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SRMS (Src-Related tyrosine kinases lacking C-terminal Regulatory tyrosine and N terminal Myristoylation Sites) belongs to a family of non-receptor tyrosine kinases, which also includes breast tumor kinase (BRK). SRMS was first identified in 1994 in a screen for the genes that regulate the growth and differentiation of neuroepithelial cells. This 54 kDa protein spanning 488 amino acids, consists of the prototypical Src homology 3 (SH3), Src homology 2 (SH2) and a tyrosine kinase domain. While BRK has been documented for its expression in over 60 % of breast carcinomas, information on SRMS on similar grounds remains absent from the literature. Furthermore, unlike BRK, knowledge of how SRMS regulates its enzymatic activity as well as the identification of its substrates remains unknown. The work in this thesis demonstrates that SRMS is potentially expressed in the majority of breast carcinomas. To understand the biochemical and cellular functions of SRMS, a series of mutants comprising point mutations as well as the deletion of the N-terminal region and the functional, SH3 and SH2 domains, were generated and assessed for enzymatic activity in cells. This study demonstrates for the first time that the wild type protein is apparently constitutively active and that its N-terminal region regulates its enzymatic activity. As well, three critical amino acid residues in the protein namely, lysine 258 (ATP binding site), tyrosine 380 (auto-phosphorylation site) and tryptophan 223 (intramolecular interaction) have been characterized. All three residues have been determined to be essential for the enzymatic activity of SRMS. Finally, the adapter protein Dok1 has been characterized as a novel substrate of SRMS. The results from the present study underscore the potential significance of the catalytically active non-receptor tyrosine kinase, SRMS that should serve as a foundation upon which further research may ensue in the context of breast tumorigenesis.

Switched reluctance machines (SRMs) have recently attracted more interest in many applications due to the volatile prices of rare-earth permanent magnets (PMs) used in permanent magnet synchronous machines (PMSMs). They also have rugged construction and can operate at high speeds and high temperatures. However, acoustic noise and high torque ripples, in addition to the relatively low torque density, present significant challenges. Geometry and topology optimization are applied to overcome these challenges and enable SRMs to compete with PMSMs. Key geometric design parameters are optimized to minimize various objective functions within geometry optimization. On the other hand, the material distribution in a particular design space within the machine domain may be optimized using topology optimization. We discuss how these techniques are applied to optimize the geometries and topologies of SRMs to enhance machine performance. As optimizing the machine geometry and material distribution at the design phase is of substantial significance, this work offers a comprehensive literature review on the current state of the art and the possible trends in the optimization techniques of SRMs. The thesis also reviews different configurations of SRMs and stochastic and deterministic optimization techniques utilized in optimizing different configurations of the machine. This thesis introduces a new ON/OFF optimization method based on the line search method to overcome the limitations of the conventional annealing-based ON/OFF optimization. The proposed method shows a faster convergence to optimal solutions than the conventional annealing-based ON/OFF method. The thesis also compares the performance of the generative optimization and the topology optimization of a 6/14 switched reluctance machine with the proposed method and the conventional method. The two methods are applied to two different design domains of the machine for topology and generative optimization and the results are compared to the results of the annealing-based ON/OFF method. The results show the effectiveness of the newly proposed method. A new technique has been introduced in this thesis for reducing the time of calculating stator radial force density waves of switched reluctance machines (SRMs). The method is based on the finite element (FE) simulation of a fraction of an electrical cycle. The new approach shows that a significant time reduction is achieved as compared to the time required for stator radial force density calculation based on the one mechanical cycle simulation method. As the switched reluctance motors introduce new challenges in aspects such as acoustic noise, vibrations, and torque ripples, the method introduced in this helps reduce the time of the optimization process of switched reluctance machines in the design stage to improve the machine performance. The proposed method is applied to radial flux switched reluctance machines. Three different SRMs configurations were used to show the effectiveness of this technique in different force components with minimal error as compared to the benchmark method based on the FE simulation of one mechanical cycle. / Dissertation / Doctor of Philosophy (PhD)

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