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Insoluble, hyper-phosphorylated aggregates of tau are a pathological hallmark of a range of clinically diverse neurodegenerative diseases termed tauopathies, of which Alzheimer's disease (AD) is the most common. The mechanisms linking neuronal death and tau dysfunction are not fully understood, but mutations uncovered in microtubule associated protein tau (MAPT) that cause aggressive frontotemporal dementia confirm a causative relationship between tau dysfunction and neurodegeneration. The tau protein exists as multiple protein isoforms in the adult human central nervous system (CNS), generated by alternative splicing of the MAPT gene. Disruptions to tau splicing are associated with a number of tauopathies, however, in vitro and in vivo models to understand the consequences of disrupted tau splicing have been lacking, due in part to species differences in tau splicing and the developmental regulation of tau in human neurons. Recently, the development of induced pluripotent stem cells (iPSC) has enabled the derivation of limitless numbers of human neurons with disease associated mutations of interest. The use of this system to model tauopathy has been challenging, in part due to the developmental regulation of tau splicing, with extended culture periods required for mature tau expression in iPSC derived neurons. Cerebral organoids are 3D based iPSC derived neuronal cultures, which help capture the heterogeneity and key aspects of architecture of the developing brain, such as distinct progenitor zones and lamination of neurons into distinct layers. We hypothesised that this may allow neurons to mature at a faster rate, resulting in earlier expression of all 6 isoforms of tau without extensive culture times. We investigated the utility of iPSC-derived cerebral organoids to model key aspects of tau biology. Cerebral organoids showed high variability in neuronal content and tau expression. To reduce this heterogeneity, we generated engineered cerebral organoids (enCORs), which utilise a floating scaffold to increase the efficiency of neural induction and reduce heterogeneity. We show that enCORs provide a robust and reproducible in vitro system for the analysis of tau expression and splicing in a 3D model. To investigate the effect of tau mutations, we generated enCORs from an isogenic series of iPSC with the MAPT 10+16 and P301S mutations. The presence of tau splicing mutations results in disease-associated alterations in tau expression, specifically a dose-dependent increase in 4R tau isoforms in the presence of the MAPT 10+16 variant. While the developmental regulation of tau splicing is conserved, maturation of tau splicing is accelerated in 3D cultures compared to 2D cultures. Finally, enCORs with coding mutations in MAPT are able to produce seed-competent tau species, suggesting enCORs recapitulate early features of tau pathology. In summary, enCORs provide a novel, robust in vitro system for the study of tau in development and disease.

Superconductivity in high temperature superconducting materials arises due to the constituent electrons becoming strongly correlated. In particular, in the Iron based family of superconductors, antiferromagnetic fluctuations of the electron spins and charge fluctuations of the Iron d-orbitals are thought to be important. The strong correlations of the electrons in an Iron based superconductor lead to the electronic ground state adopting a lower symmetry than the crystal lattice. Transport studies of these systems under the application of uniaxial strain show a strongly anisotropic response of the materials to straining along different lattice directions, suggesting that the electronic correlations are in fact coupled to the lattice. In this thesis I present a study of the response of the magnetic and superconducting states of these Iron based materials to changes of their crystal structure induced by applying uniaxial strain or through doping. I first examine the response of the magnetism in Fe1+xTe, the parent compound of the Iron chalcogenides, to the change that occurs in the crystal structure as the system is doped with Iron. I present a spin polarized STM study of the magnetism throughout the phase diagram of Fe1+xTe using in-situ prepared magnetic tips to measure the spin structure. By using the STM tip to remove excess Iron atoms from the surface I show that it is possible to decouple the effects of the excess Iron atoms from the change of crystal structure. Therefore showing the effect of the structural change on the magnetism. Next I present an STM study of how the superconductivity in the tetragonal LiFeAs system responds to the application of uniaxial strain deforming the crystal structure. I describe the construction of a modifed STM sample holder that allows for the in-situ application of a variable Strain to the LiFeAs sample. I present the resulting impact of this straining process to the superconductivity of LiFeAs on an atomic scale and report the formation of a strain induced charge density wave state that coexists with the superconductivity. In the final chapter I report a quasiparticle interference study of the superconducting state of Sulphur doped FeSe and discuss the results in comparison of those from the literature for the undoped FeSe system.

