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Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. It is not known if mineral accrual by the growing skeleton protects young people with CKD from extraosseous calcification. My hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: Multicentre longitudinal study in children and young people (5-30 years) with CKD stages 4-5 or on dialysis. Cortical (Cort) and trabecular (Trab) BMD were assessed by peripheral quantitative Computed Tomography and lumbar spine BMD by DXA (Dual Energy X-ray Absorptiometry). Vascular calcification was assessed by cardiac CT for coronary artery calcification (CAC) and ultrasound for carotid intima-media thickness (cIMT). Arterial stiffness was measured by pulse wave velocity (PWV) and carotid distensibility. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed-up after a median of 1.45 years. The cohort had a significant bone and cardiovascular disease burden. 10% suffered at least one previous atraumatic fracture, and 58% reported bone pain affecting activities of daily living. The majority had evidence of vascular calcification and arterial stiffness with increased cIMT and PWV z-scores. 10% had CAC at baseline. Baseline TrabBMD was independently associated with cIMT (R2=0.10, β=0.34, p=0.001). An annualised increase in TrabBMD was an independent predictor of cIMT increase (R2=0.48, β=0.40, p=0.03), with 6-fold greater odds of an increase in ΔcIMT in those with an increase in ΔTrabBMD [(95%CI 1.88 to 18.35), p=0.003]. Young people that demonstrated statural growth (n=33) had attenuated vascular changes compared to those with static growth. Conclusion: These hypothesis generating studies suggest that children and young adults with CKD or on dialysis may develop vascular calcification even as BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraskeletal calcification.

Interactive molecular dynamics (IMD) is a powerful technique which allows user intuition to guide and perturb a simulation. I do not believe that we have taken full advantage of this medium as by merely duplicating existing methods we do not address the new issues nor take advantage of the possibilities. It is vital to ensure that the system can be rendered efficiently to avoid motion sickness. We must use the latest techniques to allow the visualisation of large systems at a range of magnification levels. I discuss how we achieve this using raycasting imposters, as well as proposing some new primitives that can find use in molecular visualisation. Sudden visual discontinuities can be immersion-breaking and distracting when using virtual reality. I have developed two techniques to avoid these issues when visualising systems. For periodic systems, I propose a technique to crop atoms within the simulation box to ensure a smooth transition across periodic boundaries. I also correctly depict bonds across periodic boundaries. Another visual discontinuity occurs when viewing proteins using ribbon diagrams, with discrete flips in the direction the ribbon twists prevalent at the time resolution used in IMD. I address this with a novel double-normal interpolation approach, which when combined with smoothly interpolating the colour and scale yields diagrams that are no longer visually jarring. In addition to visualisation techniques, we can also exploit the additional freedom afforded in virtual reality to apply interactive forces. By leveraging the rotational degrees of freedom of a handheld virtual reality controller, I propose a new class of interactive forces that can rotate and translate a molecule without internal perturbations. By including damping forces as well, a user can now have precise control over a molecule's trajectory. This technique also extends to more complex coarse-grained systems with asymmetric particles.

Burgeoning antibiotic resistance (AR) threatens to undermine global human health by rendering antibiotic treatments ineffective. The rapid development of AR is widely attributed to excessive antibiotic use, and a greater proportion of global antibiotic sales are associated with livestock relative to human clinical use. In line with the One Health concept, increasing focus has been placed on studying the spread of AR in agricultural environments, including contamination of the human food chain. Livestock waste is a valuable resource for fertilising agricultural land worldwide; however, it also represents a source of unmetabolised antibiotics, assorted antimicrobials and antibiotic resistant bacteria (ARB). In the UK, cattle slurry comprises a substantial proportion of animal waste applied to fields. Consequently, the dispersal of AR on UK dairy farms and their environs warrants investigation. The body of work presented here therefore aimed to characterise the dynamic spread of AR on a large, high-performance commercial dairy farm in the UK. More specifically, the occurrence and prevalence of AR determinants and bacterial taxa in slurry-amended field soil were evaluated over the course of a year, with sampling occurring in May, July, September and October 2017, as well as January and May 2018. On-site slurry samples were also characterised monthly, between June and October 2017. During the period of study, additional sampling was also carried out in January and May 2018, from a nearby field site with no history of livestock waste application. Environmental DNA was extracted from all samples, processed, and sequenced to produce metagenomic libraries. Bioinformatic analyses were carried out to annotate, quantify, and visualise the ARG profile (resistome) and taxonomic composition of samples. By bringing together antibiotic usage records, soil physiochemistry, meteorological and metagenomic data, the current work produced a uniquely comprehensive temporal evaluation of AR in field soil following successive amendments of slurry at realistic rates of application. Through analyses of metagenomic data it was shown that while both slurry and soil contained a diverse array of antibiotic resistance genes (ARGs), the ARG profiles of soil were distinct from those of slurry, irrespective of the origin of the soil in the context of the sites sampled. This is further reflected in the microbial composition of soils which also demonstrated robust correspondence with ARG profiles. Together, these data allowed the identification of slurry biomarkers (ARGs and taxa). ARG slurry biomarkers included gene groups belonging to macrolide, lincosamide and tetracycline resistance gene categories. Furthermore, the wider genetic context of slurry ARGs was characterised by metagenome assembly. Specifically, the beta-lactamase resistance gene cfxA was associated with NBU-1-like elements, while the tetracyline resistance gene tetM was embedded within Tn916-like transposable mobile elements. Similarly, certain ARGs such as aph(6) (aminoglycosides), aph(3") (aminoglcosides) and sul2 (sulfonamides) were co-resident on contigs. Taxonomic slurry biomarkers included members of phylum Bacteroidetes, Firmicutes, Synergistetes, Tenericutes and Sphaerocheata. In particular, both unassembled read data and metagenomes-assembled genomes (MAGs) indicated Proteiniphilum sp.(Bacteroidetes) was a biomarker of slurry application. Temporal analyses showed that the slurry biomarkers exhibited two distinct lifecycles in soil, one of which appeared to be further modified by season. Firstly, select ARGs were consistently more abundant in soil with a long-term history of slurry application relative to soil from the 'untreated' site (e.g. tetM), indicating their prevalence related to longterm enrichment. In contrast, another set of ARGs exhibited transient increases following the first application of slurry in May 2017 (e.g. lnuB, mefB). These ARGs declined to pretreatment levels within eight weeks. In contrast, the same ARGs persisted for >12 weeks after the first application of slurry in February 2018. This suggests the timing of the first slurry application of the season can influence the survival of select slurry associated ARGs and taxa. Given current UK guidelines, the latter scenario may result in the contamination of grass-cut for silage intended for use as cattle-feed and may lead to a positive feed-back loop of AR in cattle, although this was beyond the scope of the current work. Further field-based and laboratory experiments should be carried out to confirm the broader scalability of these findings. In summary, the present work explored relationships between taxa, ARGs and mobile genetic elements, as well as the dynamic nature of ARGs within soils on a working dairy farm. Analyses enabled identification of candidate biomarkers of slurry exposure (ARGs and taxa), which can be used to develop more targeted studies in the future.

