters with difference and critical governance studies on how difference is managed and negotiated. In debates within the geographies of encounter literature, this thesis advances understandings of how practitioners design, plan and implement projects of encounter. Engaging with critical governance studies, this thesis offers a more hopeful account of ‘governance’ as I argue that the unpredictability of encounter keeps open the possibility of partnership across difference. Through developing an account of the work of practitioners, this thesis contributes to those who are setting out to engage in community development in an inter-cultural context, by highlighting the role of space in shaping capacities to act, as well as how researchers and practitioners might work together to collaborate on participatory research into safe spaces for meaningful encounters with difference.

The long-term motion of the Earth's mantle is of considerable interest to geologists and geodynamists in explaining the evolution of the planet and its internal and surface history. The inaccessible nature of the mantle necessitates the use of computer simulations to further our understanding of the processes underlying the motion of tectonic plates. Numerical methods employed to solve the equations describing this motion lead to linear systems of a size which stretch the current capabilities of supercomputers to their limits. Progress towards the satisfactory simulation of this process is dependent upon the use of new mathematical and computational ideas in order to bring the largest problems within the reach of current computer architectures. In this thesis we present an implementation of the discontinuous Galerkin method, coupled to a more traditional finite element method, for the simulation of this system. We also present an a posteriori error estimate for the convection-diffusion equation without reaction, using an exponential fitting technique and artificial reaction to relax the restrictions upon the derivative of the convection field that are usually imposed within the existing literature. This error bound is used as the basis of an h-adaptive mesh refinement strategy. We present an implementation of the calculation of this bound alongside the simulation and the indicator, in a parallelised C++ code, suitable for use in a distributed computing setting. Finally, we present an implementation of the discontinuous Galerkin method into the community code ASPECT, along with an adaptivity indicator based upon the proven a posteriori error bound. We furnish both implementations with numerical examples to explore the applicability of these methods to a number of circumstances, with the aim of reducing the computational cost of large mantle convection simulations.

Many pathogenic microorganisms are believed to stochastically switch into low metabolic states that display resistance to supra-lethal levels of antibiotics. These so-called “persister” cells have been associated with recurrent infections and the development of antibiotic resistance. Whilst a compound that eliminates Staphylococcus aureus persister cells has been described, it is not active against Gram-negative bacteria. The aim of my PhD project was to develop a high-throughput assay for compounds that eradicate persister cells in the -proteobacterium Burkholderia thailandensis. Further to this, I aimed to develop “hit” compounds from screening into lead series through investigation of structure activity relationships and, use a chemical genetics approach to elucidate potential mechanisms of action. I developed a phenotypic assay to identify compounds that eradicate persister cells. The assay was based on the reduction of the resazurin based dye PrestoBlue. Optimization of the assay gave a Z’ prime of 0.41 when screened in high throughput at the DDU. Screening of the library of 61,250 compounds identified 2,127 compounds that gave a statistically significant reduction in persister cell numbers. Follow-up assays highlighted 29 compounds with a pIC50 greater than five. Detailed investigation allowed me to down select to six “best in class” compounds, which included the licensed drug chloroxine. A time dependent killing assay showed that chloroxine reduced levels of persister cells by three orders of magnitude over 72 hours (P = 0.01). Hit expansion around chloroxine using commercially available compounds did not identify any more potent compounds, but did highlight key features of the molecule for activity. Assay protocols were provided to collaborators at DSTL who were able to iv show that chloroxine is also active against persister cells formed by the tropical pathogen and Tier 1 biological agent Burkholderia pseudomallei. Investigations into the mechanism of action of chloroxine used Next Generation Sequencing of an over expression library, identifying two putative genes involved in inhibition of persister cells by chloroxine. My findings demonstrate a phenotypic assay against persister cells in Gram-negative bacteria, which has the power to identify potent anti-persister agents to assist in chemotherapy. Structural activity relationship and mechanism of action investigations have indicated lead series and genetic starting points for future development of this research. My PhD project has concluded with sufficient data for continuation of research following a number of leads and is at an ideal stage for instigation of a medicinal chemistry program for development of chloroxine as a clinical option for treatment of persistent melioidosis.

Significant discrepancies exist in global estimates of the atmospheric methane (CH4) budget. This is particularly true for tropical South America where bottom-up approaches, rooted in field observation, tend to under estimate atmospheric observations. As such, a better understanding of soil environments, which are capable of acting as both source and sink for atmospheric CH4, is required. Soil-atmosphere CH4 exchange is fundamentally determined by the balance between strictly anaerobic methanogenic and aerobic methanotrophic microbial processes. For this reason, CH4 emissions are typically associated with anoxic wetland soils, whilst, oxic upland soils are thought to uptake CH4 from the atmosphere. However, there is increasing evidence that upland soils may act as sources of CH4 through methanogenic activity within cryptic wetlands or anoxic microsites. This thesis aims to: document soil-atmosphere CH4 fluxes in poorly represented tropical upland and montane ecosystems, investigate controls on CH4 flux with a focus on soil oxygen (O2) concentration and investigate relationships between methanogenic and methanotrophic processes under oxic conditions. These aims are addressed in three chapters focusing on lowland terra firme, premontane and montane forests and montane humid puna grasslands and wetlands along an Amazonian to Andean transect spanning ~ 3300 m of elevation in southeastern Peru. In the lowland rainforest intensive seasonal field campaigns and laboratory incubations were conducted on higher porosity ultisol and lower porosity inceptisol soils. Mean (s.e.) net CH4 fluxes for dry and wet seasons were, respectively, -1.59 (0.06) and - 1.39 (0.07) mg CH4-C m−2 d−1 for the ultisol and -0.95 (0.06) and -0.41 (0.10) mg CH4-C m−2 d−1 for the inceptisol. Greater uptake rates in the ultisol than the inceptisol were best explained by lower water-filled pore space (WFPS). Similarly, WFPS best explained between season variation in net CH4 flux from the inceptisol, whilst, we were unable to explain the smaller variations observed for the ultisol. Methanogenic processes were active in both the ultisol and inceptisol soils despite oxic conditions. In the premontane and montane forests, long-term monthly field measurements were conducted over two and a half years in premontane, lower montane and upper montane settings. Mean (s.e.) net CH4 fluxes for aggregated dry and wet season months were, respectively, -0.20 (0.15) and -0.08 (0.13) mg CH4-C m−2 d−1 for the premontane forest, -1.12 (0.13) and -0.97 (0.11) mg CH4-C m−2 d−1 for the lower montane forest and -1.55 (0.13) and -1.04 (0.11) mg CH4-C m−2 d−1 for the upper montane forest. Increased uptake with elevation was best explained by decreases in WFPS. Significant variation in net CH4 flux between seasons, driven by variation in WFPS, was only identified for the upper montane forest.

