TY - JOUR A1 - Liu, Z. A1 - Schaap, K. S. A1 - Ballemans, L. A1 - de Blois, E. A1 - Rohde, M. A1 - Paulßen, Elisabeth T1 - Measurement of reaction kinetics of [177Lu]Lu-DOTA-TATE using a microfluidic system JF - Dalton Transactions Y1 - 2017 U6 - http://dx.doi.org/10.1039/C7DT01830D SN - 1477-9234 VL - 46 IS - 42 SP - 14669 EP - 14676 ER - TY - CHAP A1 - Al-Kaidy, H. A1 - Ulber, R. A1 - Tippkötter, Nils T1 - A platform technology for the automated reaction control in magnetizable micro-fluidic droplets T2 - Biomaterials - made in bioreactors : book of abstracts, May 26 - 28, 2014, Radisson Blu Park Hotel and Conference Dentre, Radebeul, Germany Y1 - 2014 SP - 21 EP - 22 PB - DECHEMA CY - Frankfurt am Main ER - TY - CHAP A1 - Tippkötter, Nils A1 - Roikaew, W. A1 - Ulber, R. T1 - An automated pilot plant for the bioengineering processing of concentrated whey T2 - European BioPerspectives : in cooperation with BIOTECHNICA 2008 : 7 - 9 October 2008 Hannover, Germany ; book of abstracts ; abstracts, poster programme Y1 - 2008 SP - 98 PB - Dechema CY - Frankfurt am Main ER - TY - CHAP A1 - Tippkötter, Nils A1 - Stückmann, H. A1 - Winkelmann, G. A1 - Noack, U. A1 - Beutel, S. A1 - Scheper, T. A1 - Ulber, R. T1 - Optimisation of antibody-labelling of gold colloids for their application in an immunchromatographic assay for microcystin-LR T2 - European BioPerspectives : celebrating the 25th DECHEMA annual convention of biotechnologists ; 30 May - 1 June 2007, Cologne, Germany ; book of abstracts ; abstracts, poster programme Y1 - 2007 SP - 126 PB - Dechema CY - Frankfurt am Main ER - TY - JOUR A1 - Druckenmüller, Katharina A1 - Günther, Klaus A1 - Elbers, Gereon T1 - Near-infrared spectroscopy (NIRS) as a tool to monitor exhaust air from poultry operations JF - Science of the Total Environment N2 - Intensive poultry operation systems emit a considerable volume of inorganic and organic matter in the surrounding environment. Monitoring cleaning properties of exhaust air cleaning systems and to detect small but significant changes in emission characteristics during a fattening cycle is important for both emission and fattening process control. In the present study, we evaluated the potential of near-infrared spectroscopy (NIRS) combined with chemometric techniques as a monitoring tool of exhaust air from poultry operation systems. To generate a high-quality data set for evaluation, the exhaust air of two poultry houses was sampled by applying state-of-the-art filter sampling protocols. The two stables were identical except for one crucial difference, the presence or absence of an exhaust air cleaning system. In total, twenty-one exhaust air samples were collected at the two sites to monitor spectral differences caused by the cleaning device, and to follow changes in exhaust air characteristics during a fattening period. The total dust load was analyzed by gravimetric determination and included as a response variable in multivariate data analysis. The filter samples were directly measured with NIR spectroscopy. Principal component analysis (PCA), linear discriminant analysis (LDA), and factor analysis (FA) were effective in classifying the NIR exhaust air spectra according to fattening day and origin. The results indicate that the dust load and the composition of exhaust air (inorganic or organic matter) substantially influence the NIR spectral patterns. In conclusion, NIR spectroscopy as a tool is a promising and very rapid way to detect differences between exhaust air samples based on still not clearly defined circumstances triggered during a fattening period and the availability of an exhaust air cleaning system. Y1 - 2018 U6 - http://dx.doi.org/10.1016/j.scitotenv.2018.02.072 SN - 0048-9697 VL - 630 SP - 536 EP - 543 PB - Elsevier CY - Amsterdam ER - TY - BOOK A1 - Artmann, Gerhard A1 - Temiz Artmann, Aysegül A1 - Zhubanova, Azhar A. A1 - Digel, Ilya ED - Artmann, Gerhard ED - Temiz Artmann, Aysegül ED - Zhubanova, Azhar A. ED - Digel, Ilya T1 - Biological, physical and technical basics of cell engineering Y1 - 2018 SN - 978-981-10-7903-0 PB - Springer CY - Singapore ER - TY - JOUR A1 - Molinnus, Denise A1 - Muschallik, Lukas A1 - Gonzalez, Laura Osorio A1 - Bongaerts, Johannes A1 - Wagner, Torsten A1 - Selmer, Thorsten A1 - Siegert, Petra A1 - Keusgen, Michael A1 - Schöning, Michael Josef T1 - Development and characterization of a field-effect biosensor for the detection of acetoin JF - Biosensors and Bioelectronics N2 - A capacitive electrolyte-insulator-semiconductor (EIS) field-effect biosensor for acetoin detection has been presented for the first time. The EIS sensor consists of a layer structure of Al/p-Si/SiO₂/Ta₂O₅/enzyme acetoin reductase. The enzyme, also referred to as butane-2,3-diol dehydrogenase from B. clausii DSM 8716T, has been recently characterized. The enzyme catalyzes the (R)-specific reduction of racemic acetoin to (R,R)- and meso-butane-2,3-diol, respectively. Two different enzyme immobilization strategies (cross-linking