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Mathematik im ingenieurwissenschaftlichen Bachelorstudium : Lösung der Übungs- und Klausuraufgaben
(2010)
1. Die Wirksamkeitsvoraussetzungen der Verdachtskündigung gegenüber einem Arbeitnehmer - Jana Scheilen | Seite 4-66
2. Besteuerungsinkongruenzen im Internationalen Steuerrecht - die Umsetzung der ATAD II in Form des § 4k EStG in Bezug auf hybride Gesellschaften und Betriebsstätten
- Max Peiffer | Seite 67-126
3. Der Zuzug einer Gesellschaft aus einem Drittstaat nach Deutschland - Herausforderungen durch die modifizierte Sitztheorie und Lösungsmöglichkeiten
- Anna-Luisa Görlich | Seite 127-189
4. Escalation of Commitment und seine Einflussfaktoren in der unternehmerischen Entscheidungsfindung: Ein Szenario-Experiment
- Theresa Hacke | Seite 190-245
Im Rahmen des Exzellenzclusters „Integrative Produktionstechnik für Hochlohnländer“ der RWTHAachen University werden derzeit alternative Verfahren zur Herstellung von Metall/Kunststoff- Verbindungen untersucht. Eines davon ist das thermische Direktfügen, das eine stoffschlüssige Verbindung zwischen Kunststoff und Metall ermöglicht und ohne die Verwendung von Klebstoffen, Haftvermittlern oder mechanischen Verbindungshilfen auskommt.
We present a new Min-Max theorem for an optimization problem closely connected to matchings and vertex covers in balanced hypergraphs. The result generalizes Kőnig’s Theorem (Berge and Las Vergnas in Ann N Y Acad Sci 175:32–40, 1970; Fulkerson et al. in Math Progr Study 1:120–132, 1974) and Hall’s Theorem (Conforti et al. in Combinatorica 16:325–329, 1996) for balanced hypergraphs.
Das Fußballtrikot – Arbeitsbekleidung, Identifikationsmerkmal, Distinktionsmerkmal? Was ist das Fußballtrikot, was sind seine identitätsstiftenden Merkmale und welche Gestaltungsparameter prägen sein heutiges Aussehen? In dieser Publikation wird die Geschichte des Trikots ebenso wie die äußeren Einflüsse auf sein heutiges Erscheinungsbild dokumentiert und analysiert. Die Publikation definiert die verschiedenen Gestaltungsparameter, erläutert diese und ordnet sie ein. Ebenso wird ein Einblick in den kreativen Gestaltungsprozess von Fußballtrikots gewährt. Das Ziel dieser Publikation besteht darin, das Erscheinungsbild von Trikots zu verstehen und eine kritische Reflexion darüber zu ermöglichen, wie das Fußballtrikot individuell definiert wird.
1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug–drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described.
2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created.
3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug–drug interactions as well as in human metabolite testing and risk assessment.
4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.
Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug–drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.
Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.
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.
Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction.