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The introduction of concurrent engineering has led to a need to perform product development tasks with reduced information detail. Decisions taken during the early design stages will have the greatest influence on the cost of manufacture. The manufacturing requirements for alternative design options should therefore be considered at this time. Existing tools for product manufacture assessment are either too detailed, requiring the results of detailed design information, or too abstract, unable to consider small changes in design configuration. There is a need for an intermediate level of assessment which will make use of additional design detail where available, whilst allowing assessment of early designs. This thesis develops the concept of aggregate process planning as a methodology for supporting concurrent engineering. A methodology for performing aggregate process planning of early product designs is presented. Process and resources alternatives are identified for each feature of the component and production plans are generated from these options. Alternative production plans are assessed in terms of cost, quality and production time. A computer based system (CESS, Concurrent Engineering Support System) has been developed to implement the proposed methodology. The system employs object oriented modelling techniques to represent designs, manufacturing resources and process planning knowledge. A product model suitable for the representation of component designs at varying levels of detail is presented. An aggregate process planning functionality has been developed to allow the generation of sets of alternative plans for a component in a given factory. Manufacturing cost is calculated from the cost of processing, set-ups, transport, material and quality. Processing times are calculated using process specific methods which are based on standard cutting data. Process quality cost is estimated from a statistical analysis of historical SPC data stored for similar operations performed in the factory, where available. The aggregate process planning functionality has been tested with example component designs drawn from industry.

(+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.

Product adaptability is the capability to adjust a product by adding/replacing its constitu-ents for different applications. To acquire this capability, a product should be a modular structure that can form different modular combinations. The purpose of this thesis is pro-posing a design method to develop such products. The method includes the following characteristics: a product essentially implements its applications by providing proper ac-tions/reactions to interact with its surrounding conditions; such actions/reactions can be used to develop the subsystems of a product by building energy-flow or force-path con-nections; optional modules can be separated from the subsystems that contain optional applications; all modules are arranged as an open architecture to provide space and inter-face for each optional module; and each module is endued with the principal content of actions/reactions, inside energy flows or force paths, space, and interfaces constraints, so that it can be physically formed through a dual-domain formation process. Following this method, a multi-purpose electric vehicle (MEV) is developed. Adaptability Efficacy (AE) is proposed to evaluate the effectiveness of the proposed method. / February 2017

<p>Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, and</p><p>have been validated as effective enzyme target for cancer treatment. Largazole, a marine natural</p><p>product isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor that</p><p>has been shown to possess high differential cytotoxicity towards cancer cells along with excellent</p><p>HDAC class-selectivity. However, improvements can be made in the isoform-selectivity and</p><p>pharmacokinetic properties of largazole.</p><p>In attempts to make these improvements and furnish a more efficient biochemical probe</p><p>as well as a potential therapeutic, several largazole analogues have been designed, synthesized,</p><p>and tested for their biological activity. Three different types of analogues were prepared. First,</p><p>different chemical functionalities were introduced at the C2 position to probe the class Iselectivity profile of largazole. Additionally, docking studies led to the design of a potential</p><p>HDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a wide</p><p>variety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDAC</p><p>inhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize a</p><p>different prodrug strategy to modulate the pharmacokinetic properties of largazole.</p><p>Through these analogues it was shown that C2 position can be modified significantly</p><p>without a major loss in activity while also eliciting minimal changes in isoform-selectivity. While</p><p>the Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiol</p><p>can be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use of</p><p>a disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varying</p><p>functional responses in vitro and in vivo.</p><p>v</p><p>Largazole is already an impressive HDAC inhibitor that shows incredible promise.</p><p>However, in order to further develop this natural product into an anti-cancer therapeutic as well as</p><p>a chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivity</p><p>are required. Through these studies we plan on building upon existing structure–activity</p><p>relationships to further our understanding of largazole’s mechanism of inhibition so that we may</p><p>improve these properties and ultimately develop largazole into an efficient HDAC inhibitor that</p><p>may be used as an anti-cancer therapeutic as well as a chemical probe for the studying of</p><p>biochemical systems.</p> / Dissertation

We investigate the incentive to provide goods of high quality in a vertically related market for different types of business organizations, a farmer-owned cooperative and an investor-owned firm. Contrary to the firm, the cooperative is characterized by decentralized decision making, which gives rise to overproduction and problems coordinating the quality decisions of its members (free riding). Comparing both manufacturers acting as monopolists we show that the cooperative will never supply final goods of higher quality than the firm, and that the problem of quality coordination is mitigated if the cooperative succeeds in preventing overproduction. When a cooperative faces competition of an investor-owned firm (mixed duopoly), it will - except in one limit case - never produce final goods of a higher quality than the firm and will deliver lower quality in a number of scenarios.

This study focuses on critical design practice. The research challenges the colloquial understanding of ‘critical design.’ It problamatises, defines and reassesses the concept of ‘critical design’ situating it among other forms of critical design practice. The research reviews the field of activity from a historical perspective. It reviews contemporary activity in contexts of design research and the gallery system to establish domain authorities and theoretical perspectives that inform critical design practice. The research draws from a body of literature relating to design theory and critical design practice to identify several important themes by which to discuss the practice. The research employs a hermeneutic methodology and engages expert ‘critical’ designers through a series of conversational interviews. The interviews are analysed using code to theory methods of inductive qualitative analysis and subjected to hermeneutic analysis that draws on the extensive contextual review. Salient concepts found in the discourse are extracted, theorised and organised to create taxonomy of critical design practice. In the taxonomy, the field of critical design practice is categorised by three types of practice: Associative Design, Speculative Design and Critical Design. These three practices are differentiated by topics addressed in each and further differentiated by the type of Satire, Narrative and Object Rationality used in each practice. The original contribution of this research is a Taxonomy of critical practice in product design, which consists of a written and visual dimension. The taxonomy acts as a discursive tool to chart design activity and it illustrates the diversity in critical design practice beyond the colloquial understanding of ‘critical design’. The taxonomy presents three distinct types of critical design practice; it outlines the design methods used to establish the critical move through design and identifies the contexts where critical design is practiced. It can be used to compare projects, chart designers’ activity over time, illustrate trajectories of practice and identify themes in practice. The taxonomy provides theoretical apparatus to analyse the field. Such analysis contributes towards a discussion on critical design within design studies.

In this paper the Cartesian product topology for an arbitrary family of topological spaces and some of its basic properties are defined. The space is investigated to determine which of the separation properties of the component spaces are invariant.