TY - JOUR A1 - Seibler, Jost A1 - Kleinridders, Andre A1 - Küter-Luks, Birgit A1 - Niehaves, Sandra A1 - Brüning, Jens C. A1 - Schwenk, Frieder T1 - Reversible gene knockdown in mice using a tight, inducible shRNA expression system JF - Nucleic Acids Research Y1 - 2007 U6 - http://dx.doi.org/10.1093/nar/gkm122 SN - 1362-4962 VL - 35 IS - 7 SP - e54 ER - TY - JOUR A1 - Seibler, Jost A1 - Bode, Jürgen T1 - Double-reciprocal crossover mediated by FLP-recombinase: a concept and an assay JF - Biochemistry Y1 - 1997 SN - 1520-4995 VL - 36 IS - 7 SP - 1740 EP - 1747 ER - TY - JOUR A1 - Schwab, Lukas A1 - Hojdis, Nils A1 - Lacayo, Jorge A1 - Wilhelm, Manfred T1 - Fourier-Transform Rheology of Unvulcanized, Carbon Black Filled Styrene Butadiene Rubber JF - Macromolecular Materials and Engineering N2 - Rubber materials filled with reinforcing fillers display nonlinear rheological behavior at small strain amplitudes below γ0 < 0.1. Nevertheless, rheological data are analyzed mostly in terms of linear parameters, such as shear moduli (G′, G″), which loose their physical meaning in the nonlinear regime. In this work styrene butadiene rubber filled with carbon black (CB) under large amplitude oscillatory shear (LAOS) is analyzed in terms of the nonlinear parameter I3/1. Three different CB grades are used and the filler load is varied between 0 and 70 phr. It is found that I3/1(φ) is most sensitive to changes of the total accessible filler surface area at low strain amplitudes (γ0 = 0.32). The addition of up to 70 phr CB leads to an increase of I3/1(φ) by a factor of more than ten. The influence of the measurement temperature on I3/1 is pronounced for CB levels above the percolation threshold. Y1 - 2016 U6 - http://dx.doi.org/10.1002/mame.201500356 SN - 1439-2054 VL - 301 IS - 4 SP - 457 EP - 468 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Schroeter, Rebecca A1 - Hoffmann, Tamara A1 - Voigt, Birgit A1 - Meyer, Hanna A1 - Bleisteiner, Monika A1 - Muntel, Jan A1 - Jürgen, Britta A1 - Albrecht, Dirk A1 - Becher, Dörte A1 - Lalk, Michael A1 - Evers, Stefan A1 - Bongaerts, Johannes A1 - Maurer, Karl-Heinz A1 - Putzer, Harald A1 - Hecker, Michael A1 - Schweder, Thomas A1 - Bremer, Erhard T1 - Stress responses of the industrial workhorse Bacillus licheniformis to osmotic challenges JF - PLoS ONE N2 - The Gram-positive endospore-forming bacterium Bacillus licheniformis can be found widely in nature and it is exploited in industrial processes for the manufacturing of antibiotics, specialty chemicals, and enzymes. Both in its varied natural habitats and in industrial settings, B. licheniformis cells will be exposed to increases in the external osmolarity, conditions that trigger water efflux, impair turgor, cause the cessation of growth, and negatively affect the productivity of cell factories in biotechnological processes. We have taken here both systems-wide and targeted physiological approaches to unravel the core of the osmostress responses of B. licheniformis. Cells were suddenly subjected to an osmotic upshift of considerable magnitude (with 1 M NaCl), and their transcriptional profile was then recorded in a time-resolved fashion on a genome-wide scale. A bioinformatics cluster analysis was used to group the osmotically up-regulated genes into categories that are functionally associated with the synthesis and import of osmostress-relieving compounds (compatible solutes), the SigB-controlled general stress response, and genes whose functional annotation suggests that salt stress triggers secondary oxidative stress responses in B. licheniformis. The data set focusing on the transcriptional profile of