Astronomy is a field uniquely afflicted by a limited ability to design and run controlled experiments. Hydrodynamical simulations of galaxy formation and evolution are used to alleviate this problem and are widely used in contemporary astronomy. They help interpret observations, validate methodologies, and make new predictions. This thesis concerns the use of simulations in addressing two outstanding questions at the frontier of the field. What are the systematic uncertainties influencing radio continuum weak gravitational lensing surveys such as those conducted with the upcoming Square Kilometer Array (SKA) telescope? What is the predicted dependence of galaxy clustering on various properties at fixed halo mass? I first measure the morphology and orientation of the radio continuum emitting component of central and satellite galaxies in the EAGLE simulation suite, a good proxy for which is the star-forming gas. Approximating the 3-dimensional morphology as an ellipsoid whose axis ratios are specified by the eigenvalues of the moment of inertia tensor, I show that the star-forming gas characteristically takes the form of a flattened disc at z=0. This is in contrast to the morphology of the stars, which is typically more extended along the minor axis. There exists, however, a significant correlation between the morphology of the two components in individual galaxies, with flatter stellar distributions generally being associated with flatter star-forming gas distributions. The difference in 3-dimensional morphology between the two components results in differences in their projected ellipticities, with the star-forming gas exhibiting a broader spread. The consequence of this for weak lensing surveys is that there will likely be a larger shape noise for galaxies as characterised by radio continuum emission than is the case for the optical. Assessing the redshift dependence, I show that the morphology of the star-forming gas comprising the progenitors of present day ~M* galaxies (i.e. those with stellar mass similar to that which defines the knee of the galaxy stellar mass function) shows significant evolution, with flattening increasing with time. I show that this is also the case in projection for all galaxies regardless of mass, which indicates that a redshift-dependent shape-fitting algorithm is likely necessary to measure the shapes of real galaxies in SKA-based surveys. Characterising orientation in terms of the minor axis direction, I present results showing that the star-forming gas is preferentially aligned with its host dark matter halo, however the degree of this alignment is found to be weaker than is the case between stars and dark matter. I provide fitting functions to the distribution of star-forming gas-dark matter alignment angles, which may be applied to semi-analytic models to more realistically model the intrinsic alignment (IA) effect in far larger volumes than can be followed by the current generation of state of the art hydrodynamical simulations. The morphological minor axis of the star-forming gas is found to align strongly with its kinematic axis, affording a route to observational identification of the unsheared morphological axis. The internal alignment between a galaxy and its host halo has significant implications for the IA of galaxy pairs, a key source of systematic bias in cosmic shear measurements. Using EAGLE, I measure the IA of galaxies as characterised by their star-forming gas. I find that in 3-dimensions and in projection the same qualitative results hold: the star-forming gas IA is weaker at all galaxy pair separations than is seen for the stars, however it is non-negligible when one considers orientation-direction alignment. IA strength as characterised by this measure increases with decreasing galaxy pair separation, following the same general trend as the stars. I find that the strong IAs seen at short pair separation are driven primarily by the one-halo term associated with central-satellite pairs in the haloes that host M* central galaxies. At fixed comoving separation, the radial alignment is stronger at higher redshift. My findings imply that the systematic uncertainty due to IA may be less severe in radio continuum weak lensing surveys than in optical counterparts, and that this stems from former's tendency to be less well aligned with the dark matter structure of galaxies than the latter. Alignment models equating the orientation of star-forming gas discs to that of stellar discs or the DM structure of host subhaloes will therefore overestimate the impact of IAs on radio continuum cosmic shear measurements. I next address the topic of galaxy assembly bias. This is a consequence of the well-known prediction of halo assembly bias from simulations of the LCDM concordance model of cosmology, however it has yet to be conclusively observed in galaxy surveys. I first measure the galaxy assembly bias effect in EAGLE, and then assess the degree of correlation between various galaxy/halo properties with halo assembly time at fixed halo mass. Most properties which correlate with assembly time are found to be generally associated with galaxy clustering strength, however some properties which are not correlated with assembly time also exhibit secondary biases in galaxy clustering. This indicates that in EAGLE, not all of the secondary biases in galaxy clustering can be attributed to halo assembly time. While contemporary hydrodynamical simulations appear to agree in the existence of galaxy assembly bias and secondary bias, the exact nature of the signal varies, seemingly due to differences in the implementation of baryonic processes. I find that the EAGLE, BAHAMAS, and IllustrisTNG simulations agree in the prediction that galaxies with higher stellar mass cluster more strongly at fixed halo mass, EAGLE and IllustrisTNG predict a larger effect than is seen in BAHAMAS. The halo mass scale at which the secondary bias signal exhibits an inflection point is lower in EAGLE than is seen in IllustrisTNG. I next explore the possibility of using measures of environmental density to probe the dependence of clustering on properties at fixed halo mass. For such probes to be unbiased, it is required that measures of environmental density are uncorrelated with halo mass. I confirm this is the case with rho_N for M200 < 10¹² M_sun. After confirming that rho_N correlates strongly with clustering, I demonstrate that galaxies residing in more dense regions exhibit higher stellar masses at fixed halo mass. I finally explore the feasibility of conducting a similar study using a 2-dimensional environmental measure more readily accessible in observation. Sigma_N is the 2-dimensional equivalent of rho_N, and the two measures are closely linked. I minimise the scatter in Sigma_N-rho_N by optimising the selection of the recessional velocity cut used to reduce the influence of projection effects. I confirm that Sigma_N correlates strongly with clustering, and demonstrate that higher Sigma_N values are correlated with higher stellar masses at fixed halo mass.

