The temporal structure, or complexity, of torque output is thought to reflect the adaptability of motor control and has important implications for system function, with high values endowing greater adaptability in response to alterations in task demand. The aim of this thesis was to investigate the effect of neuromuscular fatigue on the complexity of isometric muscle torque output. It was hypothesised that neuromuscular fatigue would lead to a reduction in the complexity of muscle torque output, as measured by approximate entropy (ApEn), sample entropy (SampEn) and the detrended fluctuation analysis (DFA) α scaling exponent. The first experimental study (Chapter 4) demonstrated that muscle torque complexity was significantly reduced during both maximal and submaximal intermittent fatiguing contractions, with the values at task failure indicative of increasingly Brownian noise (DFA α > 1.50). It was subsequently shown in the second study (Chapter 5) that this reduction in complexity occurred exclusively during contractions performed above the critical torque. It was next demonstrated, in the third study (Chapter 6), that pre-existing fatigue significantly reduced torque complexity and time to task failure, but still resulted in consistent values of complexity at task failure regardless of the time taken to reach that point. In the fourth study (Chapter 7) caffeine ingestion was found to slow the rate of reduction in torque complexity with fatigue, seemingly through both central and peripheral mechanisms. Finally, in the fifth study (Chapter 8) eccentric exercise decreased the complexity of torque output, with values only recovering to baseline levels after 24 hours recovery, in comparison to only 10 minutes recovery following isometric exercise. These results demonstrate that torque complexity is significantly perturbed by neuromuscular fatigue. This thesis has thus provided substantial evidence that the complexity of motor control during force production becomes less complex, and that muscles become less adaptable, with neuromuscular fatigue.

Knee injuries are highly prevalent in physically active individuals and are frequently associated with sport participation. Independently of the nature of the injury, subjective and objective clinical measures are used to assess, monitor and evaluate treatment outcomes in this population. To be clinically meaningful, these outcome measures should be relevant to the condition, the anatomical area, the individual or population, and importantly, possess adequate psychometric properties. Despite a high prevalence of knee injuries, there are several aspects of the subjective and objective knee evaluation in physically active individuals that remain unclear or have not been considered in previous research. The main aim of the present thesis was to fill some of the gaps identified in the literature regarding both subjective and objective knee measures in physically active individuals. Therefore, this thesis was divided into two distinct parts. The first part looked at the patient-reported outcome (PRO) measures of the knee and physical activity, and consisted of two studies. The first study was a systematic review conducted to explore the PRO measures that are commonly used in the evaluation of physical activity and return to sport following autologous chondrocyte implantation (ACI). Aiming as well, to provide a critical analysis of these instruments from a rehabilitative perspective. This review revealed not only the heterogeneity in the selection, but also in the timing and reporting of patient-reported activity scoring instruments following ACI, which makes a systematic comparison difficult and introduces bias into the interpretation of these outcomes. Another important finding of this review, was that the instruments currently used to evaluate postoperative outcomes in an articular cartilage repair population do not always fulfil the rehabilitative needs of physically active individuals. The second study was conducted in recreational marathon runners and aimed to provide normative values for a widely used knee specific PRO measure in athletes with knee injury, the Knee Injury Osteoarthritis Outcome Score (KOOS). Alongside the normative KOOS subscales values stratified by age group and history of knee injury that were presented, this study also showed that recent history of knee running-related injury (RRI) has a negative impact on the KOOS scores. In runners with no history of knee RRI, the results observed suggested a lack of interaction between KOOS subscale values and age. Furthermore, the KOOS values seen were substantially higher compared to previously published normative population-based KOOS values. The second part of the present thesis comprised three experimental studies concerning single-leg cycling (SLC) exercise testing, in particular assessing the potential use of the self-paced test (SPT) concept as an objective measure following knee surgery. The first study analysed the reliability of a 5x2 min stages SPT anchored to the rate of perceived exertion (RPE) for SLC exercise testing. This study showed that this test protocol elicits reliable cardiorespiratory and metabolic responses. The second study examined the validity of the SPT protocol used in the previous study, through a concurrent comparison against a conventional fixed power incremental SLC exercise test. This investigation showed that the 5x2 min SPT provides a valid objective means for assessing peak aerobic capacity in SLC exercise testing. Moreover, it may be associated with increased activity enjoyment comparatively to conventional testing. The third and last experimental study investigated the effect of a 10 kg counterweight device (CW10) on cardiorespiratory, metabolic and perceptual responses to SLC exercise testing. The results of this study demonstrated that the CW10 despite eliciting an improvement in the activity enjoyment, did not affect peak cardiorespiratory and metabolic responses to SLC exercise testing. When matched for test duration the SPT elicited higher peak power output and peak oxygen consumption than conventional incremental testing, regardless of the CW10 usage or not. In conclusion, the original work of the present thesis increases the body of knowledge of two distinct, but complementary fields in the subjective and objective knee assessment of physically active individuals. The outcomes provided both on PRO measures and SLC exercise testing, may have impact on the clinical practice of clinicians, sport rehabilitation professionals and researchers.