B. licheniformis was enriched by proteomics aimed at identifying those proteins that were accumulated by the cells through increased biosynthesis in response to osmotic stress. Furthermore, these global approaches were augmented by a set of experiments that addressed the synthesis of the compatible solutes proline and glycine betaine and assessed the growth-enhancing effects of various osmoprotectants. Combined, our data provide a blueprint of the cellular adjustment processes of B. licheniformis to both sudden and sustained osmotic stress. Y1 - 2014 U6 - http://dx.doi.org/10.1371/journal.pone.0080956 SN - 1932-6203 VL - 8 IS - 11 PB - PLOS CY - San Francisco ER - TY - JOUR A1 - Schnitzler, Thomas T1 - Cultivation of hybridoma cell line CF-10H5 (DSMZ ACC477) JF - Application notes / Sartorius stedim biotech Y1 - 2009 SP - 1 EP - 4 ER - TY - CHAP A1 - Schnabel, Eberhard A1 - Berndt, Heinz ED - Nesvadba, H. T1 - Zur selektive Abspaltbarkeit der t-Butyloxycarbonylgruppe T2 - Peptides 1971 : proceedings of the Eleventh European Peptide Symposium, Vienna, Austria, April 1971 Y1 - 1973 SN - 0-7204-4120-X SP - 69 EP - 70 PB - North-Holland Publ. [u.a.] CY - Amsterdam [u.a.] ER - TY - JOUR A1 - Schmitz, M. A1 - Hirsch, E. A1 - Bongaerts, Johannes A1 - Takors, Ralf T1 - Pulse experiments as a prerequisite for the quantification of in vivo enzyme kinetics in aromatic amino acid pathway of Eschericia coli JF - Biotechnology progress Y1 - 2002 SN - 1520-6033 (E-Journal); 8756-7938 (Print) VL - Vol. 18 IS - Iss. 5 SP - 935 EP - 941 ER - TY - JOUR A1 - Schmidt, Aaron C. A1 - Turgut, Hatice A1 - Le, Dao A1 - Beloqui, Ana A1 - Delaittre, Guillaume T1 - Making the best of it: nitroxide-mediated polymerization of methacrylates via the copolymerization approach with functional styrenics JF - Polymer Chemistry N2 - The SG1-mediated solution polymerization of methyl methacrylate (MMA) and oligo(ethylene glycol) methacrylate (OEGMA, Mₙ = 300 g mol⁻¹) in the presence of a small amount of functional/reactive styrenic comonomer is investigated. Moieties such as pentafluorophenyl ester, triphenylphosphine, azide, pentafluorophenyl, halide, and pyridine are considered. A comonomer fraction as low as 5 mol% typically results in a controlled/living behavior, at least up to 50% conversion. Chain extensions with styrene for both systems were successfully performed. Variation of physical properties such as refractive index (for MMA) and phase transition temperature (for OEGMA) were evaluated by comparing to 100% pure homopolymers. The introduction of an activated ester styrene derivative in the polymerization of OEGMA allows for the synthesis of reactive and hydrophilic polymer brushes with defined thickness. Finally, using the example of pentafluorostyrene as controlling comonomer, it is demonstrated that functional PMMA-b-PS are able to maintain a phase separation ability, as evidenced by the formation of nanostructured thin films. Y1 - 2020 U6 - http://dx.doi.org/10.1039/C9PY01458F VL - 11 IS - 2 SP - 593 EP - 604 PB - Royal Society of Chemistry (RSC) CY - Cambridge ER - TY - JOUR A1 - Schmich, Peter A1 - Ederer, Hanns J. A1 - Ebert, Klaus H. T1 - Detection and identification of free radicals in hydrocarbon pyrolysis by an iodine trapping method JF - Industrial & Engineering Chemistry Research. 