High demand for egg products over the last couple of decades has increased the need of supply in egg production. As a consequence, modern laying hens are being put under increased pressure from extended periods of egg production causing increased susceptibility to skeletal disorders such as osteoporosis and skeletal damage. Assessment of skeletal health through measuring bone parameters such as bone strength or bone mineral density is common practice, however, the methods used in previous research vary between research groups and studies. The overarching aim of this study was to assess the effect of different housing systems on skeletal health and egg qualities of laying hens over the period of lay, using new methodology and modelling parameters to help maintain hen welfare whilst possibly increasing the laying cycle of future flocks. A series of trials were carried out to achieve this aim. Three pilot studies were carried out in the initial stages to determine the optimal bones to be measured in subsequent trials. These studies concluded that multiple bones showed differences due to differences in form and function, and that future studies would therefore need to measure several bones to get a true picture of the birds' skeletal health. Using methodologies influenced by the pilot studies a longer study, split into two parts was carried out to assess the effect of housing system on skeletal integrity and egg quality over the laying period. After the larger trial, another trial was performed using the previously established methodologies to see if they could be used to assess the effectiveness of a novel supplement. Part one focussed on the effects on bone parameters while part two focussed on the effects on egg quality. The longitudinal study showed that bone strength of the keel, tibiae and humeri were significantly affected by age (p < 0.001), housing system (p < 0.001), and the interaction effect between age and housing system (p < 0.001) with the caged system showing some of the poorest results ((18 weeks MT keel = 173.13N (13.542), 18 weeks C keel = 105.38N (13.542), 72 weeks MT keel = 130.80N (13.542), 72 weeks C keel = 81.74N (14.363)). Bone ash content of the keel, humerus and tibia was also significantly affected by age (p < 0.001), housing system (p < 0.001) and age*housing system (p < 0.001). Caged bone ash content showed some of the lowest values though organic some of the highest ((24 weeks O tibia = 44.36% (0.677), 24 weeks C tibia = 41.91% (0.677), 60 weeks O tibia = 44.28% (0.742), 60 weeks C tibia = 42.73% (0.697)). It was highlighted that bone strength may be more informative than bone ash content when assessing skeletal integrity, as bone ash content results are thought to be more influenced by the presence of medullary bone than bone strength. Furthermore, the modelling estimates of bone data in this chapter showed that bone weight was a significant predictor of bones strength (p < 0.001; estimate = 23.60), showing as bone weight increases, bone strength would increase at the estimated rate. Model parameters also showed free-range flat deck (p = 0.020; estimate 27.37), free-range multi-tier (p < 0.001; estimate = 38.30) and organic bone strength were significantly stronger than caged tibia strength (p < 0.001; estimate = 56.78). Barn (p = 0.024; estimate = -10.64) and free-range flat deck (p = 0.025; estimate = -10.92) bone strength declined significantly faster than caged bone strength between 18-72 weeks of age, with free range flat deck declining slightly faster than barn. Humerus bone strength declined significantly faster than tibia bone strength (p < 0.001). Keel bone strength also declined significantly faster than tibia bone strength (p < 0.001). In part two of the longitudinal study - investigating the effect of housing system on egg quality traits over the laying period - results showed that all egg quality parameters were significantly affected by age, housing system and the interaction effect (p = 0.007 or less). Egg weight increased from mid lay onwards (36 weeks onwards) with organic showing the heaviest weights of all systems. Egg height showed an increase over age (p < 0.001) from 24 weeks of age to 36 weeks of age and then another increase from 48 weeks to 72 weeks of age. Organic egg height was the largest towards the end of lay with multi-tier and cage being some of the smallest. Eggshell strength of the multi-tier and flat deck systems were highest at the beginning of lay, though declined quicker than other systems between weeks 24 and 36. In barn systems, eggshell strength was some of the weakest results during mid to late lay, whilst organic showed some of the highest breaking strengths in the same period. Results for eggshell ash content were somewhat unclear as barn data was significantly higher at 72 weeks compared to all other systems, where in other measurements barn data showed some of the lowest results. It was shown that in late lay (between 60-72 weeks) eggshell thickness is greatly influenced by age (p < 0.001), however multi-tier eggshell thickness and caged eggshell thickness increased slightly while other systems declined sharply. Regarding egg modelling data, ash weight was a significant predictor of eggshell strength (p < 0.001; estimate = 3.73), showing as ash weight increases eggshell strength would increase at the estimated rate. Furthermore, model parameters showed as age increased eggshell strength decreased when using caged eggshell strength as the baseline (p < 0.001; estimate = -0.16). Barn eggshell strength was also shown to decline significantly faster over the laying period than caged eggshell strength (p = 0.036; estimate = -0.29). When assessing if a relationship was present between egg and bone strength residual data, no relationship was found. It may be that the lack of interaction between data sets were caused by how broadly egg and bone strength data was collapsed at farm level to enable a comparison. The last part of this project was to determine if these methodologies created from the pilot studies and longitudinal study could identify differences in the effects of a novel supplement. This was done by investigating the effects of a novel silicon supplement on skeletal health and egg quality traits post laying cycle. The study found little effect of the diet on any bone parameters of any bone throughout (diet effect - bone length; p = 0.099 or higher, bone width; p = 0.285 or higher, bone weight; p = 0.157 or higher, bone strength; p = 0.083 or higher), making it difficult to the determine the useful of the methods developed previously. It was suggested that the effect of changing housing system may have concealed the effect of silicon supplementation, due to the change in exercise which is known to improve skeletal health. It was concluded from the project that when assessing skeletal health, multiple bones be used to ensure all areas of the skeletal system are assessed due to form and function varying between bone. For example, a wing bone performs a different locomotory movement compared to a leg bone. It would be recommended from work in this project that utilising the keel, humerus and tibia would be adequate to cover all aspects of skeletal form and function in the bird, in relation to assessing skeletal health. Measuring bone geometry along with strength was also considered important as these parameters were found to be sensitive to factor effects even after sexual maturity. It was unexpected that results for bone lengths and widths in pilot studies 1 and 2 were still affected by housing system, post maturity. Additionally, egg parameters were not considered meaningful data for skeletal assessment as it was somewhat evident egg production likely takes precedent over skeletal maintenance. Model parameters to assess skeletal health in laying hens would be beneficial in future work. Ultimately, the modelling of skeletal data could act as an early warning system to indicate any potential decline in skeletal parameters within the laying period and allow producers to be proactive in their response. An early response to a skeletal problem could help maintain or possibly improve productivity at a time when there is a drive to produce more eggs per bird, whilst simultaneously maintaining a high standard of hen welfare.

