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The structural and functional properties of the urokinase-type plasminogen activator (u-PA) that are involved in the mitogenic effect of this proteolytic enzyme on human melanoma cells M14 and IF6 and the role of the u-PA receptor (u-PAR) in transducing this signal were analyzed. Native u- PA purified from urine induced a mitogenic response in quiescent IF6 and M14 cells that ranged from 25 to 40% of the mitogenic response obtained by fetal calf serum. The half-maximum response in M14 and IF6 cells was reached at u- PA concentrations of approximately 35 and 60 nM, respectively. Blocking the proteolytic activity of u-PA resulted in a 30% decrease of the mitogenic effect, whereas inhibition of plasmin activity did not alter the mitogenic effect. No mitogenic response was elicited by low molecular weight u-PA, lacking the growth factor domain and the kringle domain. The ATF domain of u- PA induced a mitogenic response that was similar to complete u-PA. Defucosylated ATF and recombinant u-PA purified from Escherichia coli lacking all post-translational modifications did not induce a mitogenic response. Blocking the interaction of u-PA with u-PAR, using a specific monoclonal antibody, did not alter the mitogenic effect induced by u-PA. The binding of radiolabeled u-PA to M14 and IF6 cells was characterized by high affinity binding mediated by u-PAR and low affinity binding to an unknown binding site. These results demonstrate that proteolytically inactive u-PA is able to induce a mitogenic response in quiescent melanoma cells in vitro by a mechanism that involves the ATF domain but is independent of high affinity binding to u-PAR. Furthermore, it suggests that u-PA is able to bind with low affinity to a hitherto unidentified membrane associated protein that could be involved in u-PA-induced signal transduction.

The existence of a well-designed scheduling procedure is a major condition for an effective integration of a flexible manufacturing cell (FMC) in the material flow of a firm. This paper shows the presence and relative importance of three parameter types in the scheduling of operations on a flexible manufacturing cell: workload control parameters, sequencing parameters, and control space parameters. A (full factorial) simulation study is performed in order to study the impact of the scheduling parameters on the performance of the FMC. It is shown that workload control parameters and sequencing parameters are strongly linked to each other. The study, furthermore, indicates how important performance indicators, such as the utilization of the FMC and the average throughput time of order, can be influenced by the scheduling parameters.

This paper formalizes the problem of a concurrent design of a modular product architecture and a cellular manufacturing layout and presents a way to deal with this design problem. First, the different types of a modular product architecture are explained as well as important implications of modularity for the manufacturing process. Several advantages of a modular product architecture refer to the manufacturing process of the product. Second, it is shown that the extent in which assembly tasks are performed in the cells strongly determines the advantages of a cellular manufacturing layout. These two facts ask for a simultaneous consideration of modular product design and the design of the manufacturing layout (i.e., manufacturing cells in which parts are manufactured and modules are assembled). The relation between product design and manufacturing process is described in this paper by means of four relation matrices: a module-module matrix, a module-machine matrix, a machine-part matrix, and a part-part matrix. On the basis of this description, a systematic approach is developed to support the concurrent design of modules and manufacturing cells. The experiences of two firms are included in the paper and illustrate the advantages of including assembly activities in manufacturing cells.

This paper describes an innovative interactive decision making tool for scheduling jobs in a flexible manufacturing environment. While the proposed tool provides computer integrated mechanism for scheduling jobs to the flexible manufacturing systems, it retains the human touch needed to augment computer analysis with human experience and judgement. A practical instance where this tool is used is also discussed.