by using glutaraldehyde and adsorption) have been studied. Typical biosensor parameters such as optimal pH working range, sensitivity, hysteresis, linear concentration range and long-term stability have been examined by means of constant-capacitance (ConCap) mode measurements. Furthermore, preliminary experiments have been successfully carried out for the detection of acetoin in diluted white wine samples. Y1 - 2018 U6 - http://dx.doi.org/10.1016/j.bios.2018.05.023 VL - 115 SP - 1 EP - 6 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Pilas, Johanna A1 - Yazici, Y. A1 - Selmer, Thorsten A1 - Keusgen, M. A1 - Schöning, Michael Josef T1 - Application of a portable multi-analyte biosensor for organic acid determination in silage JF - Sensors N2 - Multi-analyte biosensors may offer the opportunity to perform cost-effective and rapid analysis with reduced sample volume, as compared to electrochemical biosensing of each analyte individually. This work describes the development of an enzyme-based biosensor system for multi-parametric determination of four different organic acids. The biosensor array comprises five working electrodes for simultaneous sensing of ethanol, formate, d-lactate, and l-lactate, and an integrated counter electrode. Storage stability of the biosensor was evaluated under different conditions (stored at +4 °C in buffer solution and dry at −21 °C, +4 °C, and room temperature) over a period of 140 days. After repeated and regular application, the individual sensing electrodes exhibited the best stability when stored at −21 °C. Furthermore, measurements in silage samples (maize and sugarcane silage) were conducted with the portable biosensor system. Comparison with a conventional photometric technique demonstrated successful employment for rapid monitoring of complex media. Y1 - 2018 U6 - http://dx.doi.org/10.3390/s18051470 SN - 1424-8220 VL - 18 IS - 5 PB - MDPI CY - Basel ER - TY - CHAP A1 - Artmann, Gerhard A1 - Meruvu, Haritha A1 - Kizildag, Sefa A1 - Temiz Artmann, Aysegül ED - Artmann, Gerhard ED - Temiz Artmann, Aysegül ED - Zhubanova, Azhar A. ED - Digel, Ilya T1 - Functional Toxicology and Pharmacology Test of Cell Induced Mechanical Tensile Stress in 2D and 3D Tissue Cultures T2 - Biological, Physical and Technical Basics of Cell Engineering N2 - Mechanical forces/tensile stresses are critical determinants of cellular growth, differentiation and migration patterns in health and disease. The innovative “CellDrum technology” was designed for measuring mechanical tensile stress of cultured cell monolayers/thin tissue constructs routinely. These are cultivated on very thin silicone membranes in the so-called CellDrum. The cell layers adhere firmly to the membrane and thus transmit the cell forces generated. A CellDrum consists of a cylinder which is sealed from below with a 4 μm thick, biocompatible, functionalized silicone membrane. The weight of cell culture medium bulbs the membrane out downwards. Membrane indentation is measured. When cells contract due to drug action, membrane, cells and medium are lifted upwards. The induced indentation changes allow for lateral drug induced mechanical tension quantification of the micro-tissues. With hiPS-induced (human) Cardiomyocytes (CM) the CellDrum opens new perspectives of individualized cardiac drug testing. Here, monolayers of self-beating hiPS-CMs were grown in CellDrums. Rhythmic contractions of the hiPS-cells induce membrane up-and-down deflections. The recorded cycles allow for single beat amplitude, single beat duration, integration of the single beat amplitude over the beat time and frequency analysis. Dose effects of agonists and antagonists acting on Ca2+ channels were sensitively and highly reproducibly observed. Data were consistent with published reference data as far as they were available. The combination of the CellDrum technology with hiPS-Cardiomyocytes offers a fast, facile and precise system for pharmacological and toxicological studies. It allows new preclinical basic as well as applied research in pharmacolgy and toxicology. Y1 - 2018 SN - 978-981-10-7904-7 U6 - http://dx.doi.org/10.1007/978-981-10-7904-7_7 SP - 157 EP - 192 PB - Springer CY - Singapore ER - TY - CHAP A1 - Duong, Minh Tuan A1 - Seifarth, Volker A1 - Temiz Artmann, Aysegül A1 - Artmann, Gerhard A1 - Staat, Manfred ED - Artmann, Gerhard ED - Temiz Artmann, Aysegül ED - Zhubanova, Azhar A. ED - Digel, Ilya T1 - Growth Modelling Promoting Mechanical Stimulation of Smooth Muscle Cells of Porcine Tubular Organs in a Fibrin-PVDF Scaffold T2 - Biological, Physical and Technical Basics of Cell Engineering N2 - Reconstructive surgery and tissue replacements like ureters or bladders reconstruction have been recently studied, taking into account growth and remodelling of cells since living cells are capable of growing, adapting, remodelling or degrading and restoring in order to deform and respond to stimuli. Hence, shapes of ureters or bladders and their microstructure change during growth