The primary aim of this project was to both investigate injury epidemiology and create methods to potentially reduce injuries within elite ice hockey athletes. Chapter Four assessed the injury problem within ice hockey by retrospectively collecting data from two National Collegiate Athletic Association (NCAA) division III teams across a four year period investigating the prevalence, location, severity and type of injuries sustained. Findings showed that contact injuries were more prevalent (58%) than non-contact injuries (42%), with the knee (15%), shoulder (12%) and hip (13%) being the most frequently injured locations when both contact and non-contact injuries were combined. When investigating only non- contact injuries the hip complex (hip, groin and thigh) (50%) was by far the most injured location with similar frequencies, in terms of injury severity, observed. Chapter Five analysed intrinsic risk factors of the ice hockey athlete by investigating differences of hip range of motion (ROM), strength and functional tests between ice hockey athletes, soccer athletes and control participants. Results demonstrated that ice hockey athletes had significantly weaker hip adduction (p = 0.023) and flexion in sitting (p = 0.001) strength compared to soccer athletes and less external rotation strength compared to control participants (p = 0.010). Ice hockey athletes also displayed greater strength than control participants in flexion in sitting (p = 0.005). Ice hockey athletes exhibited greater ROM in abduction (p = 0.001) than control participants and greater adduction than both soccer athletes (p = 0.003) and control participants (p = 0.004). Ice hockey athletes exhibited less hip flexion in lying (p = 0.001) and external rotation (p < 0.001) when compared to control participants. Ice hockey athletes also presented with an increased number of positive flexion, abduction and external rotation (FABER) tests compared to both soccer athletes and control participants. Chapter Six investigated the effectiveness of the newly created hip screen by comparing ice hockey athletes with and without a previous non-contact hip injury and their performance during the hip screen. Findings demonstrated that athletes who had no previous hip injury had greater internal (p = 0.004) and external rotation ROM (p = 0.022) on the dominant (Dom) limb and greater flexion in sitting (p = 0.031) and internal rotation ROM (p = 0.050) on the non-dominant (Ndom) limb. Although non-significant, previously injured athletes also displayed less ROM in all hip movements compared to previously uninjured athletes. Similar trends were found in strength measures with previously uninjured athletes showing significantly stronger abduction (p = 0.012) on the Dom limb and flexion in lying on both the Dom (p = 0.008) and Ndom limb (p < 0.001). Previously injured athletes displayed more positive FABER (Dom; 13% vs. 0%, Ndom; 13% vs. 5%), Trendelenburg (Dom; 75% vs. 58%, Ndom; 50% vs. 5%) and Ober’s (Dom; 13% vs. 5%, Ndom; 75% vs. 68%) tests with higher scores on the overall screen than uninjured athletes. Chapter Seven investigated the intra and inter-tester reliability of the hip screen finding that intra-class correlation coefficients (ICC) of intra-tester reliability of the ROM (0.49), strength (0.80) and overall screen (0.76) was moderate to near perfect. Inter-tester reliability again showed very large ICCs for ROM (0.71), strength (0.77) and overall screen scores (0.81). The minimum criterion change (MCC) (3.78 points) was also found to be small for the screen score change needed to be viewed as clinically worthwhile. These findings demonstrate that the screening procedure developed is useful, reliable and repeatable when assessing the ice hockey athlete’s hip. Chapter Eight demonstrated that all participants regardless of group improved their ROM and strength measures following the intervention period. However, it was demonstrated that the ice hockey intervention (IHI) group saw a decrease in the amount of positive FABER tests following the intervention compared to ice hockey control (IHC) and intervention control (IC) group (IHI: pre 15 vs. post 6; IHC: pre 15 vs. post 14; IC: pre 10 vs. post 9). It was also demonstrated that the IHI group improved above the MCC value presented within Chapter Seven with regards to the overall hip injury screen score (pre 48 vs. post 52) indicating that ice hockey athletes who participated in the intervention programme may be at a decreased risk of sustaining a non-contact hip injury due to the intervention exercises targeting weaknesses highlighted in the hip injury screen. In summary, the current project achieved the stated aims by demonstrating that the hip complex was the most common location for injuries of a non-contact nature and the creation of a reliable and repeatable hip injury screen that allows clinicians to potentially highlight athletes considered as ‘at risk’. To complete the injury prevention sequence, future work would be necessary to track athletes who scored low on the hip injury screen over time either following the intervention or as a control to assess if they were more or less likely to sustain a non-contact hip injury. Future work should also continue to optimise the intervention strategy to further develop and enhance its effectiveness in the prevention of non-contact hip injuries. This could be achieved either through a longer protocol that is incorporated into routine training or individualisation of the programme and as such provide a valuable tool for clinicians and medical teams wishing to reduce the risk of ice hockey athletes sustaining a non-contact hip injury.