The initial purpose of the Danelaw Boundary in the late 9th century may have been to create a peace agreement between Kings Alfred and Guthrum, but its role for continuity of trade must also to be taken into consideration. The purpose of the Boundary is both complex and contradictory, not merely because of its disputed position within the topographical landscape, but also the way in which it relates to the legal culture of the time. The intricate nature of the Boundary and the difficulties this raises appear to resonate with the wider discourse on Early Medieval boundaries where many uncertainties about the use of territorial borders and the methodology employed to examine them persist. Yet the Danelaw Boundary provides a valuable insight into an interconnection between boundaries, the law and, to a wider degree, governance. This thesis will explore the nature of the relationships the Danelaw Boundary had with the law and Anglo-Saxon governance employing both a hybrid theoretical and practical approach. The route and date of the Danelaw Boundary will also be discussed, and, in addition, Kernel density heat maps will be employed to explore whether the Danelaw Boundary was an open border, particularly with regard to trade. The Boundary's influence on the development of Early English governance will be examined through the various extant law codes, and as an extension to this, the implications for potential legacy. In conclusion, whilst there is evidence to suggest the Boundary had a legal legacy - and was perhaps even re-used - at present this is not yet substantial enough to challenge the existing view that the Danelaw Boundary was short-lived.

Laminated composite structures manufactured from pre-impregnated carbon fibre preforms have very high in-plane strength and stiffness. These properties make carbon-fibre composites ideal for withstanding the adverse loading conditions experienced by many aerospace primary load-carrying structures under normal operating conditions. However, such structures are very susceptible to delamination failure in the event of high-velocity impact by a foreign object. This is particularly important for aerospace components where foreign-object damage (FOD) can lead to catastrophic failure of a component due to the low composite material interlaminar fracture toughness. This property depends on the strength of the interfacial layers between plies, which for an unreinforced laminate is governed by the relatively low strength of the highly brittle matrix resin. Lack of fibrous material in the through-thickness direction means this strength is easily overcome by the large interlaminar shear stresses induced by a high-velocity impact event. Z-pin through-thickness reinforcement is an effective solution to this problem by adding fibrous material in the laminate Z-direction to enhance through-thickness impact performance. The ability of Z-pin reinforcement in enhancing the interlaminar fracture toughness of carbon-fibre composites has been well-documented for smaller scales and low strain-rates. However, Z-pins must encounter a delamination crack that is of sufficient scale to invoke large-scale bridging to have maximum efficacy in arresting crack propagation. Existing small-scale test methods do not produce this large-scale bridging effect, and full-scale Z-pinned component testing produces complex failure modes and is often prohibilitively expensive. In this thesis, a new sub-element scale test has been developed which produces large-scale Mode II crack-bridging at high strain-rate in a field of Z-pins. The test was designed using a design-by-analysis approach with the explicit finite element solver LS-DYNA R7.1.3. A cantilevered, tapered plate manufactured from IM7/8552 pre-impregnated carbon-fibre unidirectional material is subjected to impact by a gelatine projectile using a gas-gun. The specimens are produced using a combination of hand layup and autoclave curing with one-sided taper and soft tooling only for simple laminate manufacture. Undesirable additional failure modes such as fibre-failure near the fixture have been completely avoided. Test conditions, configuration and geometry have been well-scaled to produce a large, single delamination near the mid-plane which is driven in both initiation and propagation by structural bending. Experimental data shows that this large delamination crack may be effectively arrested by embedded, normally-aligned carbon-fibre Z-pins via large-scale bridging. Finite element modelling predictions are compared with experimental results and the modelling approach is developed further to establish some predictive ability in terms of predicting Z-pin large-scale bridging behaviour. Novel Z-pin configurations are then assessed using the predictive model.