and these changes strongly depend on external stimuli such as training. We present the mechanical stimulation of smooth muscle cells in a tubular fibrin-PVDFA scaffold and the modelling of the growth of tissue by stimuli. To this end, mechanotransduction was performed with a kyphoplasty balloon catheter that was guided through the lumen of the tubular structure. The bursting pressure was examined to compare the stability of the incubated tissue constructs. The results showed the significant changes on tissues with training by increasing the burst pressure as a characteristic mechanical property and the smooth muscle cells were more oriented with uniformly higher density. Besides, the computational growth models also exhibited the accurate tendencies of growth of the cells under different external stimuli. Such models may lead to design standards for the better layered tissue structure in reconstructing of tubular organs characterized as composite materials such as intestines, ureters and arteries. KW - Mechanical simulation KW - Growth modelling KW - Ureter KW - Bladder KW - Reconstruction Y1 - 2018 SN - 978-981-10-7904-7 U6 - http://dx.doi.org/10.1007/978-981-10-7904-7_9 SP - 209 EP - 232 PB - Springer CY - Singapore ER - TY - CHAP A1 - Wagemann, Kurt A1 - Tippkötter, Nils T1 - Biorefineries: a short introduction T2 - Biorefineries N2 - The terms bioeconomy and biorefineries are used for a variety of processes and developments. This short introduction is intended to provide a delimitation and clarification of the terminology as well as a classification of current biorefinery concepts. The basic process diagrams of the most important biorefinery types are shown. KW - Bioeconomy KW - Biorefinery definitions KW - Introduction KW - Process schemes KW - Renewable resources Y1 - 2019 SN - 978-3-319-97117-9 SN - 978-3-319-97119-3 U6 - http://dx.doi.org/10.1007/10_2017_4 N1 - (Advances in Biochemical Engineering/Biotechnology book series ; Vol. 166) SP - 1 EP - 11 PB - Springer CY - Cham ER - TY - JOUR A1 - Aboulnaga, E. A. A1 - Zou, H. A1 - Selmer, Thorsten A1 - Xian, M. T1 - Development of a plasmid-based, tunable, tolC-derived expression system for application in Cupriavidus necator H16 JF - Journal of Biotechnology N2 - Cupriavidus necator H16 gains increasing attention in microbial research and biotechnological application due to its diverse metabolic features. Here we present a tightly controlled gene expression system for C. necator including the pBBR1-vector that contains hybrid promoters originating from C. necator native tolC-promoter in combination with a synthetic tetO-operator. The expression of the reporter gene from these plasmids relies on the addition of the exogenous inducer doxycycline (dc). The novel expression system offers a combination of advantageous features as; (i) high and dose-dependent recombinant protein production, (ii) tight control with a high dynamic range (On/Off ratio), which makes it applicable for harmful pathways or for toxic protein production, (iii) comparable cheap inducer (doxycycline, dc), (iv) effective at low inducer concentration, that makes it useful for large scale application, (v) rapid, diffusion controlled induction, and (vi) the inducer does not interfere within the cell metabolism. As applications of the expression system in C. necator H16, the growth ability on glycerol was enhanced by constitutively expressing the E. coli glpk gene-encoding for glycerol kinase. Likewise, we used the system to overcome the expression toxicity of mevalonate pathway in C. necator H16. With this system, the mevalonate-genes were successfully introduced in the host and the recombinant strains could produce about 200 mg/l mevalonate. Y1 - 2018 U6 - http://dx.doi.org/10.1016/j.jbiotec.2018.03.007 SN - 0168-1656 VL - 274 SP - 15 EP - 27 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Teumer, T. A1 - Capitain, C. A1 - Ross-Jones, J. A1 - Tippkötter, Nils A1 - Rädle, M. A1 - Methner, F.-J. T1 - In-line Haze Monitoring Using a Spectrally Resolved Back Scattering Sensor JF - BrewingScience N2 - In the present work an optical sensor in combination with a spectrally resolved detection device for in-line particle-size-monitoring for quality control in beer production is presented. The principle relies on the size and wavelength dependent backscatter of growing particles in fluids. Measured interference structures of backscattered light are compared with calculated theoretical values, based on Mie-Theory, and fitted with a linear least square method to obtain particle size distributions. For this purpose, a broadband light source in combination with a process-CCD-spectrometer (charge ? coupled device spectrometer) and process adapted fiber optics are used. The goal is the development of an easy and flexible measurement device for in-line-monitoring of particle size. The presented device can be directly installed in product fill tubes or vessels, follows CIP- (cleaning in place) and removes the need of sample