Our understanding of protein lysine methyltransferases and their substrates remains limited despite their importance as regulators of the proteome. The SMYD (SET and MYND domain) methyltransferase family plays pivotal roles in various cellular processes, including transcriptional regulation and embryonic development. Among them, SMYD2 is associated with oesophageal squamous cell carcinoma, bladder cancer and leukemia as well as with embryonic development. Initially identified as a histone methyltransferase, SMYD2 was later reported to methylate p53, the retinoblastoma protein pRb and the estrogen receptor ERalpha and to regulate their activity. Our proteomic and biochemical analyses demonstrated that SMYD2 also methylates the molecular chaperone HSP90 on K209 and K615. We also showed that HSP90 methylation is regulated by HSP90 co-chaperones, pH, and the demethylase LSD1. Further methyltransferase assays demonstrated that SMYD2 methylates lysine K* in proteins which include the sequence [LFM]-₁-K*-[AFYMSHRK]+₁-[LYK]+₂. This motif allowed us to show that SMYD2 methylates the transcriptional co-repressor SIN3B, the RNA helicase DHX15 and the myogenic transcription factors SIX1 and SIX2. Finally, muscle cell models suggest that SMYD2 methyltransferase activity plays a role in preventing premature myogenic differentiation of proliferating myoblasts by repressing muscle-specific genes. Our work thus shows that SMYD2 methyltransferase activity targets a broad array of substrates in vitro and in situ and is regulated by intricate mechanisms.

Conceptual design synthesis is part of the conceptual phase of the design process, which focuses on creating alternative, candidate solutions. Conceptual design phase has the greatest influence on the cost and characteristics of the final product; an excellent detailed design based on a poor and inappropriate concept can never compensate for the inadequacy of the concept. Conceptual design is difficult, which currently relies on the designer’s intuition and experience to guide the process. A major issue in conceptual design is that often not many alternative candidate solutions are explored by the designer during the design process. The major reasons for this are the tendency to delimit a design problem area too narrowly and thus not being able to diversify the possible set of design solutions, possible bias towards a limited set of ideas, and time constraints. Many researchers recommended a thorough search of the design space for developing a good solution; this requires generation of a large solution space. Mechanical devices (mechanisms and machines) have fascinated the mankind throughout recorded history. Conceptual design synthesis of mechanical devices is difficult even for humans, and is also difficult to completely automate. In a single state design task, the relation between an input and output are fixed, but in a multiple state design task, the relation is not fixed. Much of the current research has been focused on supporting synthesis of single state devices, in particular where the device has to convert an input motion into an output motion. Synthesis of multiple state device is in contrast rather poorly understood and supported. Complete automation is unlikely to be possible; developing support taking into account the strength of computer and and human is important mechanical device is not adequate the biggest source for understanding of this process, and for its subsequent support, is human designers. The concept of state for a mechanical device is explained in detail by analyzing the existing multiple state mechanical devices. An operating state described by elemental functions (defined by efforts- motions of input and output components) and their associated Understanding and Supporting Conceptual Design Synthesis of Multiple State Mechanical Devices configurations and configuration changes. However, study of current literature indicates that little has been known about the actual processes carried out by designers in synthesizing multiple state devices. The main objectives of this thesis, therefore, are as follows: (1) understand the multiple state device design synthesis process carried out by designers, and (2) develop methods for supporting synthesis of multiple state mechanical devices to enhance the number of solution alternatives generated. Empirical studies are conducted to understand how designers currently carry out multiple state design tasks. Ten designers are given a multiple state design task and asked to generate as many solutions as possible. The designers are asked to think aloud while carrying out their synthesis processes. All these synthesis processes are video recorded, and analyzed to identify what activities are involved in the multiple state design synthesis, what the inputs are to each activity, and what the outcomes are from each activity. It has been found from these studies that design fixation is quite common, and the majority of the designers pursued developing a single solution to the given design task. A generic descriptive model of the multiple state mechanical device design synthesis process, explaining how this is carried by the designers, is developed. Based on this model, a prescriptive model of multiple state design synthesis process, explaining how the multiple state synthesis process should be carried by designers in order to develop a large solution space, is also developed. The prescriptive support, for synthesizing a large solution space for a given multiple state design task, has been evaluated. Eight engineering designers participated in the evaluation procedure, where each designer had to synthesize solutions for two, given multiple state design tasks. Results indicate that use of the prescriptive support, even without the power of a computational implementation, may have been beneficial in helping designers develop feasible solutions in a greater number of cases in a more efficient manner (that is, by considering fewer solution proposals and in similar amounts of time). All the designers who participated in this exercise gave a positive feedback regarding the prescriptive support. However, in none of the design sessions did the designers develop more than one feasible solution. This, along with various other comments from designers, indicates that a faster and more proactive support – implemented on computer – might be more useful in supporting the tasks. The various aspects for a potential computer support are discussed.