This thesis looks at communist-oriented opposition in the GDR. Specifically, it considers reconstructions of this phenomenon within state-mandated memory since German unification in 1990. It presents three case studies of particular representative value. The first is dedicated to Paul Merker and how his entanglement in questions surrounding antifascism and antisemitism has become a significant trope in narratives of national (de-)legitimisation since 1990. The second delves into the phenomenon of the dissident through the aperture of prominent singer-songwriter, Wolf Biermann. Viewed as a proponent of ‘true’ communism who confronted the SED with uncomfortable truths, this study interrogates the Biermann legend. The third looks at the canonised opposition of the 1980s and how memory thereof tends to omit the left-wing views of these groups in order to portray them as striving for liberal democracy and national unification. The dissertation concludes that communist-oriented opposition presents a rich seam with which the FRG’s public guardians of memory are able to communicate narratives significant to contemporary national legitimation and identity. It argues that awareness of the ideological conditioning of representations of the past and the significance of this for contemporary political debates should be taken into account more than is frequently the case.

A search for the production of a single top quark in association with a Z boson and an additional jet using data from proton-proton collisions at √s = 13TeV collected by the Compact Muon Solenoid (CMS) experiment at the Large Hadron Collider is presented. This is a rare process that is predicted by the Standard Model. This search focussed on identifying the nal state containing two leptons from the Z boson decay, two jets from the decay of the W boson produced by the top quark decay, a b-jet from the top quark decay and a recoil jet. The signal was dominated by backgrounds involving a real Z boson or two promptly produced leptons consistent with a Z boson decay, primarily Z+jet and top quark pair production. As such, a Boosted Decision Tree was used to enhance the separation between the signal and background processes. Using a dataset corresponding to 35.9 fb⁻¹, signal strengths of 6:21+2:34 -2:67 and 4:73+1:92 -2:02 were measured for this process when the Z boson decays into a pair of electron or muons, respectively, and the W boson decay hadronically. These measurements correspond to an observed (expected) signal signi cance of 2.72σ (0.46σ) and 2.50σ (0.54σ), respectively, when compared to the background-only hypothesis. These measurements are consistent within two standard deviations of the Standard Model prediction. The CMS experiment's new tracking detector at the High-Luminosity Large Hadron Collider will require the ability to reconstruct all charged tracks with transverse momentum greater than 2-3 GeV within 4 μs so that they can be used in the Level-1 trigger decision. One of the proposed track nders is an FPGA-based based solution using a fully time-multiplexed architecture, where track candidates are reconstructed using a projective binning algorithm based on the Hough Transform. Studies into the suitability of a linearised χ² algorithm for fitting track parameters were undertaken and it was found that its performance was inferior compared to that of a combinatorial Kalman Filter tter. The impact of reducing the minimum track transverse momentum from 3 GeV to 2 GeV on the proposed system was also evaluated. The resulting degradation of performance was found to be recoverable by improving the handling of multiple scattering in the track finding and fitting algorithms.

Arrays of micron sized light-emitting diodes (micro-LEDs) allow high-frequency spatial and temporal modulation of an optical signal. Contacting micro-LED arrays to complementary metal-oxide-semiconductor (CMOS) electronics provides a mm-chip-scale device with a high level of control over the optical emission through digital input. Such devices enable novel forms of optical communication and imaging to be investigated. This thesis first demonstrates the use of CMOS controlled micro-LEDs in multi-level intensity modulated optical communications. By generating signals in a discrete fashion with weighted groups of pixels in an array, the non-linearity issues of single LED elements can be avoided and the device functions as a digital-to-light converter. Pulse amplitude modulation and discrete orthogonal frequency division multiplexing were performed, yielding data rates up to 200 Mb/s, and spectral efficiencies up to 3.96 bits/s/Hz. A novel form of optical communications is introduced where data is sent through modulation of the temporal correlation of a pulsed optical signal. Utilising single-photon detection at the receiver enables transmission at low received power levels, on the order of picowatts. While data rates prove to be modest, the scheme is robust to both constant and modulated background signals. Additionally, the implementation requires only simple semiconductor components, exhibits low electrical power consumption, and has been demonstrated under power from a nanosatellite simulation testbed. The pulse correlation approach also presents opportunities in imaging. Received signals are dependent on optical power; therefore, if relative emitted power from multiple transmitters is known, information on the reectance or absorption of an intermediate material can be obtained. This potentially enables colour or hyperspectral imaging with single-photon detectors by temporally structuring light sources. Proof-of-principle experiments have been performed using commercially available LEDs of 10 different wavelengths and printed colour targets.

3D bioprinting is the additive manufacture of biological materials, such as cells, and has been implemented over the last two decades to print 3D constructs which can mature into functional tissues. Although there are many bioprinting techniques, there are few that are capable of simultaneously printing two or more cell types at high resolutions, high cell densities and high initial cell viabilities. These printing characteristics are required to pattern cells in tissue-like micro-architectures and to quickly mature physiologically relevant tissue. We developed a novel 3D bioprinter and bioprinting methodology, designed to pattern cells without compromising these printing characteristics. Initially a droplet-in-oil 3D printer was created, which assembled mm-scale aqueous droplet networks composed of thousands of picolitre volume micro-compartments. These networks were programmed to show emergent tissue-like properties, mimicking nervous tissue's rapid electrical communication or self-folding in a manner similar to muscle contractions. This printing process was then adapted to pattern HEK-293T cells within droplet networks at high droplet resolution (~50-150 μm), high initial cell viability (90±4%) and high droplet cell density (~30x106 cells/mL). Capillary-like and layered sheet cell architectures were formed with two printed fluorescent cell populations. These 3D printed constructs were transferred to culture medium with minimal loss in pattern fidelity using a novel phase transfer approach. Patterned HEK-293T cells developed into dense cell organisations which showed, high cell viabilities, high cell numbers (up to ~18,000) and mitotically active cells, when cultured over 7 days. Specialised tissues were also developed, here, patterned ovine mesenchymal stem cells were differentiated, after printing, into chondrogenic progenitor cells as affirmed by Sox9 expression.