taking. A proof of concept and preliminary results, measuring protein precipitation, are presented. Y1 - 2018 SN - 1613-2041 VL - 71 IS - 5/6 SP - 49 EP - 55 PB - Fachverlag Hans Carl CY - Nürnberg ER - TY - CHAP A1 - Tippkötter, Nils A1 - Möhring, Sophie A1 - Roth, Jasmine A1 - Wulfhorst, Helene T1 - Logistics of lignocellulosic feedstocks: preprocessing as a preferable option T2 - Biorefineries N2 - In comparison to crude oil, biorefinery raw materials are challenging in concerns of transport and storage. The plant raw materials are more voluminous, so that shredding and compacting usually are necessary before transport. These mechanical processes can have a negative influence on the subsequent biotechnological processing and shelf life of the raw materials. Various approaches and their effects on renewable raw materials are shown. In addition, aspects of decentralized pretreatment steps are discussed. Another important aspect of pretreatment is the varying composition of the raw materials depending on the growth conditions. This problem can be solved with advanced on-site spectrometric analysis of the material. KW - Analytics KW - Decentral KW - Mechanical KW - On-site KW - Pre-treatment Y1 - 2019 SN - 978-3-319-97117-9 SN - 978-3-319-97119-3 U6 - http://dx.doi.org/10.1007/10_2017_58 N1 - Advances in biochemical engineering/biotechnology ; Vol. 166 SP - 43 EP - 68 PB - Springer CY - Cham ER - TY - CHAP A1 - Duwe, A. A1 - Tippkötter, Nils A1 - Ulber, R. T1 - Lignocellulose-Biorefinery: Ethanol-Focused T2 - Biorefineries N2 - The development prospects of the world markets for petroleum and other liquid fuels are diverse and partly contradictory. However, comprehensive changes for the energy supply of the future are essential. Notwithstanding the fact that there are still very large deposits of energy resources from a geological point of view, the finite nature of conventional oil reserves is indisputable. To reduce our dependence on oil, the EU, the USA, and other major economic zones rely on energy diversification. For this purpose, alternative materials and technologies are being sought, and is most obvious in the transport sector. The objective is to progressively replace fossil fuels with renewable and more sustainable fuels. In this respect, biofuels have a pre-eminent position in terms of their capability of blending with fossil fuels and being usable in existing cars without substantial modification. Ethanol can be considered as the primary renewable liquid fuel. In this chapter enzymes, micro-organisms, and processes for ethanol production based on renewable resources are described. KW - Bioethanol KW - Biorefinery KW - Lignocellulose feedstook Y1 - 2018 U6 - http://dx.doi.org/10.1007/10_2016_72 N1 - Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE,volume 166) SP - 177 EP - 215 PB - Springer CY - Cham ER - TY - JOUR A1 - Eckert, Alexander A1 - Rudolph, Tobias A1 - Guo, Jiaqi A1 - Mang, Thomas A1 - Walther, Andreas T1 - Exceptionally Ductile and Tough Biomimetic Artificial Nacre with Gas Barrier Function JF - Advanced Materials N2 - Synthetic mimics of natural high-performance structural materials have shown great and partly unforeseen opportunities for the design of multifunctional materials. For nacre-mimetic nanocomposites, it has remained extraordinarily challenging to make ductile materials with high stretchability at high fractions of reinforcements, which is however of crucial importance for flexible barrier materials. Here, highly ductile and tough nacre-mimetic nanocomposites are presented, by implementing weak, but many hydrogen bonds in a ternary nacre-mimetic system consisting of two polymers (poly(vinyl amine) and poly(vinyl alcohol)) and natural nanoclay (montmorillonite) to provide efficient energy dissipation and slippage at high nanoclay content (50 wt%). Tailored interactions enable exceptional combinations of ductility (close to 50% strain) and toughness (up to 27.5 MJ m⁻³). Extensive stress whitening, a clear sign of high internal dynamics at high internal cohesion, can be observed during mechanical deformation, and the materials can be folded like paper into origami planes without fracture. Overall, the new levels of ductility and toughness are unprecedented in highly reinforced bioinspired nanocomposites and are of critical importance to future applications, e.g., as barrier materials needed for encapsulation and as a printing substrate for flexible organic electronics. Y1 - 2018 U6 - http://dx.doi.org/10.1002/adma.201802477 VL - 30 IS - 32 SP - Article number 1802477 PB - Wiley-VCH ER - TY - JOUR A1 - Müller, Janina A1 - Beckers, Mario A1 - Mußmann, Nina A1 - Bongaerts, Johannes A1 - Büchs, Jochen T1 - Elucidation of auxotrophic deficiencies of Bacillus pumilus DSM 18097 to develop a defined minimal medium JF - Microbial Cell Factories N2 - Background Culture media containing complex compounds like yeast extract or peptone show numerous disadvantages. The chemical composition of the complex compounds