TY - JOUR A1 - Ross, Jillian A1 - Plummer, Simon M. A1 - Rode, Anja A1 - Scheer, Nico A1 - Bower, Conrad C. A1 - Vogel, Ortwin A1 - Henderson, Colin J. A1 - Wolf, C. Roland A1 - Elcombe, Clifford R. T1 - Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo JF - Toxicological Sciences N2 - Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear. The xenoreceptors, constitutive androstane receptors (CARs), and pregnane X receptor (PXR) play key roles in these processes. Novel “humanized” and knockout models for both receptors were developed to investigate potential species differences in hepatomegaly. The effects of PB (80 mg/kg/4 days) and chlordane (10 mg/kg/4 days) were investigated in double humanized PXR and CAR (huPXR/huCAR), double knockout PXR and CAR (PXRKO/CARKO), and wild-type (WT) C57BL/6J mice. In WT mice, both compounds caused increased liver weight, hepatocellular hypertrophy, and cell proliferation. Both compounds caused alterations to a number of cell cycle genes consistent with induction of cell proliferation in WT mice. However, these gene expression changes did not occur in PXRKO/CARKO or huPXR/huCAR mice. Liver hypertrophy without hyperplasia was demonstrated in the huPXR/huCAR animals in response to both compounds. Induction of the CAR and PXR target genes, Cyp2b10 and Cyp3a11, was observed in both WT and huPXR/huCAR mouse lines following treatment with PB or chlordane. In the PXRKO/CARKO mice, neither liver growth nor induction of Cyp2b10 and Cyp3a11 was seen following PB or chlordane treatment, indicating that these effects are CAR/PXR dependent. These data suggest that the human receptors are able to support the chemically induced hypertrophic responses but not the hyperplastic (cell proliferation) responses. At this time, we cannot be certain that hCAR and hPXR when expressed in the mouse can function exactly as the genes do when they are expressed in human cells. However, all parameters investigated to date suggest that much of their functionality is maintained. Y1 - 2010 U6 - http://dx.doi.org/10.1093/toxsci/kfq118 SN - 1096-0929 VL - 116 IS - 2 SP - 452 EP - 466 PB - Oxford University Press CY - Oxford ER - TY - JOUR A1 - Scheer, Nico A1 - Kapelyukh, Yury A1 - Rode, Anja A1 - Buechel, Sandra A1 - Wolf, C. Roland T1 - Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines JF - Molecular Pharmacology N2 - 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. Y1 - 2012 U6 - http://dx.doi.org/10.1124/mol.112.080036 SN - 1521-0111 VL - 82 IS - 6 SP - 1022 EP - 1029 PB - ASPET CY - Bethesda, Md. ER - TY - JOUR A1 - Scheer, Nico A1 - Balimane, Praveen A1 - Hayward, Michael D. A1 - Buechel, Sandra A1 - Kauselmann, Gunther A1 - Wolf, C. Roland T1 - Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line JF - Drug Metabolism and Disposition N2 - The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(−/−)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(−/−) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2. Y1 - 2012 U6 - http://dx.doi.org/10.1124/dmd.112.047605 SN - 1521-0111 VL - 40 IS - 11 SP - 2212 EP - 2218 PB - ASPET CY - Bethesda, Md. ER - TY - JOUR A1 - Scheer, Nico A1 - Mclaughlin, Lesley A. A1 - Rode, Anja A1 - MacLeod, Alastair Kenneth A1 - Henderson, Colin J. A1 - Wolf, Roland C. T1 - Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism JF - Drug Metabolism and Disposition N2 - 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. Y1 - 2014 U6 - http://dx.doi.org/10.1124/dmd.114.057885 SN - 1521-009X VL - 42 IS - 6 SP - 1022 EP - 1030 PB - ASPET CY - Bethesda, Md. ER - TY - CHAP A1 - Eggert, Mathias T1 - Big Data Research - How to Structure the Changes of the Past Decade? T2 - The Art of Structuring N2 - 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. Y1 - 2019 SN - 978-3-030-06234-7 U6 - http://dx.doi.org/10.1007/978-3-030-06234-7_26 SP - 271 EP - 281 PB - Springer CY - Cham ER - TY - JOUR A1 - Vögele, Stefan A1 - Rübbelke, Dirk A1 - Govorukha, Kristina A1 - Grajewski, Matthias T1 - Socio-technical scenarios for energy-intensive industries: the future of steel production in Germany JF - Climatic Change Y1 - 2019 U6 - http://dx.doi.org/10.1007/s10584-019-02366-0 SN - 0165-0009 SP - 1 EP - 16 PB - Springer CY - Berlin ER - TY - JOUR A1 - Campen, R. A1 - Kowalski, Julia A1 - Lyons, W.B. A1 - Tulaczyk, S. A1 - Dachwald, Bernd A1 - Pettit, E. A1 - Welch, K. A. A1 - Mikucki, J.A. T1 - Microbial diversity of an Antarctic subglacial community and high‐resolution replicate sampling inform