31 (1992), H. 1 Y1 - 1992 SN - 1520-5045 SP - 29 EP - 37 ER - TY - JOUR A1 - Schiffels, Johannes A1 - Selmer, Thorsten T1 - A flexible toolbox to study protein-assisted metalloenzyme assembly in vitro JF - Biotechnology and Bioengineering Y1 - 2015 U6 - http://dx.doi.org/10.1002/bit.25658 SN - 1097-0290 VL - 112 IS - 11 SP - 2360 EP - 2372 PB - Wiley CY - Weinheim ER - TY - JOUR A1 - Schiffels, Johannes A1 - Selmer, Thorsten T1 - Combinatorial assembly of ferredoxin‐linked modules in Escherichia coli yields a testing platform for Rnf‐complexes JF - Biotechnology and Bioengineering Y1 - 2019 U6 - http://dx.doi.org/10.1002/bit.27079 IS - accepted article SP - 1 EP - 36 PB - Wiley CY - Weinheim ER - TY - JOUR A1 - Schiffels, Johannes A1 - Pinkenburg, Olaf A1 - Schelden, Maximilian A1 - Aboulnaga, El-Hussiny A. A. A1 - Baumann, Marcus A1 - Selmer, Thorsten T1 - An innovative cloning platform enables large-scale production and maturation of an oxygen-tolerant [NiFe]-hydrogenase from cupriavidus necator in Escherichia coli JF - PLOS one. 2013 Y1 - 2013 U6 - http://dx.doi.org/10.1371/journal.pone.0068812 SN - 1932-6203 PB - Public Library of Science CY - San Francisco, California ER - TY - JOUR A1 - Schiffels, Johannes A1 - Baumann, Marcus A1 - Selmer, Thorsten T1 - Facile analysis of short-chain fatty acids as 4-nitrophenyl esters in complex anaerobic fermentation samples by high performance liquid chromatography JF - Journal of Chromatography A. 1218 (2011), H. 34 Y1 - 2011 SN - 0021-9673 SP - 5848 EP - 5851 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Schiedermeier, Maximilian A1 - Rettner, Cornelius A1 - Heilmann, Marcel A1 - Schneider, Felix A1 - Marz, Martin T1 - Interference of automotive HV-DC-systems by traction voltage-source-inverters (VSI) JF - 2019 IEEE Transportation Electrification Conference (ITEC-India) Y1 - 2019 U6 - http://dx.doi.org/10.1109/ITEC-India48457.2019.ITECINDIA2019-37 SP - 1 EP - 6 PB - IEEE CY - New York ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Zimmermann, H. P. A1 - Gober, M. K. A1 - Kratz, J. V. T1 - Chemical Properties of Element 105 in Aqueous Solution: Back Extraction from Triisooctyl Amine into 0.5M HCl / H.P. Zimmermann, M.K. Gober, J.V. Kratz, M. Schädel, E. Schimpf, K.E. Gregorich, A. Türler, K.R. Czerwinski, N.J. Hannink, B. Kadkhodayan, D.M. JF - Radiochimica Acta. 60 (1993) Y1 - 1993 SN - 0033-8230 SP - 11 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Türler, A. A1 - Gäggeler, H. W. A1 - Jost, D. T. T1 - Determination of the Partial Electron-Capture- and Spontaneous-Fission Half-Lives of 254No / A. Türler, H.W. Gäggeler, D.T. Jost, P. Armbruster, W. Brüchle, H. Folger, F.P. Heßberger, S. Hofmann, JF - Zeitschrift für Physik A Hadrons and Nuclei. 331 (1988), H. 3 Y1 - 1988 SN - 0939-7922 SP - 363 EP - 364 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Türler, A. A1 - Gäggeler, H. W. A1 - Gregorich, K. E. T1 - Gas phase chromatography of halides of elements 104 and 105 / A. Türler, H. W. Gäggeler, K. E. Gregorich, H. Barth, W. Brüchle, K. R. Czerwinski, M. K. Gober, N. J. Hannink, R. A. Henderson, D. C. Hoffman, D. T. Jost, C. D. Kacher, B. Kadkhodayan, J. Kova JF - Journal of Radioanalytical and Nuclear Chemistry. 160 (1992), H. 2 Y1 - 1992 SN - 0236-5731 SP - 327 EP - 339 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Tomasberger, T. A1 - Veltkamp, T. C. A1 - Booij, A. S. T1 - Radiocesium Removal from High Level Liquid Waste and Immobilisation in Sodium SilicoTitanate for Geological Disposal / T. Tomasberger, T.C. Veltkamp, A.S. Booij, U.W. Scherer JF - Radiochimica Acta. 89 (2001), H. 3 Y1 - 2001 SN - 0033-8230 SP - 145 EP - 150 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Srivastava, Alok A1 - Singh, Vivendra A1 - Chandra, Amita T1 - Electrical conductivity studies of swift heavy ion modified PVC and PVC-PANI composite / Alok Srivastava ,Virendra Singh, Amita Chandra, K.Witte, U.W.Scherer and T.V.Singh JF - Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 