is prone to significant variations from batch to batch and quality control is difficult. Therefore, the use of chemically defined media receives more and more attention in commercial fermentations. This concept results in better reproducibility, it simplifies downstream processing of secreted products and enable rapid scale-up. Culturing bacteria with unknown auxotrophies in chemically defined media is challenging and often not possible without an extensive trial-and-error approach. In this study, a respiration activity monitoring system for shake flasks and its recent version for microtiter plates were used to clarify unknown auxotrophic deficiencies in the model organism Bacillus pumilus DSM 18097. Results Bacillus pumilus DSM 18097 was unable to grow in a mineral medium without the addition of complex compounds. Therefore, a rich chemically defined minimal medium was tested containing basically all vitamins, amino acids and nucleobases, which are essential ingredients of complex components. The strain was successfully cultivated in this medium. By monitoring of the respiration activity, nutrients were supplemented to and omitted from the rich chemically defined medium in a rational way, thus enabling a systematic and fast determination of the auxotrophic deficiencies. Experiments have shown that the investigated strain requires amino acids, especially cysteine or histidine and the vitamin biotin for growth. Conclusions The introduced method allows an efficient and rapid identification of unknown auxotrophic deficiencies and can be used to develop a simple chemically defined tailor-made medium. B. pumilus DSM 18097 was chosen as a model organism to demonstrate the method. However, the method is generally suitable for a wide range of microorganisms. By combining a systematic combinatorial approach based on monitoring the respiration activity with cultivation in microtiter plates, high throughput experiments with high information content can be conducted. This approach facilitates media development, strain characterization and cultivation of fastidious microorganisms in chemically defined minimal media while simultaneously reducing the experimental effort. Y1 - 2018 U6 - http://dx.doi.org/10.1186/s12934-018-0956-1 SN - 1475-2859 VL - 17 IS - 1 SP - Article No. 106 PB - BioMed Central ER - TY - JOUR A1 - Röhlen, Desiree A1 - Pilas, Johanna A1 - Dahmen, Markus A1 - Keusgen, Michael A1 - Selmer, Thorsten A1 - Schöning, Michael Josef T1 - Toward a Hybrid Biosensor System for Analysis of Organic and Volatile Fatty Acids in Fermentation Processes JF - Frontiers in Chemistry N2 - Monitoring of organic acids (OA) and volatile fatty acids (VFA) is crucial for the control of anaerobic digestion. In case of unstable process conditions, an accumulation of these intermediates occurs. In the present work, two different enzyme-based biosensor arrays are combined and presented for facile electrochemical determination of several process-relevant analytes. Each biosensor utilizes a platinum sensor chip (14 × 14 mm²) with five individual working electrodes. The OA biosensor enables simultaneous measurement of ethanol, formate, d- and l-lactate, based on a bi-enzymatic detection principle. The second VFA biosensor provides an amperometric platform for quantification of acetate and propionate, mediated by oxidation of hydrogen peroxide. The cross-sensitivity of both biosensors toward potential interferents, typically present in fermentation samples, was investigated. The potential for practical application in complex media was successfully demonstrated in spiked sludge samples collected from three different biogas plants. Thereby, the results obtained by both of the biosensors were in good agreement to the applied reference measurements by photometry and gas chromatography, respectively. The proposed hybrid biosensor system was also used for long-term monitoring of a lab-scale biogas reactor (0.01 m³) for a period of 2 months. In combination with typically monitored parameters, such as gas quality, pH and FOS/TAC (volatile organic acids/total anorganic carbonate), the amperometric measurements of OA and VFA concentration could enhance the understanding of ongoing fermentation processes. Y1 - 2018 U6 - http://dx.doi.org/10.3389/fchem.2018.00284 IS - 6 PB - Frontiers CY - Lausanne ER - TY - JOUR A1 - Engel, Mareike A1 - Holtmann, Dirk A1 - Ulber, Roland A1 - Tippkötter, Nils T1 - Increased Biobutanol Production by Mediator‐Less Electro‐Fermentation JF - Biotechnology Journal N2 - A future bio-economy should not only be based on renewable raw materials but also in the raise of carbon yields of existing production routes. Microbial electrochemical technologies are gaining increased attention for this purpose. In this study, the electro-fermentative production of biobutanol with C. acetobutylicum without the use of exogenous mediators is investigated regarding the medium composition and the reactor design. It is shown that the use of an optimized synthetic