The main focus of this thesis was to determine psychologically-informed methods of enhancing endurance performance, particularly in endurance sport events. There were three main research aims. First, this thesis aimed to synthesise research conducted to date on the psychological determinants of endurance performance. A systematic literature review was conducted to identify psychological interventions that affect endurance performance in experimental research. Learning psychological skills, verbal encouragement, and head-to-head competition enhanced endurance performance, whereas mental fatigue undermined endurance performance. Second, this thesis aimed to inform the design of performance-enhancement psychological interventions for endurance sports. In the first study addressing this aim, focus group interviews were conducted with recreational endurance athletes of various endurance sports, distances, and competitive levels to identify psychological demands that are commonly experienced by endurance athletes. Seven common psychological demands were identified using a thematic analysis. These demands were commonly encountered away from the competitive environment (time investment and lifestyle sacrifices, commitment to training sessions, concerns about optimising training, and exercise sensations during training), preceding an event (pre-event stressors), and during an event (exercise sensations, optimising pacing, and remaining focused despite adversity). Psychological interventions that help endurance athletes to cope with these psychological demands could potentially enhance performance in endurance events. In the second study that aimed to inform the design of an intervention, a psychophysiology experiment applied research on the facial feedback hypothesis to determine whether frowning modulates perception of effort during endurance performance. Contrary to hypotheses, intentionally frowning throughout a cycling time-to-exhaustion test did not influence perception of effort or time to exhaustion. This finding suggests that novel interventions that are informed by the facial feedback hypothesis and that target the expression of a frown would be unlikely to enhance endurance performance. Finally, this thesis aimed to examine the effect of a psychological skills training intervention on performance in a real-life endurance event. A randomised, controlled experiment was conducted to examine the effect of learning motivational self-talk on performance in a 60-mile, overnight ultramarathon. Although performance times indicated that motivational self-talk possibly produced a performance enhancement that might benefit ultramarathon runners, additional data will be collected at the same ultramarathon in 2016 to draw firmer conclusions. Overall, the findings of this thesis draw attention to psychological factors that influence performance in endurance events and demonstrate that psychologically-informed interventions can enhance endurance performance. People involved in endurance sports, such as athletes and coaches, are therefore encouraged to systematically work on the psychological aspects of training, preparing for a competition, and competing. Suggestions for how to approach this practically are scrutinised throughout the thesis.

The aetiology of overactive bladder (OAB) is poorly understood. Current treatment modalities are associated with low success rates and poor long-term compliance. The aim of this thesis was to explore the new and alternative treatment, mirabegron, to assess the efficacy of traditional treatment options such as cystodistension for women with OAB and to ascertain whether underlying baseline parameters (e.g. urodynamic studies, cystoscopic findings, bladder biopsy results) have any impact on treatment outcomes. The aetiology of OAB was also studied to understand the impact of bladder wall thickness and the bladder microbiome in OAB to improve our understanding of the possible mechanisms of OAB. In this thesis, I have reviewed the current literature on OAB, cystodistension and the role of infection in OAB. The work presented in this MD investigates the effectiveness of mirabegron and cystodistension as treatment options for OAB. All studies were conducted in a 'real-life' clinical setting to recreate the challenges in daily clinical practice. Mirabegron was found to be an effective treatment option for patients with OAB. However, the benefits were not striking with 70% of patient reporting improvement of their symptoms at 6 weeks. This was converted into only a minority of patients (36%) reporting their incontinence was "much better" or "very much better". More research should be targeted at identifying patient characteristics that are associated with a better outcome. It was found to be a suitable non-invasive alternative to Botulinum Toxin A (BTXA) in 59% of patients with refractory OAB. However, over two thirds of patients discontinued mirabegron therapy within 1 year. A significant number of patient who persevered with mirabegron were on combination therapy with an antimuscarinic at 1 year. Randomised controlled trial comparing cystodistension with cystoscopy demonstrated no benefit from cystodistension in the treatment of OAB. In this group, the presence of bladder trabeculation on cystoscopy was found to be associated with a direct effect on maximum detrusor muscle contraction with a significant increase in contraction compared to patients with an absence of trabeculation (42.71 cmH2O vs 31.41cmH2O, p = 0.01). The presence of trabeculation also affected the symptoms of OAB with a significant decrease in the Filling Scores of the ICIQ-FLUTS LF questionnaire (8.45 vs 9.58, p=0.04). There was no relationship between urodynamic findings and bladder biopsy on baseline symptomology and outcome of treatment. In this cohort, a feasibility study assessing bladder wall thickness (BWT) recorded a significant increase in BWT in OAB patients with detrusor overactivity (DO) (5.6mm vs 4.2mm, p=0.006). Though ultrasound is unable to replace urodynamic studies, it may be useful tool in understanding the aetiology, disease progression and prediction of treatment outcomes in OAB. The bladder microbiome demonstrated a significant difference between the patients with OAB and healthy controls. Proteus was found to be significantly more prevalent in OAB patients (p=0.01) whilst Lactobacillus was significantly more common in healthy controls (p=0.02). The work in this MD suggests there may be variety of sub-types of OAB with different underlying mechanisms of action that may explain the large variation in outcomes with different treatment modalities. Further research will need to be performed to further explore and confirm these findings.