Gravitational lensing studies the distortions of a distant galaxy’s observed size, shape or flux due to the tidal bending of photons by matter between the source and observer. Such distortions can be used to infer knowledge on the mass distribution of the intervening matter, such as the dark matter halos in which clusters of individual galaxies may reside, or on cosmology through the statistics of the matter density of large scale structure and geometrical factors. In particular, gravitational lensing has the advantage that it is insensitive to the nature of the lensing matter. However, contamination of the signal by correlations between galaxy shape or size and local environment complicate a lensing analysis. Further, measurement of traditional lensing estimators is made more difficult by limitations on observations, in the form of atmospheric distortions or optical limits of the telescope itself. As a result, there has been a large effort within the lensing community to develop methods to either reduce or remove these contaminants, motivated largely by stringent science requirements for current and forthcoming surveys such as CFHTLenS, DES, LSST, HSC, Euclid and others. With the wealth of data from these wide-field surveys, it is more important than ever to understand the full range of independent probes of cosmology at our disposal. In particular, it is desirable to understand how each probe may be used, individually and in conjunction, to maximise the information of a lensing analysis and minimise or mitigate the systematics of each. With this in mind, I investigate the use of galaxy clustering measurements using photometric redshift information, including a contribution from flux magnification, as a probe of cosmology. I present cosmological forecasts when clustering data alone are used, and when clustering is combined with a cosmic shear analysis. I consider two types of clustering analysis: firstly, clustering with only redshift auto-correlations in tomographic redshift bins; secondly, clustering using all available redshift bin correlations. Finally, I consider how inferred cosmological parameters may be biased using each analysis when flux magnification is neglected. Results are presented for a Stage–III ground-based survey, and a Stage–IV space-based survey modelled with photometric redshift errors, and values for the slope of the luminosity function inferred from CFHTLenS catalogues. I find that combining clustering information with shear gives significant improvement on cosmological parameter constraints, with the largest improvement found when all redshift bins are included in the analysis. The addition of galaxy-galaxy lensing gives further improvement, with a full combined analysis improving constraints on dark energy parameters by a factor of > 3. The presence of flux magnification in a clustering analysis does not significantly affect the precision of cosmological constraints when combined with cosmic shear and galaxy-galaxy lensing. However if magnification is neglected, inferred cosmological parameter values are biased, with biases in some cosmological parameters found to be larger than statistical errors. We find that a combination of clustering, cosmic shear and galaxy-galaxy lensing can provide a significant reduction in statistical errors from each analysis individually, however care must be taken to measure and model flux magnification. Finally, I consider how measurements of galaxy size and flux may be used to constrain the dark matter profile of a foreground lens, such as galaxy- or galaxy-cluster-dark matter halos. I present a method of constructing probability distributions for halo profile free parameters using Bayes’ Theorem, provided the intrinsic size-magnitude distribution may be measured from data. I investigate the use of this method on mock clusters, with an aim of investigating the precision and accuracy of returned parameter constraints under certain conditions. As part of this analysis, I quantify the size and significance of inaccuracies in the dark matter reconstruction as a result of limitations in the data from which the sample and size-magnitude distribution is obtained. This method is applied to public data from the Space Telescope A901/902 Galaxy Evolution Survey (STAGES), and results are presented for the four STAGES clusters using measurements of source galaxy size and magnitude, and a combination of both. I find consistent results with existing shear measurements using measurements of galaxy magnitudes, but interesting inconsistent results when galaxy size measurements are used. The simplifying assumptions and limitations of the analysis are discussed, and extensions to the method presented.