culture medium allows higher product concentrations, increased biofilm formation, and higher conductivities compared to a synthetic medium supplemented with yeast extract. Moreover, the optimization of the reactor system results in a doubling of the maximum product concentrations for fermentation products. When a working electrode is polarized at −600 mV vs. Ag/AgCl, a shift from butyrate to acetone and butanol production is induced. This leads to an increased final solvent yield of Yᴀᴃᴇ = 0.202 gg⁻¹ (control 0.103 gg⁻¹), which is also reflected in a higher carbon efficiency of 37.6% compared to 23.3% (control) as well as a fourfold decrease in simplified E-factor to 0.43. The results are promising for further development of biobutanol production in bioelectrochemical systems in order to fulfil the principles of Green Chemistry. Y1 - 2018 U6 - http://dx.doi.org/10.1002/biot.201800514 SN - 1860-7314 IS - Volume 14, Issue 4 SP - Artikel 1800514 PB - Wiley-VCH ER - TY - CHAP A1 - Kazuki, Yasuhiro A1 - Kobayashi, Kaoru A1 - Hirabayashi, Masumi A1 - Abe, Satoshi A1 - Kajitani, Naoyo A1 - Kazuki, Kanoko A1 - Takehara, Shoko A1 - Takiguchi, Masato A1 - Satoh, Daisuke A1 - Kuze, Jiro A1 - Sakuma, Tetsushi A1 - Kaneko, Takehito A1 - Mashimo, Tomoji A1 - Osamura, Minori A1 - Hashimoto, Mari A1 - Wakatsuki, Riko A1 - Hirashima, Rika A1 - Fujiwara, Ryoichi A1 - Deguchi, Tsuneo A1 - Kurihara, Atsushi A1 - Tsukazaki, Yasuko A1 - Senda, Naoto A1 - Yamamoto, Takashi A1 - Scheer, Nico A1 - Oshimura, Mitsuo T1 - Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism T2 - PNAS Proceedings of the National Academy of Sciences of the United States of America Y1 - 2019 U6 - http://dx.doi.org/10.1073/pnas.1808255116 SN - 1091-6490 VL - 116 IS - 8 SP - 3072 EP - 3081 ER - TY - JOUR A1 - Wilson, C. E. A1 - Dickie, A. P. A1 - Schreiter, K. A1 - Wehr, R. A1 - Wilson, E. M. A1 - Bial, J. A1 - Scheer, Nico A1 - Wilson, I. D. A1 - Riley, R. J. T1 - The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice JF - Archives of Toxicology N2 - The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans. Y1 - 2018 U6 - http://dx.doi.org/10.1007/s00204-018-2212-1 SN - 1432-0738 VL - 92 IS - 6 SP - 1953 EP - 1967 PB - Springer ER - TY - JOUR A1 - Wilson, Ian D. A1 - Wilson, Claire E. A1 - Scheer, Nico A1 - Dickie, A.P. A1 - Schreiter, K. A1 - Wilson, E. M. A1 - Riley, R. J. A1 - Wehr, R. A1 - Bial, J. T1 - The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice JF - Biochemical pharmacology Y1 - 2017 U6 - http://dx.doi.org/10.1016/j.bcp.2017.03.015 SN - 1873-2968 VL - Volume 135 SP - 139 EP - 150 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Zhang, Jin A1 - Heimbach, Tycho A1 - Scheer, Nico A1 - Barve, Avantika A1 - Li, Wenkui A1 - Lin, Wen A1 - He, Handan T1 - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling JF - Journal of Pharmaceutical Sciences N2 - NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir. Y1 - 2016 U6 - http://dx.doi.org/doi.org/10.1016/j.xphs.2016.01.021 SN - 0022-3549 VL - Volume 105 IS - Issue 4 SP - 1398 EP - 1404 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Dallas, Shannon A1 - Salphati, Laurent A1 - Gomez-Zepeda, David A1 - Wanek, Thomas A1 - Chen, Liangfu A1 - Chu, Xiaoyan A1 - Kunta, Jeevan A1 - Mezler, Mario A1 - Menet, Marie-Claude A1 - Chasseigneaux, Stephanie A1 - Declèves, Xavier A1 - Langer, Oliver A1 - Pierre, Esaie A1 - DiLoreto, Karen A1 - Hoft, Carolin A1 - Laplanche, Loic A1 - Pang, Jodie A1 - Pereira, Tony A1 - Andonian, Clara A1 - Simic, Damir A1 - Rode, Anja A1 - Yabut, Jocelyn A1 - Zhang, Xiaolin A1 - Scheer, Nico T1 - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model JF - Molecular Pharmacology N2 - Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP. Y1 - 2016 U6 - http://dx.doi.org/10.1124/mol.115.102079 SN - 1521-0111 VL - 89 IS - 5 SP - 492 EP - 504 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 - Hough, Lindsay B. A1 - Nalwalk, Julia W. A1 - Ding, Xinxin A1 - Scheer, Nico T1 - Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms JF - Drug Metabolism and Disposition Y1 - 2015 U6 - http://dx.doi.org/10.1124/dmd.115.065490 SN - 1521-009x VL - 43 IS - 9 SP - 1326 EP - 1330 ER - TY - JOUR A1 - Henderson, Colin J. A1 - Mclaughlin, Lesley A. A1 - Scheer, Nico A1 - Stanley, Lesley A. A1 - Wolf, C. Roland T1 - Cytochrome b5 Is a Major Determinant of Human Cytochrome P450 CYP2D6 and CYP3A4 Activity In Vivo s JF - Molecular Pharmacology Y1 - 2015 U6 - http://dx.doi.org/10.1124/mol.114.097394 SN - 1521-0111 VL - 87 IS - 4 SP - 733 EP - 739 PB - ASPET CY - Bethesda ER - TY - JOUR A1 - Luisier, Raphaëlle A1 - Lempiäinen, Harri A1 - Scherbichler, Nina A1 - Braeuning, Albert A1 - Geissler, Miriam A1 - Dubost, Valerie A1 - Müller, Arne A1 - Scheer, Nico A1 - Chibout, Salah-Dine A1 - Hara, Hisanori A1 - Picard, Frank A1 - Theil, Diethilde A1 - Couttet, Philippe A1 - Vitobello, Antonio A1 - Grenet, Olivier A1 - Grasl-Kraupp, Bettina A1 - Ellinger-Ziegelbauer, Heidrung A1 - Thomson, John P. A1 - Meehan, Richard R. A1 - Elcombe, Clifford R. A1 - Henderson, Colin J. A1 - Wolf, C. Roland A1 - Schwarz, Michael A1 - Moulin, Pierre A1 - Terranova, Remi A1 - Moggs, Jonathan G. T1 - Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors JF - Toxicological Sciences N2 - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB. Y1 - 2014 U6 - http://dx.doi.org/https://doi.org/10.1093/toxsci/kfu038 SN - 1094-2025 VL - 139 IS - 2 SP - 501 EP - 511 PB - Oxford University Press CY - Oxford ER - TY - JOUR A1 - Salpati, Laurent A1 - Chu, Xiaoyan A1 - Chen, Liangfu A1 - Prasad, Bhagwat A1 - Dallas, Shannon A1 - Evers, Raymond A1 - Mamaril-Fishman, Donna A1 - Geier, Ethan G. A1 - Kehler, Jonathan A1 - Kunta, Jeevan A1 - Mezler, Mario A1 - Laplanche, Loic A1 - Pang, Jodie A1 - Soars, Matthew G. A1 - Unadkat, Jashvant D. A1 - van Waterschoot, Robert A.B. A1 - Yabut, Jocelyn A1 - Schinkel, Alfred H. A1 - Scheer, Nico A1 - Rode, Anja T1 - Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins JF - Drug Metabolism and Disposition N2 - Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography–tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans. Y1 - 2014 U6 - http://dx.doi.org/10.1124/dmd.114.057976 SN - 1521-009X VL - 42 IS - 8 SP - 1301 EP - 1313 PB - ASPET CY - Bethesda, Md. ER - TY - BOOK A1 - Wagemann, Kurt A1 - Tippkötter, Nils T1 - Biorefineries / Kurt Wagemann, Nils Tippkötter (editors) T3 - Advances in biochemical engineering/biotechnology book series (ABE) Y1 - 2019 SN - 978-3-319-97117-9 SN - 978-3-319-97119-3 U6 - http://dx.doi.org/10.1007/978-3-319-97119-3 PB - Springer CY - Cham (Switzerland) ER - TY - JOUR A1 - Raupp, Sebastian M. A1 - Schmitt, Marcel A1 - Walz, Anna-Lena A1 - Diehm, Ralf A1 - Hummel, Helga A1 - Scharfer, Philip A1 - Schabel, Wilhelm T1 - Slot die stripe coating of low viscous fluids JF - Journal of Coatings Technology and Research N2 - Slot die coating is applied to deposit thin and homogenous films in roll-to-roll and sheet-to-sheet applications. The critical step in operation is to choose suitable process parameters within the process window. In this work, we investigate an upper limit for stripe coatings. This maximum film thickness is characterized by stripe merging which needs to be avoided in a stable process. It is shown that the upper limit reduces the process window for stripe coatings to a major extent. As a result, stripe coatings at large coating gaps and low viscosities are only possible for relatively thick films. Explaining the upper limit, a theory of balancing the side pressure in the gap region in the cross-web direction has been developed. Y1 - 2018 U6 - http://dx.doi.org/10.1007/s11998-017-0039-y SN - 1935-3804 VL - 15 IS - 5 SP - 899 EP - 911 PB - Springer 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 - 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 - 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 - Lempiäinen, Harri A1 - Couttet, Philippe A1 - Bolognani, Federico A1 - Müller, Arne A1 - Dubost, Valérie A1 - Luisier, Raphaëlle A1 - Rio-Espinola, Alberto del A1 - Vitry, Veronique A1 - Unterberger, Elif B. A1 - Thomson, John P. A1 - Treindl, Fridolin A1 - Metzger, Ute A1 - Wrzodek, Clemens A1 - Hahne, Florian A1 - Zollinger, Tulipan A1 - Brasa, Sarah A1 - Kalteis, Magdalena A1 - Marcellin, Magali A1 - Giudicelli, Fanny A1 - Braeuning, Albert A1 - Morawiec, Laurent A1 - Zamurovic, Natasa A1 - Längle, Ulrich A1 - Scheer, Nico A1 - Schübeler, Dirk A1 - Goodman, Jay A1 - Chibout, Salah-Dine A1 - Marlowe, Jennifer A1 - Theil, Dietlinde A1 - Heard, David J. A1 - Grenet, Olivier A1 - Zell, Andreas A1 - Templin, Markus F. A1 - Meehan, Richard R. A1 - Wolf, Roland C. A1 - Elcombe, Clifford R. A1 - Schwarz, Michael A1 - Moulin, Pierre A1 - Terranova, Rémi A1 - Moggs, Jonathan G. T1 - Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion JF - Toxicological Sciences N2 - The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds. Y1 - 2012 U6 - http://dx.doi.org/10.1093/toxsci/kfs303 SN - 1094-2025 VL - 131 IS - 2 SP - 375 EP - 386 PB - Oxford University Press CY - Oxford ER - TY - JOUR A1 - Kapelyukh, Yury A1 - Henderson, Colin James A1 - Scheer, Nico A1 - Rode, Anja A1 - Wolf, Charles Roland T1 - Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice JF - Drug Metabolism and Disposition Y1 - 2019 U6 - http://dx.doi.org/10.1124/dmd.119.087718 IS - Early view ER - TY - CHAP A1 - Hoffmann, Katharina A1 - Nieren, Monika A1 - Gäb, Martina A1 - Kasper, Anna A1 - Elbers, Gereon T1 - The potential of near infrared spectroscopy (NIRS) for the environmental biomonitoring of plants T2 - International conference on Life Sciences and Technology N2 - In the current environmental condition, the increase in pollution of the air, water, and soil indirectly will induce plants stress and decrease vegetation growth rate. These issues pay more attention to be solved by scientists worldwide. The higher level of chemical pollutants also induced the gradual changes in plants metabolism and decreased