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N.Sh. Akimbekov
; Ilya Digel
; C. O´Heras
; K.T. Tastambek
; I.S. Savitskaya
; P.S. Ualyeva
; Z.A. Mansurov
; A.A. Zhubanova
The scope of this study is the measurement of endotoxin adsorption rate for carbonized rice husk. It showed good adsorption properties for LPS. During the batch experiments, several techniques were used and optimized for improving the material’s adsorption behavior. Also, with the results obtained it was possible to differentiate the materials according to their adsorption capacity and kinetic characteristics.
N.Sh. Akimbekov
; Ilya Digel
; C. O’Heras
; K.T. Tastambek
; I.S. Savitskaya
; P.S. Ualyeva
; Z.A. Mansurov
; A.A. Zhubanova
Altynay Sagymbay
; Nusupbaeva G.E.
; Tleumbetova N.Zh
; Mutalieva A.S.
; Ainur Nurpeisova
; Jussupova D.B.
; Ilya Digel
The necessity of e-books as a primary of learning, its opportunities for realization of competence during training biologist and biotechnologist specialists are determined. Definitions and requirements to the e-books, its advantages in comparison with traditional textbooks, and the ways of creation of e-books in the SunRav BookEditor program are considered.
N. Sh. Akimbekov
; A. A. Zhubanova
; Z. A. Mansurov
; Ilya Digel
; Gerhard Artmann
; Aysegül Temiz Artmann
On the model of musculocutaneous wound in rats, the effect of applicative sorption by carbonized rise shell (CRS) on the healing of festering wound was studied. It has been shown, that cytological changes end with rapid scar formation. The use of CRS at the period of severe purulent wound contributes to its favorable course, prevents the development of complications of the animals from sepsis.
M. Turaliyeva
; A. Yeshibaev
; A. Saparbekova
; L. Akynova
; R. Abildayeva
; M. Sadenova
; K. Sartayeva
; Andre Schieffer
; Ilya Digel
At the present time, one of the most serious environmental problems of Central Asia and South Kazakhstan is the ongoing large-scale deterioration of principal urban tree populations. Several major centers of massive spread of invasive plant pests have been found in urban dendroflora of this region. The degree of damage of seven most wide-spread aboriginal tree species was found to range from 21.4±1.1 to 85.4±1.8%. In particular, the integrity of the native communities of sycamore (Platanus spp.), willow (Salix spp.), poplar (Populus spp.) and elm (Ulmus spp.) is highly endangered. Our taxonomic analysis of the most dangerous tree pests of the region has revealed them as neobiontic xylophilous insects such as Cossus cossus L. (Order: Lepidoptera L.) Monochamus urussovi Fisch., Monochamus sutor L., Acanthocinus aedelis L. and Ñetonia aureate L. (Order: Coleoptera L.). We relate the origin of this threatening trend with the import of industrial wood in the mid 90s of the last century that was associated with high degree of the constructional work in the region. Because of the absence of efficient natural predators of the pest species, the application of microbiological methods of the pest control and limitation is suggested.
Z. Mansurov
; Ilya Digel
; M. Biisenbaev
; I. Savistkaya
; A. Kistaubaeva
; N. Akimbekov
; A. Zhubanova
Suspension depletion approach for exemption of infected Solanum jasminoides cells from pospiviroids
(2018)
Despite numerous studies, viroid elimination from infected plants remains a very challenging task. This study introduces for the first time a novel ‘suspension depletion’ approach for exemption of Solanum jasminoides plants from viroids. The proposed method implies initial establishment of suspension cultures of the infected plant cells. The suspended cells were then physically treated (mild thermotherapy, 33 °C), which presumably delayed the replication of the viroid. The viroid concentration in the treated biomass was monitored weekly using pospiviroid-specific PCR. After 10–12 weeks of continuous treatment, a sufficient decrease in viroid concentration was observed such that the infection became undetectable by PCR. The treated single cells then gave rise to microcolonies on a solid culture medium and the obtained viroid-negative clones were further promoted to regenerate into viroid-free plants. Three years of accumulated experimental data suggests feasibility, broad applicability, and good efficacy of the proposed approach.