Natural exposure to Plasmodium falciparum’s asexual blood-stage results in protection against severe disease, but no vaccine using the widely-studied blood-stage antigens apical membrane antigen 1 (AMA1) or merozoite surface protein 1 (MSP1) has proven convincingly protective in clinical trials. Challenges include antigenic polymorphism, the apparent requirement for exceptionally high antibody concentrations for protection, and clinical-grade production of conformationally-accurate recombinant protein antigens followed by formulation with a human-compatible adjuvant. This thesis describes the generation of viral-vectored vaccines targeting ten less-studied blood-stage antigens, focusing upon antigens implicated in erythrocyte invasion. These vaccines were immunogenic in mice and rabbits. The rabbit antibodies raised were functionally active in the in vitro assay of parasite growth inhibitory activity (GIA). GIA with antibodies against one antigen, RH5, exceeded that achieved with antibodies against the ‘gold standard’ AMA1 or MSP1 antigens. This antigen’s amino acid sequence is relatively conserved between parasite strains. Importantly, and unlike anti-AMA1 and MSP1 antibodies, the GIA effects transcend genetically diverse strains. It was hypothesised that blockade of the interaction of RH5 with its receptor basigin was likely to be a mechanism of action of anti-RH5 antibodies. Vaccine-induced polyclonal anti-RH5 serum was found to be capable of blocking this interaction, as well as merozoite attachment to erythrocytes. A panel of RH5-specific monoclonal antibodies were raised: those which block the RH5-receptor interaction were capable of neutralising parasites. Minimal linear epitopes recognised by these antibodies were mapped, and are likely to be within or close to RH5’s receptor binding site. These data support prompt clinical testing of RH5-based vaccines, and shed light upon the mechanism of action of anti-RH5 antibodies. However substantial challenges remain in establishing whether this antigen, selected on the basis of the in vitro assay of GIA, will be capable of achieving in vivo protection against P. falciparum. Further work presented in this thesis addresses the use of quantitative PCR data to assess blood-stage vaccine efficacy in experimental human challenge with P. falciparum, and the use of surface plasmon resonance to establish more detailed characterisation of vaccine-induced antibody responses. Finally, the results of P. falciparum challenge of RH5-vaccinated Aotus nancymaae non-human primates are presented.

Lithium-ion mobility in solid-state systems is an important field with significance for a range of technological interests, especially in the field of energy materials. The binary lithium compounds Li2O and Li3N have been studied using modern computational techniques to elucidate their diffusion properties. The macroscopic diffusion coefficients have been calculated and the underlying microscopic diffusion processes elucidated using molecular-dynamics-based techniques. In both systems studied the diffusion has been modelled over a wider temperature range than previously attempted. The agreement between the calculated diffusion coefficients and the best available experimental data surpasses previous computational studies. The level of agreement achieved is due to the use of force-field non-equilibrium molecular dynamics (FF-NEMD). This method, which has only recently been applied to solid-state diffusion, allows rates of diffusion that are typically too low to be studied with equilibrium molecular dynamics to be modelled. NEMD uses a fictitious external field to increase the frequency of the rare diffusion events in a predictable manner without changing the nature of the diffusion mechanisms. In the case of Li2O the transition from the non-superionic to the superionic regime has been modelled. The dominant mechanism in each regime has been determined: in the non-superionic regime a concerted mechanism dominates and in the superionic regime an interstitial-mediated mechanism dominates. For Li3N the anisotropic nature of the lithium diffusion coefficient has been modelled. The diffusion mechanisms dominant for different directions have also been elucidated. The rapid diffusion in the (001) plane of the hexagonal structure has been explained by the presence of vacancies on the in-plane Li sites, both in this thesis and in previous works. Previous studies have explained this by the presence of contaminants leading to non-stoichiometric Li3N. However, in this thesis the under occupation of these sites has been explained by the formation of Li2 dumbbells, or site sharing, largely about the interlayer Li sites, but also about the in-plane Li sites. The existence of these dumbbells explains the experimental diffusion coefficients of stoichiometric Li3N.

Background and Aims: Breast cancer is a leading cause of female mortality in the Western world. It is well established that the spread of breast cancer, first locally and later distally, is the major factor in patient prognosis. Experimental systems of breast cancer rely on cell lines usually derived from primary tumours or pleural effusions. Two major obstacles hinder this research: (i) Some known sub-types of breast cancers are not represented within current cell line collections; (ii) the influence of the tumour microenvironment is not usually taken into account. Experimental Design: We developed a three-dimensional assay prepared from freshly harvested breast cancer tissue embedded in soft rat collagen I cushions. Invasive behaviour and tumour response to tamoxifen therapy was measured. Changes in proliferation, apoptosis and tumour volume in response to tamoxifen treatment were quantified using image analysis software and optical projection tomography. Further cell line based experiments and histopathological analysis of resection specimens were subsequently investigated to investigate the role of EGFR signalling pathways in driving invasion. Results: We demonstrate a technique to culture primary breast cancer specimens of all sub-types. Within 2-3 weeks, individual and collective invasion of epithelial cells into the surrounding collagen I was observed using phase contrast light microscopy and histopathological methods. Addition of tamoxifen to preparations derived from ER+ tumours demonstrated a range of response as measured by proliferative and apoptotic markers and significant reduction in tumour volume not seen in ER-specimens. Changes in tumour volume allowed stratification into responsive and nonresponsive tumours. EGF within the culture medium appeared to drive a change in phenotype from ER+ to triple negative phenotype and acted as a driver for epithelial invasiveness. Conclusion: Here, we developed an assay to culture human breast tumours without sub-type bias and to investigate and quantify the spread of these ex vivo. This method could be used to quantify drug sensitivity in primary cancers under conditions closer to real life. This may provide a more predictive model than currently used cell lines.

