Target cascading is a key challenge in the early product development stages of large complex artifacts: how to propagate the desirable top level design specifications (or targets) to appropriate specifications for the various subsystems and components in a consistent and efficient manner. Consistency means that all parts of the designed system should work well together, while efficiency means that the process itself should avoid iterations at later stages, which are costly in time and resources. In the present article target cascading is formalized by a process modeled as a multilevel optimal design problem. Design targets are cascaded down to lower levels using partitioning of the original problem into a hierarchical set of subproblems. For each design problem at a given level, an optimization problem is formulated to minimize deviations from the propagated targets and thus achieve intersystem compatibility. A coordination strategy links all subproblem decisions so that the overall system performance targets are met. The process is illustrated with an explicit analytical problem and a simple automotive chassis design model that demonstrates how the process can be applied in practice.

Background-Apoptosis of vascular endothelial cells (ECs

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The Aurora-A kinase gene is amplified in a subset of human tumors and in radiation-induced lymphomas from p53 heterozygous mice. Normal tissues from p53-/- mice have increased Aurora-A protein levels, but lymphomas from these mice exhibit heterozygous deletions of Aurora-A and/or reduced protein expression. A similar correlation between low p53 levels and Aurora-A gene deletions and expression is found in human breast cancer cell lines. In vitro studies using mouse embryo fibroblasts demonstrate that inhibition of Aurora-A can have either positive or negative effects on cell growth as a function of p53 status. These data have implications for the design of approaches to targeted cancer therapy involving the crosstalk between Aurora-A kinase and p53 pathways.