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In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.
In the past decade, many IS researchers focused on researching the phenomenon of Big Data. At the same time, the relevance of data protection gets more attention than ever before. In particular, since the enactment of the European General Data Protection Regulation in May 2018 Information Systems research should provide answers for protecting personal data. The article at hand presents a structuring framework for Big Data research outcome and the consideration of data protection. IS Researchers might use the framework in order to structure Big Data literature and to identify research gaps that should be addressed in the future.
Socio-technical scenarios for energy-intensive industries: the future of steel production in Germany
(2019)
In competition with other modes of transport, rail freight transport is looking for solutions to become more attractive. Short-term success can be achieved through the data-driven optimization of operations and maintenance as well as the application of novel strategies such as prescriptive maintenance. After introducing the concept of prescriptive maintenance, this paper aims to prove that vehicle-focused applications of this approach indeed have the potential to increase attractiveness. However, even greater advantages can be activated if data from the horizontal network of the vehicle is available. Drawing on the state of the art in research and technology in the field of cyber-physical systems (CPS) as well as digital twins and shadows, our work serves to design a system of systems for the horizontal interconnection of a rail vehicle and to conceptualize a draft for a digital twin of a locomotive.