S. Schael
; A. Atanasyan
; J. Berdugo
; T. Bretz
; Markus Czupalla
; Bernd Dachwald
; P. von Doetinchem
; M. Duranti
; H. Gast
; W. Karpinski
; T. Kirn
; K. Lübelsmeyer
; C. Maña
; P.S. Marrocchesi
; P. Mertsch
; I.V. Moskalenko
; T. Schervan
; M. Schluse
; K.-U. Schröder
; A. Schultz von Dratzig
; C. Senatore
; L. Spies
; S.P. Wakely
; M. Wlochal
; D. Uglietti
; J. Zimmermann
Speicher statt Kohle. Integration thermischer Stromspeicher in vorhandene Kraftwerksstandorte
(2019)
A new in vitro tool to investigate cardiac contractility under physiological mechanical conditions
(2019)
Peter Linder
; Matthias Beckler
; Leo Doerr
; Sonja Stoelzle-Feix
; Niels Fertig
; Alexander Jung
; Manfred Staat
; Matthias Gossmann
Mark Schieren
; Joris Kleinschmidt
; Axel Schmutz
; Torsten Loop
; Karl-Heinz Gatzweiler
; Manfred Staat
; Frank Wappler
; Jerome Defosse
Stephan Orzada
; Klaus Solbach
; Marcel Gratz
; Sascha Brunheim
; Thomas M. Fiedler
; Sören Johst
; Andreas Bitz
; Samaneh Shooshtary
; Asjraf Abuelhaija
; Maximilian N. Voelker
; Stefan H. G. Rietsch
; Oliver Kraff
; Stefan Maderwald
; Martina Flöser
; Mark Oehmingen
; Harald H. Quick
; Mark E. Ladd
Henryk Wolisz
; Thomas Schütz
; Tobias Blanke
; Markus Hagenkamp
; Markus Kohrn
; Mark Wesseling
; Dirk Müller
Tim Leschinger
; Katharina Besch
; Cansu Aydin
; Manfred Staat
; Martin Scaal
; Lars Peter Müller
; Kilian Wegmann
Hydrogen peroxide (H2O2) is a typical surface sterilization agent for packaging materials used in the pharmaceutical, food and beverage industries. We use the finite-elements method to analyze the conceptual design of an in-line thermal evaporation unit to produce a heated gas mixture of air and evaporated H2O2 solution. For the numerical model, the required phase-transition variables of pure H2O2 solution and of the aerosol mixture are acquired from vapor-liquid equilibrium (VLE) diagrams derived from vapor-pressure formulations. This work combines homogeneous single-phase turbulent flow with heat-transfer physics to describe the operation of the evaporation unit. We introduce the apparent heat-capacity concept to approximate the non-isothermal phase-transition process of the H2O2-containing aerosol. Empirical and analytical functions are defined to represent the temperature- and pressure-dependent material properties of the aqueous H2O2 solution, the aerosol and the gas mixture. To validate the numerical model, the simulation results are compared to experimental data on the heating power required to produce the gas mixture. This shows good agreement with the deviations below 10%. Experimental observations on the formation of deposits due to the evaporation of stabilized H2O2 solution fits the prediction made from simulation results.
