Reliability and realizability risk evaluation of concept designs

This thesis addresses the improvement in quality of decision making in design through the use of decomposed design evaluation. The research reported in this thesis is supported by the Design Research Methodology. To perform decomposed decision making, it is necessary to identify criteria that are deemed important for this activity. Questionnaire surveys, literature review and interviews with industry helped to identify these criteria. Reliability and realizability are two criteria that are selected for research in this thesis. The questionnaire surveys are discussed in chapter 2. A review of literature on decision making, reliability and realizability is reported in chapters 3 and 4. Methodologies for evaluating reliability and physical realizability are discussed in chapter 5. Relative reliability risk assessment methodology is applied to various examples consisting of university and industry projects in chapter 6. The application helps to reveal the strengths of the methodology and is termed ‘Verification of the methodology’. Validation issues of both the methodologies are dealt with in chapter 7 using the controlled experimental design. It is found that both the methodologies help to improve the quality of decision making during design evaluation. Relative reliability risk evaluation methodology helps to improve the quality of decision making to a substantial extent but physical realizability evaluation methodology shows only a little improvement in quality of decision making. Finally, it is suggested that the decomposed design evaluation methodology helps to improve the quality of decision making and is therefore proposed to be used by both novice and experienced designers.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Insulin and Hypertonicity Recruit GLUT4 to the Plasma Membrane of Muscle Cells by Using N-Ethylmaleimide-sensitive Factor-dependent SNARE Mechanisms but Different v-SNAREs: Role of TI-VAMP

Insulin and hypertonicity each increase the content of GLUT4 glucose transporters at the surface of muscle cells. Insulin enhances GLUT4 exocytosis without diminishing its endocytosis. The insulin but not the hypertonicity response is reduced by tetanus neurotoxin, which cleaves vesicle-associated membrane protein (VAMP)2 and VAMP3, and is rescued upon introducing tetanus neurotoxin-resistant VAMP2. Here, we show that hypertonicity enhances GLUT4 recycling, compounding its previously shown ability to reduce GLUT4 endocytosis. To examine whether the canonical soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) mechanism is required for the plasma membrane fusion of the tetanus neurotoxin-insensitive GLUT4 vesicles, L6 myoblasts stably expressing myc-tagged GLUT4 (GLUT4myc) were transiently transfected with dominant negative N-ethylmaleimide-sensitive factor (NSF) (DN-NSF) or small-interfering RNA to tetanus neurotoxin-insensitive VAMP (TI-VAMP siRNA). Both strategies markedly reduced the basal level of surface GLUT4myc and the surface gain of GLUT4myc in response to hypertonicity. The insulin effect was abolished by DN-NSF, but only partly reduced by TI-VAMP siRNA. We propose that insulin and hypertonicity recruit GLUT4myc from partly overlapping, but distinct sources defined by VAMP2 and TI-VAMP, respectively

Insulin sensitization following a single exercise bout is uncoupled to glycogen in human skeletal muscle : a meta-analysis of 13 single-center human studies

Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition