The force response of the locust hind leg extensor muscle to input excitation pulses is modelled. Despite the processes behind muscle contraction being well established, no broadly valid method of modelling skeletal muscle exists. Studies that compare the merits of existing models are extremely scarce and researchers make various assumptions in order to simplify the complex, nonlinear behaviour of the muscle. Locusts provide an opportunity to develop a muscle model in a simpler system, that will still show similar properties to that of mammalian muscles. In developing a model previous work is considered, and complexity is introduced in the experimental conditions in stages. This meant a model could be built up in parts. This approach reduces the need for questionably valid assumptions. The main focus of this work is modelling activated isometric muscle. Experimental data was collected by stimulating the extensor muscle and measuring the force generated at the tibia. In the first instance the response to individual stimulus pulses is modelled. This is extended to develop a predictive model capable of estimating the isometric force response to general pulse train inputs. In developing the model, data was fit to existing models, and from this an improved isometric model developed. The effect of changing the isometric muscle length is considered. Commonly changing the muscle length is assumed to just scale the force response. This assumption is poor. The dynamics of the force response were found to be modifed by the change in muscle length, and the isometric model adapted to include this dependency. Results related to the non-isometric behaviour are also presented. Passive muscle is usually just modelled over the lengthening period, however, the whole stretch-shorten cycle is considered here. A model, adapted from the standard linear model, is developed to describe the passive force response.

This work examined the mechanical properties of single bovine trabeculae and cortical bone tissue experimentally. In particular, microdamage and local strains were assessed for bovine bone tissue. A three-point bending experimental setup was designed capable of measuring local strains at the surface of such small specimens, using the digital image correlation technique. Microdamage formation and propagation were detected using the bone whitening effect, an optical non-invasive technique. This technique enabled to follow the progression of local strains and microdamage in real-time from which local strains at microdamage initiation and failure could be derived. This technique was used to investigate three fundamental aspects of bone mechanics. The first study examined the strain rate sensitivity of single bovine trabeculae. No linear relationship was observed between the strain rate and the Young’s modulus, the amount of microdamage, the maximum tensile strain at failure and at microdamage initiation. The second study compared the mechanical behaviour of single bovine trabeculae and similarly sized cortical bone samples. Cortical bone tissue exhibited significantly lower maximum strains and less accumulated damage at failure. However, no significant difference was detected for the maximum strain at microdamage initiation. Finally, the anisotropy of bovine cortical bone tissue was investigated. No significant difference was found between the Young’s modulus, the amount of microdamage and failure strains of longitudinal and tangential bone samples. However, these parameters were significantly lower for the radial samples. For strains at whitening onset, no significant difference was seen for the longitudinal and radial groups, whereas the tangential values were significantly greater. The insights gained from this work enhanced our understanding of the damage properties of bovine bone at the microstructural level. Future work is required to investigate the relevance of the above findings to human bone tissue.

The mammalian target of rapamycin (mTOR), which controls diverse cellular processes, is regulated by the integration of many signals. Rapamycin strongly inhibits the proliferation of many cancer cell lines and there is a high level of interest in its potential use as an anti-cancer agent. However, some tumours and cancer cells are resistant to rapamycin. This has prompted the development of mTOR kinase inhibitors (mTOR-KIs), such as PP242 and AZD8055, which compete with ATP for binding to the kinase domain in mTOR. In this research, I have studied whether the effects of mTOR-KIs on cell signalling and protein synthesis differed in comparison to those of rapamycin. My data shows that mTOR-KIs have strikingly different effects on proteins (including formation of the eIF4F translation factor complex) that control mRNA translation. Furthermore, while rapamycin only has a very small inhibitory effect on the rate of protein synthesis, mTOR-KIs have a much bigger effect. A new mass spectrometric approach, ‗pSILAC‘, was applied to explore the effects of rapamycin and mTOR-KIs on the synthesis of specific proteins. The data from pSILAC reveal (i) mTOR-KIs impair synthesis of many proteins; (ii) rapamycin always inhibits less than mTOR-KIs; (iii) their effects are strongest for proteins encoded by 5‘-TOP mRNAs, but mTOR-KIs again inhibit more strongly; (iv) synthesis of some other proteins which are not encoded by known 5‘-TOP mRNAs shows a similar pattern of inhibition to 5‘-TOP mRNAs. These data show that pSILAC is a valuable tool for studying the control of the synthesis of specific proteins. I have also investigated the effects of disruption of eukaryotic translation initiation factor 4E (eIF4E) phosphorylation on (i) its modification by SUMO-1 (ii) TNFα biosynthesis in macrophages and (iii) the interaction with specific mRNAs encoding protumourigenic factors.