AP Ermolaev
; VP Erichev
; AA Antonov
; GL Grigoryan
; Konstantin Kotliar
; YV Levitsky
; K Hderi
; YV Mazurova
Amanzhol Turlybekuly
; Alexander Pogrebnjak
; L. F. Sukhodub
; Liudmyla B. Sukhodub
; A. S. Kistaubayeva
; Irina Savitskaya
; D. H. Shokatayeva
; Oleksandr V. Bondar
; Z. K. Shaimardanov
; Sergey V. Plotnikov
; B. H. Shaimardanova
; Ilya Digel
Purpose — to compare the chemical elemental composition of vitreous cavity content taken from cadaveric eyes compared to samples taken from the eyes with terminal stage refractory glaucoma with decompensated intraocular pressure (IOP). Material and methods. The vitreous contents of the eyes from 2 groups were studied. The 1st group included 15 cadaveric eyes; the 2nd group included 15 eyes with refractory glaucoma in the terminal stage of the disease with decompensated IOP in patients with hypertension pain. The vitreal content samples were taken in the course of antiglaucoma surgery aimed at preserving the eye as an organ and involving employment of drainage in the vitreous cavity. The study of virtual contents was carried out on energy dispersive spectrometer Oxford X-Max 50 integrated into scanning electron microscope Zeiss EVO LS10. Results. Increased concentrations of Kalium and Phosphorus were detected in the vitreous content of cadaveric eyes compared with the vitreal content from the eyes with terminal glaucoma with decompensated IOP taken in vivo (K — 0.172/0.093; P — 0.045/0.025 mmol/L). In the vitreous cavity in the eyes with end-stage glaucoma with decompensated IOP, the concentration of Nitrogen was higher in comparison with human cadaver eyes (2.030/1.424 mmol/L). Conclusion. The increased concentrations of Kalium and Phosphorus in the vitreous content of cadaveric eyes is associated with postmortem autolytic processes and with the release of intracellular content in the destruction of cell membranes. The increased Nitrogen concentration in the vitreal contents of the eyes with terminal stage glaucoma with decompensated IOP may be associated with the presence of osmotically active nitrogen-containing compounds in the eyes with increased IOP.
Till Hofmann
; Nicolas Limpert
; Victor Mataré
; Sebastian Schönitz
; Tim Niemueller
; Alexander Ferrein
; Gerhard Lakemeyer
The Carologistics team participates in the RoboCup Logistics League for the seventh year. The RCLL requires precise vision,
manipulation and path planning, as well as complex high-level decision
making and multi-robot coordination. We outline our approach with an
emphasis on recent modifications to those components.
The team members in 2018 are David Bosen, Christoph Gollok, Mostafa
Gomaa, Daniel Habering, Till Hofmann, Nicolas Limpert, Sebastian Schönitz,
Morian Sonnet, Carsten Stoffels, and Tarik Viehmann.
This paper is based on the last year’s team description.
Extrem hohe Blitzströme
(2018)
Blitze sind nach wie vor eine enorme Schadensquelle für Personenschäden, Brände, mechanische Zerstörungen und insbesondere auch Überspannungen. Das zeigen nicht zuletzt aktuelle Statistiken der Schadensversicherer. Immer wieder gibt es Meldungen über extrem hohe Blitzströme, die natürlich auch zu großen Schäden und Zerstörungen führen können. Dabei werden Scheitelwerte von teilweise deutlich über 300 kA genannt. Dies wirft Fragen auf, da die „klassische“ Blitzstatistik (z. B. nach CIGRE und IEC [8][10]) bisher solche Werte nicht kennt. Diese extremen Blitzströme werden meist aus den Daten von Blitzortungssystemen ermittelt.
We present and discuss an exploration of the possibilities and properties of 3D printing with a printing space of 1 cubic meter, and how those can be integrated into architectural education through an experimental design and research course with students of architecture.We expand on issues presented at the eCAADe conference 2017 in Rome [Ref 6] by increasing the complexity and size of our prints, printing not a model to scale, but a full scale funtional prototype of a usable architectural object: A coffee bar.