hydrological connectivity in a polar desert JF - Environmental Microbiology Y1 - 2019 U6 - http://dx.doi.org/10.1111/1462-2920.14607 SN - 1462-2920 IS - accepted article PB - Wiley CY - Weinheim ER - TY - JOUR A1 - Lyons, W. Berry A1 - Mikucki, Jill A. A1 - German, Laura A. A1 - Welch, Kathleen A. A1 - Welch, Susan A. A1 - Gardener, Christopher B. A1 - Tulaczyk, Slawek M. A1 - Pettit, Erin C. A1 - Kowalski, Julia A1 - Dachwald, Bernd T1 - The Geochemistry of Englacial Brine from Taylor Glacier, Antarctica JF - Journal of Geophysical Research: Biogeosciences Y1 - 2019 U6 - http://dx.doi.org/10.1029/2018JG004411 SN - 2169-8961 PB - Wiley CY - Hoboken ER - TY - CHAP A1 - Franzen, Julian A1 - Stecken, Jannis A1 - Pfaff, Raphael A1 - Kuhlenkötter, Bernd T1 - Using the Digital Shadow for a Prescriptive Optimization of Maintenance and Operation : The Locomotive in the Context of the Cyber-Physical System T2 - Advances in Production, Logistics and Traffic N2 - 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. Y1 - 2019 SN - 978-3-030-13535-5 U6 - http://dx.doi.org/10.1007/978-3-030-13535-5_19 SP - 265 EP - 276 PB - Springer CY - Cham ER - TY - JOUR A1 - Funke, Harald A1 - Beckmann, Nils A1 - Abanteriba, Sylvester T1 - An overview on dry low NOx micromix combustor development for hydrogen-rich gas turbine applications JF - International Journal of Hydrogen Energy Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.ijhydene.2019.01.161 SN - 0360-3199 VL - 44 IS - 13 SP - 6978 EP - 6990 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Breuer, Lars A1 - Pilas, Johanna A1 - Guthmann, Eric A1 - Schöning, Michael Josef A1 - Thoelen, Ronald A1 - Wagner, Torsten T1 - Towards light-addressable flow control: responsive hydrogels with incorporated graphene oxide as laser-driven actuator structures within microfluidic channels JF - Sensor and Actuators B: Chemical Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.snb.2019.02.086 SN - 0925-4005 VL - 288 SP - 579 EP - 585 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Jung, Alexander A1 - Müller, Wolfram A1 - Staat, Manfred T1 - Optimization of the flight technique in ski jumping: the influence of wind Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.jbiomech.2019.03.023 IS - Early view PB - Elsevier CY - Amsterdam ER - TY - CHAP A1 - Grundmann, Jan Thimo A1 - Bauer, Waldemar A1 - Borchers, Kai A1 - Dumont, Etienne A1 - Grimm, Christian D. A1 - Ho, Tra-Mi A1 - Jahnke, Rico A1 - Lange, Caroline A1 - Maiwald, Volker A1 - Mikulz, Eugen A1 - Quantius, Dominik A1 - Reershemius, Siebo A1 - Renger, Thomas A1 - Riemann, Johannes A1 - Sasaki, Kaname A1 - Seefeldt, Patric A1 - Spietz, Peter A1 - Spröwitz, Tom A1 - Toth, Norbert A1 - Wejmo, Elisabet A1 - Biele, Jens A1 - Krause, Christian A1 - Cerotti, Matteo A1 - Peloni, Alessandro A1 - Dachwald, Bernd T1 - Small Spacecraft Solar Sailing for Small Solar System Body Multiple Rendezvous and Landing T2 - 2018 IEEE Aerospace Conference : 3-10 March 2018 Y1 - 2018 SN - 978-1-5386-2014-4 ER - TY - JOUR A1 - Scheer, Nico A1 - Henderson, Colin James A1 - Kapelyukh, Yury A1 - Rode, Anja A1 - Mclaren, Aileen W. A1 - MacLeod, Alastair Kenneth A1 - Lin, De A1 - Wright, Jayne A1 - Stanley, Lesley A1 - Wolf, C. Roland T1 - An extensively humanised mouse model to predict pathways of drug disposition, drug/drug interactions, and to facilitate the design of clinical trials JF - Drug Metabolism and Disposition Y1 - 2019 U6 - http://dx.doi.org/10.1124/dmd.119.086397 IS - Early view ER - TY - JOUR A1 - Jan Thimo, Grundmann A1 - Bauer, Waldemar A1 - Biele, Jens A1 - Boden, Ralf A1 - Ceriotti, Matteo A1 - Cordero, Federico A1 - Dachwald, Bernd A1 - Dumont, Etienne A1 - Grimm, Christian D. A1 - Hercik, David T1 - Capabilities of Gossamer-1 derived small spacecraft solar sails carrying Mascot-derived nanolanders for in-situ surveying of NEAs JF - Acta Astronautica Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.actaastro.2018.03.019 SN - 0094-5765 VL - 156 IS - 3 SP - 330 EP - 362 PB - Elsevier CY - Amsterdam ER - TY - CHAP A1 - Götten, Falk A1 - Havermann, Marc A1 - Braun, Carsten A1 - Gomez, Francisco A1 - Bil, Cees T1 - On the Applicability of Empirical Drag Estimation Methods for Unmanned Air Vehicle Design Read More: https://arc.aiaa.org/doi/10.2514/6.2018-3192 T2 - 2018 Aviation Technology, Integration, and Operations Conference, AIAA AVIATION Forum Y1 - 2018 U6 - http://dx.doi.org/10.2514/6.2018-3192 SN - 1533-385X N1 - AIAA 2018-3192 SP - Article 3192 ER -