Accurate and robust localisation is a fundamental aspect of any autonomous mobile robot. However, if these are to become widespread, it must also be available at low-cost. In this thesis, we develop a new approach to localisation using monocular cameras by leveraging a coloured 3D pointcloud prior of the environment, captured previously by a survey vehicle. We make no assumptions about the external conditions during the robot's traversal relative to those experienced by the survey vehicle, nor do we make any assumptions about their relative sensor configurations. Our method uses no extracted image features. Instead, it explicitly optimises for the pose which harmonises the information, in a Shannon sense, about the appearance of the scene from the captured images conditioned on the pose, with that of the prior. We use as our objective the Normalised Information Distance (NID), a true metric for information, and demonstrate as a consequence the robustness of our localisation formulation to illumination changes, occlusions and colourspace transformations. We present how, by construction of the joint distribution of the appearance of the scene from the prior and the live imagery, the gradients of the NID can be computed and how these can be used to efficiently solve our formulation using Quasi-Newton methods. In order to reliably identify any localisation failures, we present a new classifier using the local shape of the NID about the candidate pose and demonstrate the performance gains of the complete system from its use. Finally, we detail the development of a real-time capable implementation of our approach using commodity GPUs and demonstrate that it outperforms a high-grade, commercial GPS-aided INS on 57km of driving in central Oxford, over a range of different conditions, times of day and year.

The work in this thesis falls into three parts. The first part relates to the time spent with the industry as part of this CASE Studentship, whilst the second and third parts relate to stochastic transmission models and the analysis of interventions imposed upon these models. The second and third parts are linked by a common aim, which is to develop models to understand the dynamics of Salmonella transmission on a pig farm and thus identify key drivers of Salmonella. The thesis begins with an assessment and analysis of a Farm Tool Questionnaire that was developed by the industry. A total of 28 farms were visited, had pooled faecal samples taken and completed the Farm Tool Questionnaire. The main aim of this study was to pilot the developed tool and identify any areas that could be modified in order to enhance its usability. Furthermore, the results from the study were used in an attempt to highlight any possible areas of farm management that differ between Platinum farms and non-Platinum farms. It was shown that Platinum farms were likely to adopt a subset of biosecurity practices, which should consequently encourage farms to adopt a range of biosecurity practices rather than focusing on one aspect of biosecurity. The thesis then turns to the development of mathematical models in order to try and understand how the components of the system interact by using both numerical simulation and mathematical analysis. As farming methods differ considerably between farms, two key forms of unit structure were analysed: a fully slatted unit and a solid floored unit. The models were developed using a semi-stochastic transmission model similar to Xiao et al. [2006] (Y. Xiao, D. Clancy, N. P. French & R. G. Bowers. A semi-stochastic model for Salmonella infection in a multi-group herd. Mathematical Biosciences, 200(2):214-233, 2006). These were then used to assess any differences in dynamics as a result of farm structure. Finally, both sets of models were analysed in order to identify any possible interventions that could have some form of control on Salmonella prevalence at slaughter. The models showed that the key drivers of Salmonella transmission were the amount of bacteria shed and the probability of infection after exposure. As such, interventions focusing on these aspects should be implemented in order to see the most beneficial results. The rate at which infection was able to spread when shedding was high was found to be of great importance within the various models; indicating that solid flooring is a potential risk factor. Furthermore, as infection was able to spread quickly within the solid-floored unit, the time interval at which cleaning and disinfection were carried out could be of importance. However, this would require further investigation.

This research project is an enquiry into a social abstraction. It is a theory building exercise that centres on a descriptive multiple-case study of two senior high schools, a private Jesuit school with a mission to educate students for university disciplines and a public charter school aimed for career preparation, in the United States’ capital city of Washingto, District of Colombia. A combination of survey, dialogic, observational and documentary techniques was employed in a multi-methodological approach. This enterprise draws on Basil Bernstein’s pedagogical theory of symbolic educational knowledge codes whilst attempting to fill a gap in its theoretical apparatus.  The endeavour highlights some effects of alliances between business and education whilst exploring concepts of power, critical thinking, and knowledge. A realist theoretical lens is a key component in this study where business norms are conceptualised as a social entity ontologically effectual to educational processes. Other theorised perspectives were valuable to this study as well. This project demonstrates that social business norms penetrate the learning processes affecting school administration, instruction, and pupil conceptions of knowledge. Traditional forms of education are revealed to be in competition with other forms of education such as training for employable and transferable social skills where the virtual high technology age is perceived as a contributor to rapid social change. One of the unique analyses drawn from the research field work elucidated differences between a religious paradigm and a careerist pedagogical approach, both functioning in a democratic market economy. Ultimately, three contextual themes emerge from the data: entrepreneur ethics, social skills, and technology; all indications of how business mores are apparent in education. Whilst the sociology of education is central, basic economics of market dynamics were recognised and considered in this analysis. The salient theme in this endeavour is the control of knowledge by institutions and/or individuals.