To train end users how to interact with digital systems is indispensable to ensure a strong computer security. 'Competence Developing Game'-based approaches are particularly suitable for this purpose because of their motivation-and simulation-aspects. In this paper the Competence Developing Game 'GHOST' for cybersecurity awareness trainings and its underlying patterns are described. Accordingly, requirements for an 'Competence Developing Game' based training are discussed. Based on these requirements it is shown how a game can fulfill these requirements. A supplementary game interaction design and a corresponding evaluation study is shown. The combination of training requirements and interaction design is used to create a 'Competence Developing Game'-based training concept. A part of these concept is implemented into a playable prototype that serves around one hour of play respectively training time. This prototype is used to perform an evaluation of the game and training aspects of the awareness training. Thereby, the quality of the game aspect and the effectiveness of the training aspect are shown.
Katharina Schmidt
; Katarina Forkmann
; Heidrun Schultz
; Marcel Gratz
; Andreas Bitz
; Katja Wiech
; Ulrike Bingel
Recent Unmanned Aerial Vehicle (UAV) design procedures rely on full aircraft steady-state Reynolds-Averaged-Navier-Stokes (RANS) analyses in early design stages. Small sensor turrets are included in such simulations, even though their aerodynamic properties show highly unsteady behavior. Very little is known about the effects of this approach on the simulation outcomes of small turrets. Therefore, the flow around a model turret at a Reynolds number of 47,400 is simulated with a steady-state RANS approach and compared to experimental data. Lift, drag, and surface pressure show good agreement with the experiment. The RANS model predicts the separation location too far downstream and shows a larger recirculation region aft of the body. Both characteristic arch and horseshoe vortex structures are visualized and qualitatively match the ones found by the experiment. The Reynolds number dependence of the drag coefficient follows the trend of a sphere within a distinct range. The outcomes indicate that a steady-state RANS model of a small sensor turret is able to give results that are useful for UAV engineering purposes but might not be suited for detailed insight into flow properties.
Miriam Capri
; Cristina Morsiani
; Aurelia Santoro
; Manuela Moriggi
; Maria Conte
; Morena Martucci
; Elena Bellavista
; Cristina Fabbri
; Enrico Giampieri
; Kirsten Albracht
; Martin Flück
; Severin Ruoss
; Lorenza Brocca
; Monica Canepari
; Emanuela Longa
; Irene Di Giulio
; Roberto Bottinelli
; Paolo Cerretelli
; Stefano Salvioli
; Cecilia Gelfi
; Claudio Franceschi
; Marco Narici
; Jörn Rittweger
Alexander K. Bartella
; Mohammad Kamal
; Ingrid Scholl
; Stefan Schiffer
; Julius Steegmann
; Dominik Ketelsen
; Frank W. Hölzle
; Bernd Lethaus
Digital Image Correlation (DIC) is a powerful tool used to evaluate displacements and deformations in a non-intrusive manner. By comparing two images, one of the undeformed reference state of a specimen and another of the deformed target state, the relative displacement between those two states is determined. DIC is well known and often used for post-processing analysis of in-plane displacements and deformation of specimen. Increasing the analysis speed to enable real-time DIC analysis will be beneficial and extend the field of use of this technique.
Here we tested several combinations of the most common DIC methods in combination with different parallelization approaches in MATLAB and evaluated their performance to determine whether real-time analysis is possible with these methods. To reflect improvements in computing technology different hardware settings were also analysed. We found that implementation problems can reduce the efficiency of a theoretically superior algorithm such that it becomes practically slower than a suboptimal algorithm. The Newton-Raphson algorithm in combination with a modified Particle Swarm algorithm in parallel image computation was found to be most effective. This is contrary to theory, suggesting that the inverse-compositional Gauss-Newton algorithm is superior. As expected, the Brute Force Search algorithm is the least effective method. We also found that the correct choice of parallelization tasks is crucial to achieve improvements in computing speed. A poorly chosen parallelisation approach with high parallel overhead leads to inferior performance. Finally, irrespective of the computing mode the correct choice of combinations of integerpixel and sub-pixel search algorithms is decisive for an efficient analysis. Using currently available hardware realtime analysis at high framerates remains an aspiration.