245 (2006), H. 1 Y1 - 2006 SN - 0168-583X SP - 277 EP - 280 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Schädel, M. A1 - Brüchle, W. A1 - Schimpf, E. T1 - Chemical Properties of Element 105 in Aqueous Solution: Cation Exchange Separations with α-Hydroxyisobutyric Acid / M. Schädel, W. Brüchle, E. Schimpf, H.P. Zimmermann, M.K. Gober, J.V. Kratz, N. Trautmann, H. Gäggeler, D. Jost, J. Kovacs, U.W. Sche JF - Radiochimica Acta. 57 (1992) Y1 - 1992 SN - 0033-8230 SP - 85 EP - 92 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Schädel, M. A1 - Brüchle, W. A1 - Jäger, E. T1 - ARCA II - A New Apparatus for Fast Repetitive HPLC-Separations / M. Schädel, W. Brüchle, E. Jäger, E. Schimpf, J.V. Kratz, U.W. Scherer, H.P. Zimmermann JF - Radiochimica Acta. 48 (1989) Y1 - 1989 SN - 0033-8230 SP - 171 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Santana, H. H. S. A1 - Maier, G. A1 - Rodenas, J. T1 - Analysis of mechanical strength in ceramic pellets of nuclear fuel / Santana, H. H. S. ; Maier, G. ; Scherer, U. W. ; Rodenas, J. JF - Radiation effects and defects in solids. 164 (2009), H. 5-6 Y1 - 2009 SN - 1042-0150 SP - 313 EP - 318 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Kratz, J. V. A1 - Zimmermann, H. P. A1 - Schädel, M. T1 - Chemical Properties of Element 105 in Aqueous Solutions: Halide Complex Formation and Anion Exchange into Triisooctylamine / J.V. Kratz, H.P. Zimmermann, U.W. Scherer, M. Schädel, W. Brüchle, K.E. Gregorich, C.M. Gannett, H.L. Hall, R.A. Henderson, D.M. L JF - Radiochimica Acta. 48 (1989) Y1 - 1989 SN - 0033-8230 SP - 121 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Kratz, J. V. A1 - Schädel, M. A1 - Brüchle, W. T1 - Lawrencium Chemistry: No Evidence for Oxidation States Lower than 3+ in Aqueous Solution / U.W. Scherer, J.V. Kratz, M. Schädel, W. Brüchle, K.E. Gregorich, R.A. Henderson, D. Lee, M. Nurmia, D.C. Hoffman JF - Inorganica Chimica Acta. 146 (1988) Y1 - 1988 SN - 0020-1693 SP - 249 EP - 254 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Kratz, J. V. A1 - Gober, M. K. A1 - Zimmermann, H. P. T1 - New nuclide 263 105 / J.V. Kratz, M.K. Gober, H.P. Zimmermann, M. Schädel, W. Brüchle, E. Schimpf, K.E. Gregorich, A. Türler, N.J. Hannink, K.R. Czerwinski, B. Kadkhodayan, D.M. Lee, M.J. Nurmia, D.C. Hoffman, H. Gäggeler, D. Jost, U.W. Scherer, A. Weber JF - Physical Review C . 45 (1992) Y1 - 1992 SP - 1064 EP - 1069 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Jacobi, M. A1 - Castillo, J. A1 - Foerstel, D. H. T1 - Ultra-low-level measurements of 3H and 14C in wines and champagne / Scherer, U. W. ; Jacobi, M. ; Castillo, J. ; Foerstel, D. H. JF - Radiation effects and defects in solids. 164 (2009), H. 5-6 Y1 - 2009 SN - 1042-0150 SP - 382 EP - 385 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Hör, G. A1 - Kranert, W. T. A1 - Maul, F. D. T1 - Gated Metabolic Positron Emission Tomography (GAPET) of Myocardium: 18F-FDG/PET to optimize Recognition of Myocardial Hibernation / G. Hör, W.T. Kranert, F.D. Maul, O. Schröder, A. Karimian-Tatriz, O. Geb, R.P. Baum, U.W. Scherer JF - Nuclear Medicine Communications. 19 (1998) Y1 - 1998 SN - 0143-3636 SP - 535 EP - 545 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Hör, G. T1 - Artifacts and Pitfalls in FDG-PET Whole-Body Scans / U.W. Scherer, G. Hör JF - Radionuclides for Mammary Gland - Current Status and Future Aspects / G. S. Limouris [Hrsg.] Y1 - 1997 SN - 960-85227-6-5 SP - 37 EP - 42 PB - Mediterra Publishers CY - Athen ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Heßberger, F. P. A1 - Gäggeler, H. W. A1 - Armbruster, P. T1 - The New Nuclide 225U / F.P. Heßberger, H. Gäggeler, P. Armbruster, W. Brüchle, H. Folger, S. Hofmann, D. Jost, J.V. Kratz, M.E. Leino, G. Münzenberg, V. Ninov, M. Schädel, U.W. Scherer, K. Sümmerer, A. Türler, D. Ackerman JF - Zeitschrift für Physik A Hadrons and Nuclei. 