A realtime wireless motion tracking system is developed. The system is capable of tracking the orientations of multiple wireless sensors, using a semi-distributed implementation to reduce network bandwidth and latency, to produce real-time animation of rigid body models, such as the human skeleton. The system has been demonstrated to be capable of full-body posture tracking of a human subject using fifteen devices communicating with a basestation over a single, low bandwidth, radio channel. The thesis covers the theory, design, and implementation of the tracking platform, the evaluation of the platform’s performance, and presents a summary of possible future applications.

Laminated composites are increasingly employed in a variety of industries ranging from Aerospace to Wind Power. The high specific stiffness and strength of these materials renders their wider application advantageous in many fields. However, the broader implementation of such composites is frequently restrained by their poor impact resistance and damage tolerance. Even events as innocuous as a dropped tool can impart significant damage to such materials. Such damage can lead to drops in the strength and stiffness that are unacceptable for many applications, particularly those in Aerospace. 3D woven composites present a possible means of improving the impact resistance and damage tolerance of composite materials. The incorporation of out-of-plane fibres, transversely passing through layers of in-plane fibres, is the means by which this improvement in performance is obtained. This body of work presents an investigation into the behaviour of three dimensionally woven carbon fibre composites. Specifically, the subject composite fabric had an orthogonally woven three dimensional structure. The novelty of these materials is such that knowledge and understanding of their mechanical behaviour is very limited. The purpose of this work was to remedy this through experimental and analytical analysis of these composites. The 3D woven materials were characterized experimentally using a variety of techniques. In addition to evaluating the material experimentally, analytical methods were also used. Current analytical methods were found to be deficient in their incapacity to account for in-plane crimp on a micro scale. As a result a new micro scale approach for predicting the stiffness and strength of these 3D woven materials was developed. The composites used for this thesis were tested using a variety of means. The range of test methodologies used subjected the materials to in-plane, out-of-plane, dynamic and quasi- static loadings. Techniques used included; tension, shear, impact, compression after impact, bolt shear out and bearing pull through. Other means implemented included microscopy, C-scanning and Digital Image Correlation. In addition, conventional composites made from unidirectional pre-pregs or Non-Crimp Fabrics (NCFs) were tested to provide a basis for comparison. Analysis and prediction of the behaviour of conventional laminated composites can be performed using a variety of methods. While the range of methods available is broad, they commonly use individual plies of composite as their fundamental building blocks. This is both convenient analytically and experimentally as the properties of such individual lamina may be found with reasonable ease. However, 3D woven composites are integrated laminates due to the out‐of‐plane fibres they possess. As a result, the accuracy of conventional experimental or analytical methods for evaluating these materials is likely to be poor. In order to gain a better understanding of the behaviour of these 3D woven materials a new micromechanics model was developed. In contrast to other available methods, this micromechanics approach examines the effect of crimp at the fibre level. The method proposed is also distinct in its capability of simultaneously accounting for varying crimp across and along a section of composite.

There is interest in modelling the industrially important intermetallic phase transformation of Al6(Fe,Mn) to a-Al-(Fe,Mn)-Si that occurs during homogenisation of direct-chill cast ingots of 3XXX aluminium alloy. The kinetics of this "6-to-a" transformation are studied to aid the modelling. The initial investigation uses an Al-0.5Fe-1.0Mn-0.2Si (wt.%) alloy. The morphology of the transformation and the associated local composition changes are studied using a range of electron optical techniques, including energy-filtered transmission electron microscopy (TEM), convergent-beam electron diffraction and field-emission-gun scanning electron microscopy. The transformation proceeds by eutectoid decomposition of the Al6(Fe,Mn) phase into a-phase and aluminium solid solution. The transformation requires intake of silicon from the surrounding matrix, which we believe is supplied along the migrating transformation front. This gives a eutectoid growth rate that is comparatively fast; hence nucleation is found to be the key rate-controlling factor. Intake of manganese is not required for transformation, but does occur on continued annealing. The morphology of transformed particles is not static: eutectoid aluminium coalesces and ripens into "Al-spots", and wetting of Al6(Fe,Mn)/a-phase interfaces by the matrix may ultimately lead to fragmentation of two-phase particles. Roll-bonded diffusion couples permit the study of 6-to-a nucleation by steadily increasing the silicon content in an Al-Fe-Mn alloy (initially containing only Al6(Fe,Mn) particles). Nucleation is found to be sporadic. Results also indicate that the transformation preferentially nucleates at boundaries in the matrix - this is confirmed by TEM studies. If there is insufficient eutectoid nucleation, transformation is by the dissolution of Al6(Fe,Mn) supplying solute for the growth of a-phase. However, preliminary diffusion studies using silicon-coated alloy blocks indicate that a typical ingot microstructure gives sufficient 6-to-a nucleation for the alloy to achieve equilibrium levels of a-phase eutectoidally.

This thesis examines the post-transcriptional regulation of the gluconeogenic mRNAs PCK1 and FBP1 in Saccharomyces cerevisiae. By construction of a set of chimaeric PCK1-PGK1 reporter genes, it was possible to show that sequences from the 5' end of the PCK1 mRNA were capable of conferring post-transcriptional glucose regulation on the reporter. These regions were presumably the ultimate target of the glucose signal on the wild-type PCK1 mRNA. Sequences from the 5' end of the SDH2 mRNA had previously been shown to be required for the rapid degradation of that transcript observed in the presence of glucose. In addition, a number of other elements within the PCK1 gene proved capable of constitutively destabilising the reporter mRNA. One of these bore similarity to a 70 bp mRNA destabilising element from the highly unstable MATα1 mRNA. Overall, the decay patterns of the chimaeric PCK1-PGK1 and FBP1-PGK1 mRNAs were consistent with other studies of the decay of chimaeric PGK1 mRNAs.