Tribological performance of biodegradable lubricants under different surface roughness of tools
(2019)
A light-addressable potentiometric sensor (LAPS) is a field-effect-based (bio-) chemical sensor, in which a desired sensing area on the sensor surface can be defined by illumination. Light addressability can be used to visualize the concentration and spatial distribution of the target molecules, e.g., H+ ions. This unique feature has great potential for the label-free imaging of the metabolic activity of living organisms. The cultivation of those organisms needs specially tailored surface properties of the sensor. O2 plasma treatment is an attractive and promising tool for rapid surface engineering. However, the potential impacts of the technique are carefully investigated for the sensors that suffer from plasma-induced damage. Herein, a LAPS with a Ta2O5 pH-sensitive surface is successfully patterned by plasma treatment, and its effects are investigated by contact angle and scanning LAPS measurements. The plasma duration of 30 s (30 W) is found to be the threshold value, where excessive wettability begins. Furthermore, this treatment approach causes moderate plasma-induced damage, which can be reduced by thermal annealing (10 min at 300 °C). These findings provide a useful guideline to support future studies, where the LAPS surface is desired to be more hydrophilic by O2 plasma treatment.
Heiko Iken
; Thomas Bronder
; Alexander Goretzki
; Jana Kriesel
; Kristina Ahlborn
; Frank Gerlach
; Winfried Vonau
; Willi Zander
; Jürgen Schubert
; Michael Josef Schöning
Shahriar Dantism
; Desiree Röhlen
; Thorsten Selmer
; Torsten Wagner
; Patrick Wagner
; Michael Josef Schöning
Yacine Noureddine
; Oliver Kraff
; Mark E. Ladd
; Karsten Wrede
; Bixia Chen
; Harald H. Quick
; Georg Schaefers
; Andreas Bitz
Experience has shown that a priori created static resource allocation plans are vulnerable to runtime deviations and hence often become uneconomic or highly exceed a predefined soft deadline. The assumption of constant task execution times during allocation planning is even more unlikely in a cloud environment where virtualized resources vary in performance. Revising the initially created resource allocation plan at runtime allows the scheduler to react on deviations between planning and execution. Such an adaptive rescheduling of a many-task application workflow is only feasible, when the planning time can be handled efficiently at runtime. In this paper, we present the static low-complexity resource allocation planning algorithm (LCP) applicable to efficiently schedule many-task scientific application workflows on cloud resources of different capabilities. The benefits of the presented algorithm are benchmarked against alternative approaches. The benchmark results show that LCP is not only able to compete against higher complexity algorithms in terms of planned costs and planned makespan but also outperforms them significantly by magnitudes of 2 to 160 in terms of required planning time. Hence, LCP is superior in terms of practical usability where low planning time is essential such as in our targeted online rescheduling scenario.
Thermal and Optical Study on the Frequency Dependence of an Atmospheric Microwave Argon Plasma Jet
(2019)
Production and Characterization of Porous Fibroin Scaffolds for Regenerative Medical Application
(2019)
Alexander Kopp
; Ralf Schmeets
; Martin Gosau
; Reinhard E. Friedrich
; Sandra Fuest
; Mehdi Behbahani
; Mike Barbeck
; Rico Rutkowski
; Simon Burg
; Lan Kluwe
; Anders Henningsen
Peter Cornelis
; Stella Givanoudi
; Derick Yongabi
; Heiko Iken
; Sam Duwé
; Olivier Deschaume
; Johan Robbens
; Peter Dedecker
; Carmen Bartic
; Michael Wübbenhorst
; Michael Josef Schöning
; Marc Heyndrickx
; Patrick Wagner
Kyphoplasty of Osteoporotic Fractured Vertebrae: A Finite Element Analysis about Two Types of Cement
(2019)
Carolin Meyer
; Kerstin van Gaalen
; Tim Leschinger