333 (1989), H. 1 Y1 - 1989 SN - 0939-7922 SP - 111 EP - 112 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Gäggeler, H. W. A1 - Jost, D. T. A1 - Türler, A. T1 - Cold Fusion Reactions with 48Ca / H.W. Gäggeler, D.T. Jost, A. Türler, P. Armbruster, W. Brüchle, H. Folger, F.P. Heßberger, S. Hofmann, G. Münzenberg, V. Ninov, W. Reisdorf, M. Schädel, K. Sümmerer, J.V. Kratz, U. Scherer, M.E. Leino JF - Nuclear Physics A . 502 (1989), H. 1 Y1 - 1989 SN - 0375-9474 SP - 561 EP - 570 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Gäggeler, H. W. A1 - Jost, D. T. A1 - Kovacs, J. T1 - Gas Phase Chromatography Experiments with Bromides of Tantalum and Element 105 / H.W. Gäggeler, D.T. Jost, J. Kovacs, U.W. Scherer, A. Weber, D. Vermeulen, A. Türler, K.E. Gregorich, R.A. Henderson, K.R. Czerwinski, B. Kadkhodayan, D.M. Lee, M. Nurmia, D. JF - Radiochimica Acta. 57 (1992) Y1 - 1992 SN - 0033-8230 SP - 93 EP - 100 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Gober, M. K. A1 - Kratz, J. V. A1 - Zimmermann, H. P. T1 - Chemical Properties of Element 105 in Aqueous Solution: Extractions into Diisobutylcarbinol / M.K. Gober, J.V. Kratz, H.P. Zimmermann, M. Schädel, W. Brüchle, E. Schimpf, K.E. Gregorich, A. Türler, N.J. Hannink, K.R. Czerwinski, B. Kadkhodayan, D.M. Lee, JF - Radiochimica Acta. 57 (1992) Y1 - 1992 SN - 0033-8230 SP - 77 EP - 84 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Brüchle, W. A1 - Schädel, M. A1 - Kratz, J. V. T1 - The Hydration Enthalpies of Md3+ and Lr3+ / W. Brüchle, M. Schädel, U.W. Scherer, J.V. Kratz, K.E. Gregorich, D. Lee, M. Nurmia, R.M. Chasteler, H.L. Hall, R.A. Henderson, D.C. Hoffman JF - Inorganica Chimica Acta. 146 (1988), H. 2 Y1 - 1988 SN - 0020-1693 SP - 267 EP - 276 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Brüchle, W. A1 - Brügger, M. A1 - Frink, C. T1 - Reactions of 40Ar with 233U,,235U, and 238U at the Barrier / U.W. Scherer, W. Brüchle, M. Brügger, C. Frink, H. Gäggeler, G. Herrmann, J.V. Kratz, K.J. Moody, M. Schädel, K. Sümmerer, N. Trautmann, G. Wirth JF - Zeitschrift für Physik A Hadrons and Nuclei. 335 (1990), H. 4 Y1 - 1990 SN - 0939-7922 SP - 421 EP - 430 ER - TY - JOUR A1 - Scherer, Ulrich W. A1 - Baltensperger, Urs A1 - Ammann, Markus A1 - Bochert, Ulrich K. T1 - Use of 13N for Studies of the Selective Reduction of NO by NH3 over Vanadia/Titania Catalyst at Very Low Reactant Concentrations / Urs Baltensperger, Markus Ammann, Ulrich K. Bochert, Bernd Eichler, Heinz W. Gäggeler, Dieter T. Jost, Joseph A. Kovacs, An JF - Journal of Physical Chemistry. 97 (1993) Y1 - 1993 SN - 0022-3654 SP - 12325 EP - 12330 ER - TY - JOUR A1 - Scherer, Ulrich W. T1 - Controlled ion track etching / J. George; M. Irkens ; S. Neumann ; U. W. Scherer ; A. Srivastava ; D. Sinha ; D. Fink JF - Radiation Effects and Defects in Solids. 161 (2006), H. 3 Y1 - 2006 SP - 161 EP - 175 ER - TY - JOUR A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications JF - Xenobiotica N2 - 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. KW - transporters KW - human metabolites KW - drug metabolising enzymes KW - drug–drug interactions KW - bioavailability Y1 - 2014 U6 - http://dx.doi.org/10.3109/00498254.2013.815831 SN - 1366-5928 VL - 44 IS - 2 SP - 96 EP - 108 PB - Taylor & Francis CY - Abingdon ER - TY - JOUR A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Xenobiotic receptor humanized mice and their utility JF - Drug Metabolism Reviews Y1 - 2013 U6 - http://dx.doi.org/10.3109/03602532.2012.738687 SN - 1097-9883 IS - 1 SP - 110 EP - 121 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Scheer, Nico A1 - Wilson, Ian D. T1 - A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity JF - Drug Discovery Today N2 - 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. Y1 - 2016 U6 - http://dx.doi.org/10.1016/j.drudis.2015.09.002 SN - 1359-6446 VL - 21 IS - 2 SP - 250 EP - 263 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Scheer, Nico A1 - Snaith, Mike A1 - Wolf, C. Roland A1 - Seibler, Jost T1 - Generation and utility of genetically humanized mouse models JF - Drug Discovery Today Y1 - 2013 U6 - http://dx.doi.org/10.1016/j.drudis.2013.07.007 SN - 1359-6446 VL - Vol 18 IS - 23-24 SP - 1200 EP - 1211 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Scheer, Nico A1 - Ross, Jillian A1 - Rode, Anja A1 - Zevnik, Branko A1 - Niehaves, Sandra A1 - Faust, Nicole A1 - Wolf, C. Roland T1 - A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response JF - Journal of Clinical Investigation Y1 - 2008 U6 - http://dx.doi.org/https://doi.org/10.1172/JCI35483 SN - 1558-8238 VL - 118 IS - 9 SP - 3228 EP - 3239 ER - TY - JOUR A1 - Scheer, Nico A1 - Ross, Jillian A1 - Kapelyukh, Yury A1 - Rode, Anja A1 - Wolf, C. Roland T1 - In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice JF - Drug Metabolism and Disposition N2 - 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. Y1 - 2010 U6 - http://dx.doi.org/10.1124/dmd.109.031872 SN - 1521-009X VL - 38 IS - 7 SP - 1046 EP - 1053 PB - ASPET CY - Bethesda ER - TY - JOUR A1 - Scheer, Nico A1 - Riedl, Iris A1 - Warren, J.T. A1 - Kuwada, John Y. A1 - Campos-Ortega, José A. T1 - A quantitative analysis of the kinetics of Gal4 activator and effector gene expression in the zebrafish JF - Mechanism of Development Y1 - 2002 U6 - http://dx.doi.org/10.1016/S0925-4773(01)00621-9 SN - 0925-4773 VL - 112 IS - 1-2 SP - 9 EP - 14 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 - JOUR A1 - Scheer, Nico A1 - Kapelyukh, Yury A1 - Rode, Anja A1 - Oswald, Stefan A1 - Busch, Diana A1 - Mclaughlin, Lesley A. A1 - Lin, De A1 - Henderson, Colin J. A1 - Wolf, C. Roland T1 - Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model JF - Drug Metabolism and Disposition Y1 - 2015 U6 - http://dx.doi.org/10.1124/dmd.115.065656 SN - 1521-009x VL - 43 IS - 11 SP - 1679 EP - 1690 PB - ASPET CY - Bethesda 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 - Kapelyukh, Yury A1 - McEwan, Jillian A1 - Beuger, Vincent A1 - Stanley, Lesley A. A1 - Rode, Anja A1 - Wolf, C. Roland T1 - Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines JF - Molecular Pharmacology N2 - The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine. Y1 - 2012 U6 - http://dx.doi.org/10.1124/mol.111.075192 SN - 1521-0111 VL - 81 IS - 1 SP - 63 EP - 72 PB - ASPET CY - Bethesda, Md. 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 - Scheer, Nico A1 - Groth, Anne A1 - Hans, Stefan A1 - Campos-Ortega, José A. T1 - An instructive function for Notch in promoting gliogenesis in the zebrafish retina JF - Development Y1 - 2001 SN - 0950-1991 VL - 128 IS - 7 SP - 1099 EP - 1107 ER - TY - CHAP A1 - Scheer, Nico A1 - Chu, Xiaoyan A1 - Salphati, Laurent A1 - Zamek-Gliszczynski, Maciej J. ED - Nicholls, Glynis T1 - Knockout and humanized animal models to study membrane transporters in drug development T2 - Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development Y1 - 2016 SN - 978-1-78262-379-3 U6 - http://dx.doi.org/10.1039/9781782623793-00298 SP - 298 EP - 332 PB - Royal Society of Chemistry CY - Cambridge ER -