Duchenne muscular dystrophy (DMD) is the second most commonly inherited disorder in man, the phenotype of which displays pathological characteristics of altered skeletal muscle function including, amongst others, abnormal Ca2+ homeostasis and cell signaling. This study used the mdx mouse model of DMD to analyse purinergic responses in dystrophic muscle cells in vitro and skeletal muscles in situ. Initial investigations excluded reduction in ATPe hydrolysing potential from explaining previous observations of heightened nucleotide sensitivities in dystrophic myoblasts. Instead, this study demonstrates for the first time that significant P2X7 receptor abnormalities exist in dystrophic myoblasts and skeletal muscles of the adult mdx mouse; significantly elevated levels of P2X7 receptor mRNA and protein expression were found in primary myoblast cultures, myoblast lines and muscles in situ at 4 months of age and this was extended to analysis of changes in individual P2X7 splice variants. These abnormalities were shown to extend to functional responses in cultured myoblast lines, where heightened P2X7 receptor-specific sensitivity was shown to be associated with significantly higher basal and induced levels of, and altered time course of, extracellular-signal regulated kinase (ERK1/2)phosphorylation in dystrophic myoblasts. ERK activation responses were shown to be inducible by ATP and BzATP stimulation, inhibited by P2X7 antagonists, and unresponsive to ivermectin, thus confirming P2X7 receptor involvement. Similar up-regulation of P2X7 receptor expression coinciding with ERK phosphorylation was demonstrated in mdx muscles in vivo. Additionally, NAD was identified as a mediator of P2X7 responses in dystrophic myoblasts. This study has also employed a mass spectrometry based approach to investigate the immediate downstream effects of P2X7 activation in cultured myoblasts; allowing identification of multiple potential signaling relays for future study that are discussed. The potential for a link between P2X7 receptor and dystrophin expression has been suggested here through the demonstration that abnormalities in P2X7 receptor expression and function are corrected by micro-dystrophin expression in dystrophic myoblasts. In vivo pharmacological P2X7 receptor inhibition using CBBG significantly reduced the number of revertant fibres in dystrophic muscle, indicating a reduction in degenerative/regenerative activity. The data presented in this thesis highlight a novel role for P2X7 receptor signaling in dystrophic myoblasts and muscles in situ; proposing the potential for beneficial therapeutic strategies aimed at manipulating P2X7 signaling responses in vivo, with a view to slowing the progression of what is at present an incurable and invariably fatal disease.