enzymatic activity. Importantly, environmental biomonitoring may play a pivotal contribution to prevent biodiversity degradation and plants stress due to pollutant exposure. Several previous studies have been done to monitor the effect of environmental changes on plants growth. Among that, Near Infrared spectroscopy (NIRS) offers an alternative way to observe the significant alteration of plant physiology caused by environmental damage related to pollution. Impairment of photosynthesis, nutrient and oxidative imbalances, and mutagenesis. Y1 - 2019 U6 - http://dx.doi.org/10.1088/1755-1315/276/1/012009 SN - 1755-1315 N1 - IOP Conference Series: Earth and Environmental Science : 276 VL - 276 IS - 012009 SP - 1 EP - 3 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 - 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 - Delaittre, Guillaume T1 - Telechelic Poly(2-Oxazoline)s JF - European Polymer Journal Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.eurpolymj.2019.109281 SN - 0014-3057 IS - In Press, Journal Pre-proof, 109281 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Engel, Mareike A1 - Gemünde, Andre A1 - Holtmann, Dirk A1 - Müller-Renno, Christine A1 - Ziegler, Christiane A1 - Tippkötter, Nils A1 - Ulber, Roland T1 - Clostridium acetobutylicum’s connecting world: cell appendage formation in bioelectrochemical systems JF - ChemElectroChem Y1 - 2019 U6 - http://dx.doi.org/10.1002/celc.201901656 SN - 2196-0216 IS - Accepted Article PB - Wiley CY - Weinheim 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 - 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 - Henderson, Colin J. A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Advances in the generation of mouse models to elucidate the pathways of drug metabolism in rodents and man JF - Expert Review of Clinical Pharmacology Y1 - 2009 U6 - http://dx.doi.org/10.1586/17512433.2.2.105 SN - 1751-2441 VL - 2 IS - 2 SP - 105 EP - 109 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Stanley, Lesley A. A1 - Horsburgh, Brian C. A1 - Ross, Jillian A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Drug transporters: Gatekeepers controlling access of xenobiotics to the cellular interior JF - Drug Metabolism Reviews Y1 - 2009 U6 - http://dx.doi.org/10.1080/03602530802605040 SN - 1097-9883 VL - 41 IS - 1 SP - 27 EP - 65 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Stanley, Lesley A. A1 - Horsburgh, Brian C. A1 - Ross, Jillian A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Nuclear Receptors which play a pivotal role in drug disposition and chemical toxicity JF - Drug Metabolism Reviews Y1 - 2006 U6 - http://dx.doi.org/10.1080/03602530600786232 SN - 1097-9883 VL - 38 IS - 3 SP - 515 EP - 597 ER - TY - CHAP A1 - Samuelsson, K. A1 - Scheer, Nico A1 - Wilson, I. A1 - Wolf, C.R. A1 - Henderson, C.J. ED - Chackalamannil, Samuel T1 - Genetically Humanized Animal Models T2 - Comprehensive Medicinal Chemistry III. 3rd Edition N2 - Genetically humanized mice for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging as promising in vivo models for improved prediction of the pharmacokinetic, drug–drug interaction, and safety characteristics of compounds in humans. This is an overview on the genetically humanized and chimeric liver-humanized mouse models, which are illustrated with examples of their utility in drug metabolism and toxicity studies. The models are compared to give guidance for selection of the most appropriate model by highlighting advantages and disadvantages to be carefully considered when used for studies in drug discovery and development. KW - Chimeric liver-humanized mice KW - Drug distribution KW - Drug metabolism KW - Toxicology KW - Knockout mice Y1 - 2017 SN - 978-0-12-803201-5 U6 - http://dx.doi.org/10.1016/B978-0-12-409547-2.12376-5 SP - 130 EP - 149 PB - Elsevier CY - Saint Louis 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 - TY - CHAP A1 - Wolf, C. Roland A1 - Kapelyukh, Yury A1 - Scheer, Nico A1 - Henderson, Colin J. ED - Wilson, Alan G. E. T1 - Application of Humanised and Other Transgenic Models to Predict Human Responses to Drugs N2 - The use of transgenic animal models has transformed our knowledge of complex biochemical pathways in vivo. It has allowed disease processes to be modelled and used in the development of new disease prevention and treatment strategies. They can also be used to define cell- and tissue-specific pathways of gene regulation. A further major application is in the area of preclinical development where such models can be used to define pathways of chemical toxicity, and the pathways that regulate drug disposition. One major application of this approach is the humanisation of mice for the proteins that control drug metabolism and disposition. Such models can have numerous applications in the development of drugs and in their more sophisticated use in the clinic. Y1 - 2015 SN - 978-1-78262-778-4 U6 - http://dx.doi.org/10.1039/9781782622376-00152 SP - 152 EP - 176 PB - RSC Publ. CY - Cambridge ER -