Dosage compensation serves to equalise the levels of X-linked gene products between males and females. In mammals this occurs through the transcriptional silencing of the majority of the genes on one of the two female X chromosomes. The inactive X chromosome (Xi) differs from its active homologue in a number of ways, including the hypoacetylation of core histones, a common property of genetically inactive chromatin. This study has used Xi to explore the functional significance of hypoacetylation and patterns of histone methylation in silent chromatin. Xi was shown to be depleted for di- and tri-methylated lysine 4 of H3, but retained di-methylated lysine 9 of H3. I have examined the temporal order of these modifications as they become established using an in vitro model system for X inactivation; differentiating female embryonic stem cells. The results showed that the loss of tri-methylated lysine 4 of H3 preceded the loss of its di-methylated equivalent, which occurs during a time period of concurrent core histone deacetylation supporting a functional role to the level of lysine methylation. I have used cases of X;autosome translocation to examine how these modifications relate to late replication and transcriptional silencing. Results show that whilst the spread of X inactivation can occur in the absence of both of these properties, histone modifications are a more reliable indicator of the extent of spread of X inactivation than late replication. To explore mechanisms that drive changes in histone modification I have analysed the distribution of histone deacetylases across a region of defined histone deacetylation. The results showed a ubiquitous distribution that did not correlate with acetylated H3 or H4 suggesting that the global association of the Hdacs might serve to provide a rapid return the basal level of histone acetylation following specific targeting events.

The thymus is a primary lymphoid organ that supports the production, differentiation and selection of self-tolerant T cells from immature precursors of extrathymic origin. T cell development is a dynamic process involving the movement of thymocytes through specialised regions of the thymus, each directing distinct developmental stages. The formation of these microenvironments is crucial for providing the ordered and continuous signalling required to drive the non-cell autonomous process of T cell development. The development of thymocytes and thymic epithelial cells (TEC) are interdependent processes involving reciprocal signalling termed “thymic crosstalk”. Using novel in vitro and in vivo experimental techniques we elucidated novel processes in the regulation of thymic epithelial cell development. We corroborated the importance of thymic crosstalk by revealing a new role for innate like  T cells in influencing medullary thymic epithelial cell development. Furthermore, this study argues against a specific time frame for the occurrence of thymic crosstalk by demonstrating that adult thymic epithelium retains its receptivity to lymphostromal signalling. In addition, we have recognised the importance of intrathymic niches in regulating early T cell progenitor development. Collectively these data have provided an insight into the development of the thymic epithelium and thus have important implications in relation to developing rejuvenation strategies for the atrophied thymus and following ablative therapy.

Cycling is increasing in popularity which is accompanied with a higher rate of injuries sustained due to collisions, crashes or falls. A high proportion of these events happen when the bicycle rider loses control of the bicycle. In order to improve bicycle rider control, the skill of riding a bicycle needs to be understood. Therefore, the overall aim of this PhD work was to explore bicycle rider control skills and to examine the effects of different constraints on the control of a bicycle. The first part of this thesis focuses on developing a valid and reliable methodology that can be further used for studying bicycle rider control skill. Firstly, a protocol to determine knee angle during cycling is being developed. Secondly, some technical approaches when studying muscle activity during cycling are being questioned. Lastly, a portable device based on a single angular rate sensor to record steering rate and bicycle roll rate was tested for reliability in an outdoor setup. Second part of the thesis examines the effects on bicycle rider control of three different constraints: 1) expertise, 2) body position and 3) cycle lane design. Results overall showed that all three constraints significantly affect steering and bicycle roll rate.

The control of balance and orientation comprises various forms of sensory input, reflexive action and anticipatory mechanisms. An important sensory input is the vestibular system. When a destabilising or disorientating perturbation is sensed by the vestibular apparatus a corrective response is generated. This thesis investigated how the processing of vestibular signals is affected by postural and sensory context. Orientation reflexes evoked by a vestibular signal of head roll were shown to be continuously modulated and even reversed direction during self-generated head pitch movements (Chapter 2). Results also raised the possibility that the direction of a vestibular-evoked balance reflex is automatically rotated following adaptation of motor output (Chapter 3). In addition to modulating the response direction, the context was also found to affect the response amplitude. Passive cutaneous sensory input was shown to attenuate a vestibular-evoked balance reflex (Chapter 4). If, however, such changes in sensory context were anticipated, then response amplitude was unchanged (Chapter 5). Furthermore, the initial balance reflex was not affected by a fear of falling (Chapter 6). The present findings demonstrate that the processing of vestibular signals is indeed context-dependent. However, the modulation of vestibular-evoked reflexes is seemingly automatic, and is not affected by cognition or emotion.