This thesis presents experimental results on two complex oxide systems: Cu1-xZnxO and La0.7Sr0.3MnO3:ZnO. The dynamic magnetoelectric response of these materials is obtained using terahertz time-domain spectroscopy, supported by Fourier-transform infrared spectroscopy, Raman spectroscopy and X-ray diffraction. Evidence for an electromagnon in the multiferroic phase of CuO is presented for the first time. This high temperature (213-230K) electromagnon is linked to intersublattice exchange between two Cu sublattices. The temperature dependence of a magnon in the collinear antiferromagnetic phase is indicative of biquadratic exchange. Broadening of the multiferroic phase on substitution of copper with zinc is reported along with a 25% depression of the Néel temperature due to spin dilution. Phonons and magnons broaden and shift in energy on alloying. However, the electromagnon is relatively insensitive, increasing in energy without widening. This indicates that electromagnons and dynamic magnetoelectric coupling can be mantained even in disordered spin systems. Strong spin-phonon coupling is present in both magnetically ordered phases as shown by the anomalous behavior of the A3_u phonon at TN1 and a Raman-active mode associated with a magnetic modulation of a zone-folded acoustic phonon. Dynamic 1THz magnetoresistance is found to be significantly larger than static magnetoresistance in La0.7Sr0.3MnO3:ZnO vertically-aligned nanocolumns on LaAlO3 substrates. The metal-insulator transition temperature is determined to be 300 K. Temperature dependent static and dynamic resistivity and magnetoresistance are discussed in terms of strain and grain boundary effects. Negative photoconductivity is observed and the dynamic response analysed.

SiO2 plasma etching is conventionally carried out using CF4, C2F6, C3F8, CHF3, and c- C4F8. These species have high global warming potentials (GWP) because they absorb strongly in the infrared and have very long residence times in the Earth's atmosphere. The current generation of plasma reactors release a large proportion of feed gas into the atmosphere. An effective way to meet the environmental targets imposed upon the industry is therefore to introduce new etch gases with minimal global warming effects. This thesis provides the spectroscopic analysis of a range of experimental results to assist in the evaluation of potential environmentally-friendly feed gases for the plasma etching of SiO2. CF3I is plausible alternative since, due to the weak C-I bond, it is possible to produce high yields of CF3(+) etching fragments in a plasma by direct electron impact dissociation and ionisation. The present results include the first electron scattering evidence for the dominantly singlet to triplet nature of the lowest energy electronic excitation; that from the HOMO localised on the iodine lone pair to the repulsive C-I [sigma]* LUMO. Comparisons with the photoabsorption spectra of CF3Br, CF3CI, CH3CI and CH3I suggest that CF3I maintains its ground state symmetry in the low-energy Rydberg excited states. Electron scattering results provide evidence for the formation of temporary negative ions at incident energies between 5 and 9 eV. The atmospheric lifetime of CF3I due to solar photolysis is calculated to be less than one day at low altitudes. Therefore, industrial emissions of the gas are expected to have negligible global warming and ozone depleting effects. C2F4 has attracted considerable interest as a feed gas for the plasma etching of SiO2 as it can be an excellent source of CF2(+) ions and radicals in an industrial plasma and has a short atmospheric lifetime due to reactions with OH radicals. High-resolution photoabsorption and electron energy loss spectra reveal new features including a proposed vibrational series coupled to the dissociative C=C [pi] [pi]* transition. New vibrational structure observed in the ionic ground state by photoelectron spectroscopy provides evidence to distinguish vibrational structure associated with valence and Rydberg states. Analogies with C2F4 have proved useful in the analysis of the previously unmeasured VUV photoabsorption spectrum of CF2CFCF3, another potential environmentally-friendly feed gas for SiO2 etching. The relatively high energy of the onset of pre-dissociative Rydberg excitations in the spectrum of CF2CFCF3 suggests that the molecule may be a less effective source of CF2(+) in an industrial plasma than C2F4. Precise experimental cross sections for electron and photon interactions with molecules are essential to understand the processes which can occur in future reactors and in the atmosphere. The present studies thus add to the body of research aimed to activate new etching chemistries which can reduce the environmentally damaging effects of the plasma processing industry.