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The purpose of this research is the development of guiding principles and rules for the design of running systems for aluminium castings, employing both the "virtual" experiment, a computational modelling package, and the "physical" experiment, the real-time X-ray radiography study. "Diverging-Bend" geometry has an essential feature in which the flow rate of the system could achieve the maximum and the velocity of advancing flow could reduce without developing surface turbulence. In liquid aluminium, the surface tension becomes more significant compared to water during the flow transformation from supercritical to subcritical velocities. To describe the phenomenon of hydraulic jump for liquid aluminium it is necessary to include the surface tension, giving the relation pV 2 = (pxgxH) + (4T/H) where p: density, V: average velocity, g: gravitational acceleration, H: the height of the hydraulic jump, and T: surface tension. Guidelines for the designing of L-junctions are developed. Five geometries of L-junctions can be applied and assembled in the design of runners and multiple-gate system. Progressive filling along the L-junction geometry can be achieved by reducing the area of the "dead zone". In a multiple-gate system uniform distribution of flow rate through each gate into the mould cavity is achieved. Quantification of a running system is established by the measurement of coefficient of discharge Cd. The loss coefficient K for individual component of runners is also estimated.

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Although nestin has served as a marker of neural stem/progenitor cells for close to twenty years, its function is still poorly understood. During development, this intermediate filament protein is expressed in many different progenitors including those of the central nervous system, heart, skeletal muscle and kidney. The adult expression of nestin is mainly restricted to the subependymal zone and dentate gyrus of the brain, the neuromuscular junction and renal podocytes. I have used two approaches of gain of function and loss of function to elucidate the role of nestin in vivo. Although I was able to generate transgenic lines in which the transgene was ubiquitously expressed at the RNA level, over-expression of nestin at the protein level was not achieved possibly due to post transcriptional regulation of this gene. My data from loss of function approach indicates that nestin-deficient mice have impaired coordination. Balance and muscle strength are not affected and there are no apparent anatomical defects. I found that nestin deficiency is compatible with normal development of the central nervous system but results in abnormal clustering of acetylcholine receptors in the neuromuscular junctions, similar to the phenotype described for deficiency of cyclin-dependent kinase 5 (Cdk5) a candidate downstream effector of nestin. In renal podocytes, where both nestin and Cdk5 are normally expressed, we found reduced branching and abnormally contoured podocyte processes. To further connect the phenotype of nestin deficiency to Cdk5, I demonstrated that nestin deficiency can rescue maintenance of acetylcholine receptor clusters in the absence of agrin, similar to Cdk5/agrin double knockouts, indicating that the observed nestin deficiency phenotypes are the consequence of aberrant Cdk5 activity.

Although nestin has served as a marker of neural stem/progenitor cells for close to twenty years, its function is still poorly understood. During development, this intermediate filament protein is expressed in many different progenitors including those of the central nervous system, heart, skeletal muscle and kidney. The adult expression of nestin is mainly restricted to the subependymal zone and dentate gyrus of the brain, the neuromuscular junction and renal podocytes. I have used two approaches of gain of function and loss of function to elucidate the role of nestin in vivo. Although I was able to generate transgenic lines in which the transgene was ubiquitously expressed at the RNA level, over-expression of nestin at the protein level was not achieved possibly due to post transcriptional regulation of this gene. My data from loss of function approach indicates that nestin-deficient mice have impaired coordination. Balance and muscle strength are not affected and there are no apparent anatomical defects. I found that nestin deficiency is compatible with normal development of the central nervous system but results in abnormal clustering of acetylcholine receptors in the neuromuscular junctions, similar to the phenotype described for deficiency of cyclin-dependent kinase 5 (Cdk5) a candidate downstream effector of nestin. In renal podocytes, where both nestin and Cdk5 are normally expressed, we found reduced branching and abnormally contoured podocyte processes. To further connect the phenotype of nestin deficiency to Cdk5, I demonstrated that nestin deficiency can rescue maintenance of acetylcholine receptor clusters in the absence of agrin, similar to Cdk5/agrin double knockouts, indicating that the observed nestin deficiency phenotypes are the consequence of aberrant Cdk5 activity.

Recent evidence has challenged the prevalent view that neural factors induce the formation of a de novo postsynaptic apparatus during development of the vertebrate neuromuscular junction. The latest experiments suggest an alternative, muscle-dependent model in which the muscle induces the nascent postsynaptic apparatus and sets the location of the future synapse. Once contacted by the incoming axons, these sites, laid out in a pre-pattern in the central area of developing muscle fibers, mature into synapses by the combined action of neural factors such as agrin and ACh. In this study, I sought to provide a test in mammals for these two models of neuromuscular synaptogenesis. Previously, our laboratory showed that continuous muscle expression of constitutively active ErbB2 (CAErbB2) during embryogenesis leads to synaptic loss, exuberant axonal sprouting and lethality at birth. Here, I transiently induced CAErbB2 during midgestation and examined the process of synapse restoration after inducer withdrawal. Centrallyenriched AChR transcription and AChR clustering were abolished as a result of transient CAErbB2 induction. After inducer withdrawal, synapses were restored but were distributed widely over the entire surface of the diaphragm. Under the nerve-dependent model, this distribution would have been explained by the wide pattern of axonal sprouting triggered by CAErbB2 expression. Yet, in the absence of the nerve, introduced in our transgenic animals by mating to Hb9+/- mice, a very similar, wide distribution of aneural AChR clusters was generated. Thus, even in a case where the central pre-pattern of AChR transcription and clustering is missing, it is the muscle, and not the nerve, that seems to set the site for synapse formation. My results support a muscle-dependent model for the induction of neuromuscular synaptogenesis in mammals.

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