An animal’s locomotor abilities facilitate its interactions with the surrounding environment. Extant hominoids (apes) have evolved diverse ranges of locomotor strategies which allow them to exploit terrestrial and arboreal habitats despite their large body size. However, hominins (modern humans and their ancestors) are traditionally defined by their restriction to upright, bipedal posture and locomotion. Reconstructions of locomotor capacity in fossil hominoids allow investigation of the evolution of extant ape locomotion; yet these reconstructions rely on detailed understanding of the relationships between morphology, locomotor behaviour and the environment in extant apes. This thesis explores variation in locomotor behaviour and skeletal morphology among extant apes in order to shed light on these relationships. Studies of chimpanzees, gorillas and modern humans reveal considerable mechanical variation in gait, and demonstrate the importance of considering environmental context in ape locomotion. Anatomical studies find reduced reliability of inferring locomotor capacity in fossil hominoids due to significant variation among extant apes in skeletal predictors of habitual bipedality and estimations of joint range of motion. These studies highlight the importance of behavioural flexibility in determining hominoid locomotor capacity, and suggest that fossil hominoids were less constrained in their locomotor repertoires than previous reconstructions imply.

The thesis is concerned with the role played by mineral substance in determining mechanical properties of bone. A variety of techniques have been used to study the physical nature of bone mineral and the mechanical properties of compact bone tissue. Bones obtained from male and female cadavera ranging in age from 3 and-a-half to 92 years were studied. X-ray powder diffraction analysis has confirmed the calcium hydroxyapatite-like structure of crystalline bone mineral (chapter 2), but failed to provide evidence of the presence of any other inorganic crystalline component in bone tissue. Observed diffraction patterns each comprised a number of well-resolved reflections with comparatively little diffuse scattering, suggesting a high degree of crystallinity of bone mineral.

The role of vibration in exercise is controversial, with much debate about its potential benefits. The aim of the research reported in this PhD thesis was to inform evidence based practice by investigating the underlying responses of the human body during exercise with vibration. Human neuromuscular and cardiovascular systems were investigated using 3D motion analysis, near infra-red spectroscopy (NIRS), laser Doppler blood flow analysis and electromyography (EMG). Analysis of a prototype vibrating stationary cycle identified significant increases in muscle activation. However, the validity of the results was limited by a confounding issue of increasing resistance with increasing cadence due to the cycle’s vibration mechanism. Consistency of exercise performance on vibration platforms was measured by 3D analysis; vibration did not affect the kinematic parameters of exercises such as heel raises or press ups, even though significant physiological changes occurred. NIRS indicated a significant reduction in the depletion of oxygenated haemoglobin, total haemoglobin and the normalised tissue haemoglobin index of the lateral gastrocnemius in heel raise exercises. During quiet standing laser Doppler measurements of the dorsalis pedis artery indicated that the NIRS results were not a consequence of vasospastic responses or increased resistance to blood flow in response to vibration. Whilst heart rate and blood pressure remained constant, blood flow velocity significantly increased, suggesting the peripheral changes occurred independently of central cardiovascular function. Heel raise exercises with whole body vibration showed significant increases in muscle activation of the soleus, but not the gastrocnemius, indicating varied muscular responses to vibration. The influence of blood flow and tissue oxygenation on EMG parameters was demonstrated via the protection of muscle conduction velocity during static squats, despite a downward shift in median frequency of the EMG power spectra. Analysis of upper body muscles during press ups yielded significant increases in muscle activation, equivalent to increasing the load of the bench press by 10% of the one repetition maximum. The results indicate that vibration influenced the dynamic muscles more than stabiliser muscles; reinforcing the lower body studies showing that vibration has a varied influence on muscle function. The aforementioned results demonstrate the ability of vibration to augment the effects of exercise on the muscular and vascular physiological systems of the human body.

Patello-femoral joint syndrome (PFJS) is a common problem that is challenging to treat. The dominant theory of its aetiology is „patellar malalignment‟, in which the vastus medialis oblique (VMO) muscle is ineffective in controlling patellar position but this is based on assumption. The Q-angle, a frontal plane measure, indicates patellar position relative to the pelvis and tibia; however, there is no standardised measurement protocol and it is assumed to be a fixed value. The work reported highlights the tension between measurement rigour and clinical utility. Valid measurement of the Q-angle and VMO muscle were established using: motion analysis, magnetic resonance imaging (MRI) and ultrasound imaging, in recreationally active healthy participants, then applied in various experiments involving people with PFJS, with the following conclusions: The Q-angle: * varied over 60 seconds in relaxed standing * exhibited differences in movement patterns of the three markers which form the Q-angle between healthy and PFJS groups during the stance phase of gait * was generally at its maximum at the beginning of the stance phase of gait and at its minimum at the end * did not correlate with pronation at the sub-talar joint VMO muscle size: * linear and CSA measures of the VMO muscle correlated well * measures of VMO muscle size from ultrasound were shown to be valid when compared with MRI and were equally reliable No correlation between the Q-angle and VMO muscle size was found. These results increase our understanding of the usefulness of the Q-angle, particularly its natural variation of between 30 and 40 in static standing and its different movement pattern during gait in PFJS. It was established that ultrasound imaging provides valid measures of VMO muscle size and the relationships between its CSA and linear dimensions were characterised.

The knee is a complex joint, prone to instability and damage, meaning a complicated architecture of soft tissues is necessary to ensure any stability of the joint. These structures are innervated, and play an important role in both proprioception, the sensing of a body’s own limb positions, and nociception, the sensing of painful stimuli. The purpose of this project has been to develop a computational model that can replicate the behaviour of the mechanical sensing nerve endings in the knee joint. An adapted Hodgkin-Huxley model has been developed and used to simulate the behaviour of the nerve endings. These models have been coupled with a three dimensional finite element model of a feline knee joint, which has been built with use of x-ray CT and MRI scans of a cat’s hind limb, allowing neural responses to be predicted as the position of the knee joint changes. Once the behaviour of the complete model has been verified, through comparisons with recordings of neural responses in the literature, it was possible to observe the effect of removing a soft tissue structure on the neural response. The anterior cruciate ligament (ACL) was removed from the model, and a series of tests run to determine the effect of ligament damage on neural response. It was predicted that removing the ACL from the knee joint can increase the neural responses to changes in knee position, agreeing with data in the literature. This could indicate an increase in pain at the joint, and could help with understanding the causes of pain and changes proprioception experienced by patients with damaged ACL.

Neurological rehabilitation technologies such as Robot Therapy (RT) and noninvasive brain stimulation (NIBS) can promote motor recovery after stroke. The novelty of this research was to explore the feasibility and the effect of the combination method of NIBS called transcranial Direct Current Stimulation (tDCS) with uni-lateral and three-dimensional RT for the impaired upper limb (UL) in people with sub-acute and chronic stroke. This thesis involved three studies: (a) systematic review with meta-analyses (b) a pilot double-blinded randomised controlled trial with a feasibility component and (c) a reliability study of the measurement of Motor Evoked Potential (MEP) response using Transcranial Magnetic Stimulation in healthy adults. The first study involved a review of seven papers exploring the combination of tDCS with rehabilitation programmes for the UL in stroke. For the second study, stroke participants underwent 18 x one hour sessions of RT (Armeo®) over eight weeks during which they received 20 minutes real tDCS or sham tDCS. Outcome measures were applied at baseline, post-intervention and at three-month follow-up. The qualitative component explored the views and experiences of the participants of RT and NIBS using semi-structured interviews. The third study involved age-matched healthy adults exploring intrarater and test-retest reliability of the TMS assessment. Results of the three studies were the following: Seven papers were reviewed and a small effect size was found favouring real tDCS and rehabilitation programmes for the UL in stroke. 22 participants (12 sub-acute and 10 chronic) completed the pilot RCT. Participants adhered well to the treatment. One participant dropped out of the trial due to painful sensations and skin problems. The sub-acute and chronic groups showed a clinically significant improvement of 15.5% and 8.8% respectively in UL impairments at post-intervention from baseline. There was no difference in the effects of sham and anodal tDCS on UL impairments. Participants found the treatment beneficial and gave suggestions how to improve future research. In summary, the TMS assessment showed excellent reliability for measurement of resting motor threshold but poor to moderate reliability for MEP amplitude. In conclusion, it was indicated that RT may be of benefit in sub-acute and chronic stroke however, adding tDCS may not result in an additive effect on UL impairments and dexterity. The present study provided a power calculation for a larger RCT to be carried out in the future.