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Role of Growth Factor Receptors in Mitogenesis and Human Cancer
Axel Ullrich 한국유전학회 1990 Genes & Genomics Vol.12 No.4
Cell-Cell interaction is an essential requirement for the integrated function of a multicellular organism during development and mature life. Molecules secreted by one cell type and their specific plasma membrane receptors on the target cell are key components of this cellular communication network. Ligand-receptor interaction on the cell surface is translated into activation of intracellular signal transduction pathways, initiating a sequence of events that eventually results in specific cellular responses. Currently, two general mechanisms of cellular signal transduction are relatively well understood: coupling of receptors to various effectors by means of G proteins or coupling through the activation of a tyrosine-specific protein kinase activity that is intrinsic to the receptor molecule. Signaling by tyrosine kinase (TK) activation is shared by at least nine known hormones and growth factors and their corresponding receptors. These receptor tyrosine kinases (RTKs) constitute a family of structurally related receptor polypeptides with a rapidly increasing number of members. In recent years it has become clear that the study of receptor function and particularly RTK-activated signaling pathways will provide a better understanding of fundamental processes in the areas of cell biology, endocrinology, and development. Furthermore, one can expect that understanding receptor-mediated signal transduction will provide insights into the molecular basis of important human diseases, such as cancer and Type II diabetes, and open new avenues for diagnosis and therapy. Two advances have brought us substantially closer to an elucidation of RTK function. The primary structures of a number of RTKs have become available from cloned cDNA sequences, and comparative analysis has offered clues to receptor domain function. This family of cell surface glycoproteins can now be classified into several distinct structural subclasses that may reflect unique molecular pathways of cellular activation. In combination with classical biochemical approaches, the availability of cloned cDNAs for RTKs and their respective ligands opened the way for detailed dissection of the mechanism(s) of growth signal generation. cDNA clones encoding RTKs allowed the construction of structually altered receptors, which provided insights into the molecular mechanism of signal transduction. Such studies employed a large variety of receptor mutants to address the role of structural domains and subdomains in diverse functions, such as ligand binding, affinity definition and modulation, transmembrane activation, ATP binding, kinase activity, endocytosis, degradation, recycling, Ca^(2+) release, auto/transphosphorylation, substrate phosphorylation, and signal generation. These studies, as well as the torrent state of knowledge with respect to the characteristics of RTK-mediated cellular signals, will be discussed. Further studies are aimed at understanding which alterations in receptor structure and expression lead to transformation of cells in culture, formation of tumors in animals, and oncogenesis in humans. Furthermore, initial attempts towards new approaches for cancer therapy will be discussed.
Calibration of Timetable Parameters for Rail-Guided Systems
Weiting Zhao,Ullrich Martin,Yong Cui,Maureen Kosters 한국철도학회 2016 International Journal of Railway Vol.9 No.1
In order to achieve a comprehensive utilization of railway networks, it is necessary to accurately assess the timetable indicators that effect the train operation. This paper describes the parameter calibration for two timetable indicators: scheduled running time and scheduled dwell time. For the scheduled running time, an existing model is employed and the single timetable parameter (percentage of minimum running time) in that model is optimized. For the scheduled dwell time, two intrinsic characteristics: the significance of stations and the average headway at each station are proposed firstly to form a new model, and the corresponding timetable parameters (the weight of the significance and the weight of the average headway) are calibrated subsequently. The Floyd Algorithm is used to obtain the connectivity among stations, which represents the significance of the stations. A case study is conducted in a light rail transportation system with 17 underground stations. The results of this research show that the optimal value of the scheduled running time parameter can be automatically determined, and the proposed model for the scheduled dwell time works well with a high coefficient of determination and low relative root mean square error through the leave-one-out validation.