This thesis aims to investigate the formation of vesicles by the use of synthetic molecules and then seeks to enhance their stability through the addition of hydrophobic monomer or a second polymeric species. Prior to this, Chapter 1 reviews vesicle forming molecules, methods for production, analytical techniques for vesicles and finally applications of vesicle technology. Chapter 2 uses Dioctadecyldimethylammonium Bromide (DODAB) to form vesicles and through the swelling and polymerisation of hydrophobic monomers, seeks to enhance the stability of the vesicles. Transmission electron microscopy reveals vesicles with polymer beads on the bilayer, due to phase separation between polymer and DODAB. Based on the observed phase separation in the DODAB system, a change to the use of block copolymers is made. Chapter 3. Three block copolymers are synthesised and characterised (NMR, GPC, (Cryo) TEM) with a view to forming a more compatible vesicle forming system. Analysis reveals that PEG4S-b-PMA164 forms polymer vesicles (polymersomes) upon dissolution in THF and slow addition of water. Cryo-TEM is used to create a morphology diagram of the block copolymer. Chapter 4 uses the polymersome forming block copolymer in a bid to enhance compatibility between vesicle and monomer. The polymersomes are swollen in place of the DODAB system. Despite an envisaged compatibility between monomer and polymersomes, the resultant polymersome structures adopt a 'tube walled' arrangement. Cryo and negative stain TEM are used to judge the effectiveness of this approach. Finally in Chapter 5 the effect of the addition of a Brij surfactant to the polymersomes in an attempt to form rafts in the bilayer is investigated. Additionally the effect of adding PMMA homopolymer to PEG4S-b-PMMA164 during polymersome formation is investigated as an alternative approach to monomer swelling.

Selection has been primarily focussed on the use of ability and aptitude measures as they have been shown to predict job performance in uniformed organisations. Personality assessment has largely been ignored as a possible contributor to improving predictions of performance. The emergence of the Five Factor Model as a framework for personality research, together with the development of the Trait Self Description Inventory (TSDI), has provided the opportunity to investigate how personality assessment might improve upon existing selection methods to predict performance in training. It was found that existing criterion measures did not fully reflect the core aims of the training organizations. This led to the use of a Leadership Trait Rating Scale as a criterion measure for subsequent investigation of the psychometric properties of the TSDI, and the development of a performance taxonomy. Five studies were carried out. Four of the studies involved soldiers and officers from the British Army as participants. These studies were undertaken to contrast the predictive validity of the Big Five factors against overall and specific areas of performance and to examine the incremental validity of the Big Five factors and their sub factors over general ability measures. The fifth study examined the general isability of the findings using similar data gathered from the Metropolitan Police Service. Contextual factors were found to have great influence on relationships between personality assessment and criterion measures. A novel, robust, two factor leadership model was identified. The first factor represented cognitively orientated leadership traits and the second, personality orientated leadership traits. These factors broadly equated to 'can do' and 'will do' attributes. Overall, the Big Five personality measures predicted no worse than, and, in some cases, as well as, some of the Army's Regular Commissions Board (RCB) dimensions. Big Five sub factors (facets) in certain situations were shown to predict performance better than the Big Five factors. The development potential of personality assessment for improving existing selection systems in uniformed organizations was confirmed by the findings.

We have used high resolution N-body simulations to investigate the internal properties of Cold Dark Matter (CDM) halos with virial masses of M(_200) ~ 10(^10) M(_o) at z = 0, comparable to those of dwarf galaxy halos, forming in the ACDM cosmology. In particular, we have focused on providing accurate constraints on the mass distribution in these objects at ~ 1% of the virial radius, r(_200)-. After a brief introduction (chapter 1), the first part of this thesis is concerned with establishing the conditions under which the distribution of mass in simulated CDM halos is unaffected by finite numerical resolution. In chapter 2, we present results from a comprehensive set of simulations of a single galaxy mass halo in which numerical parameters have been varied systematically in order to determine their impact on the spherically averaged mass profile. Based on these results, we have defined a set of convergence criteria that allow us to identify the radial extent over which the spherically averaged circular velocity profile can be considered reliably resolved to better than 10%. In chapter 3, we have examined the abundance of substructure found in three sets of "converged" simulations, and quantified the effect of increasing mass resolution on the number of resolved subhalos of a given mass. The second part of this thesis is concerned with the detailed analysis of the internal structure and kinematics of the simulated dwarf galaxy halos in our sample. In chapter 4, we analyse the structure and kinematics of the dwarfs for possible redshift dependence, and investigate whether these halos could sustain a gaseous disk. In chapter 5, we concentrate on mass dependent trends by performing a detailed comparison with galaxy and cluster mass halos. Finally, chapter 6 provides a summary of the main findings of this work and highlights aspects that may prove rewarding for further study.