Recent advances in genome sequencing are improving our better understanding of genetic variation. However, the investigation of the genotype-phenotype relationship is still challenging, especially for the interpretation of the myriad of discovered genetic variants that weakly relate to disease. Recently, researchers have confirmed that disease causing genetic variants typically occur at functional sites, such as protein-protein or protein-ligand interaction sites. Giving this observation, several bioinformatics tools have been developed. This thesis first details VarMod (Variant Modeller), an algorithm that predicts whether nonsynonymous single nucleotide variants (nsSNVs) affect protein function. The recent Ebola virus outbreak in West Africa demonstrated the potential for the virus to cause edipdemics and highlighted our limited understanding of Ebola virus biology. The second part of this thesis focuses on the investigation of the molecular determinants of Ebolavirus pathogenicity. In two related analyses knowledge of differing pathogenicity of Ebolavirus species is used. Firstly, comparison of the sequences of Reston viruses (the only Ebolavirus species that is not pathogenic in humans) with the four pathogenic Ebolavirus species, enabled the identification of Specificity Determining Positions (SDPs) that are differentially conserved between these two groups. These SDPs were further investigated using analysis of protein structure and identified variation in the Ebola virus VP24 as likely to have a role in determining species-specific pathogenicity. The second approach investigated rodent-adapted Ebola virus. Ebola virus is not pathogenic in rodents but it can be passaged to induce pathogenicity. Analysis of the mutations identified in four adaption studies identified that very few mutations are required for adaptation to a new species and once again the VP24 is likely to have a central role. Subsequent molecular dynamics simulations compared the interaction of Ebola and Reston virus VP24 with human karyopherin alpha5. The analysis suggests that Reston virus VP24 has weaker binding with karyopherins and we propose that this change in binding may reduce the ability of Reston VP24 to inhibit human interferon signaling.

In this Thesis we explore the problem of structural alignment of protein molecules using statistical shape analysis techniques. The structural alignment problem can be divided into three smaller ones: the representation of protein structures, the sampling of possible alignments between the molecules and the evaluation of a given alignment. Previous work done in this field, can be divided in two approaches: an adhoc algorithmic approach from the Bioinformatics literature and an approach using statistical methods either in a likelihood or Bayesian framework. Both approaches address the problem from a different scope. For example, the algorithmic approach is easy to implement but lacks an overall modelling framework, and the Bayesian address this issue but sometimes the implementation is not straightforward. We develop a method which is easy to implement and is based on statistical assumptions. In order to asses the quality of a given alignment we use a size and shape likelihood density which is based in the structure information of the molecules. This likelihood density is also extended to include sequence infor- mation and gap penalty parameters so that biologically meaningful solution can be produced. Furthermore, we develop a search algorithm to explore possible alignments from a given starting point. The results suggest that our approach produces better or equal alignments when it is compared to the most recent struc- tural alignment methods. In most of the cases we managed to achieve a higher number of matched atoms combined with a high TMscore. Moreover, we extended our method using Bayesian techniques to perform alignments based on posterior modes. In our approach, we estimate directly the mode of the posterior distribution which provides the final alignment between two molecules. We also, choose a different approach for treating the mean parameter. In previous methods the mean was either integrated out of the likelihood density or considered as fixed. We choose to assign a prior over it and obtain its posterior mode. Finally, we consider an extension of the likelihood model assuming a Normal density for both the matched and unmatched parts of a molecule and diagonal covariance structure. We explore two different variants. In the first we consider a fixed zero mean for the unmatched parts of the molecules and in the second we consider a common mean for both the matched and unmatched parts. Based on simulated and real results, both models seems to perform well in obtaining high number of matched atoms and high TMscore.