; Max J. Scheyerer
; Wolfram F. Neiss
; Manfred Staat
; Lars P. Müller
; Kilian Wegmann
Michael Puppe
; Stefano Giuliano
; Cathy Frantz
; Ralf Uhlig
; Ralph Schumacher
; Wagdi Ibraheem
; Stefan Schmalz
; Barbara Waldmann
; Christoph Guder
; Dennis Peter
; Christian Schwager
; Cristiano José Teixeira Boura
; Spiros Alexopoulos
; Michael Spiegel
; Jürgen Wortmann
; Matthias Hinrichs
; Manfred Engelhard
; Michael Aust
In this paper the results of a techno-economic analysis of improved and optimized molten salt solar tower plants (MSSTP plants) are presented. The potential improvements that were analyzed include different receiver designs, different designs of the HTF-system and plant control, increased molten salt temperatures (up to 640°C) and multi-tower systems. Detailed technological and economic models of the solar field, solar receiver and high temperature fluid system (HTF-system) were developed and used to find potential improvements compared to a reference plant based on Solar Two technology and up-to-date cost estimations. The annual yield model calculates the annual outputs and the LCOE of all variants. An improved external tubular receiver and improved HTF-system achieves a significant decrease of LCOE compared to the reference. This is caused by lower receiver cost as well as improvements of the HTF-system and plant operation strategy, significantly reducing the plant own consumption. A novel star receiver shows potential for further cost decrease. The cavity receiver concepts result in higher LCOE due to their high investment cost, despite achieving higher efficiencies. Increased molten salt temperatures seem possible with an adapted, closed loop HTF-system and achieve comparable results to the original improved system (with 565°C) under the given boundary conditions. In this analysis all multi tower systems show lower economic viability compared to single tower systems, caused by high additional cost for piping connections and higher cost of the receivers.
REFERENCES
We propose the so-called chance constrained programming model of stochastic programming theory to analyze limit and shakedown loads of structures under random strength with a lognormal distribution. A dual chance constrained programming algorithm is developed to calculate simultaneously both the upper and lower bounds of the plastic collapse limit and the shakedown limit. The edge-based smoothed finite element method (ES-FEM) is used with three-node linear triangular elements.
Walid Albanna
; Jan Niklas Lüke
; Gerrit Alexander Schubert
; Maxine Dibué-Adjei
; Konstantin Kotliar
; Jürgen Hescheler
; Hans Clusmann
; Hans-Jakob Steiger
; Daniel Hänggi
; Marcel A. Kamp
; Toni Schneider
; Felix Neumaier
Stefan H. G. Rietsch
; Sascha Brunheim
; Stephan Orzada
; Maximilian N. Voelker
; Stefan Maderwald
; Andreas Bitz
; Marcel Gratz
; Mark E. Ladd
; Harald H. Quick
Harri Lempiäinen
; Philippe Couttet
; Federico Bolognani
; Arne Müller
; Valérie Dubost
; Raphaëlle Luisier
; Alberto del Rio-Espinola
; Veronique Vitry
; Elif B. Unterberger
; John P. Thomson
; Fridolin Treindl
; Ute Metzger
; Clemens Wrzodek
; Florian Hahne
; Tulipan Zollinger
; Sarah Brasa
; Magdalena Kalteis
; Magali Marcellin
; Fanny Giudicelli
; Albert Braeuning
; Laurent Morawiec
; Natasa Zamurovic
; Ulrich Längle
; Nico Scheer
; Dirk Schübeler
; Jay Goodman
; Salah-Dine Chibout
; Jennifer Marlowe
; Dietlinde Theil
; David J. Heard
; Olivier Grenet
; Andreas Zell
; Markus F. Templin
; Richard R. Meehan
; Roland C. Wolf
; Clifford R. Elcombe
; Michael Schwarz
; Pierre Moulin
; Rémi Terranova
; Jonathan G. Moggs
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.
Paulo V. Morais
; Anielle C. A. Silva
; Noelio O. Dantas
; Michael Josef Schöning
; José R., Jr. Siqueira
1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug–drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described.
2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created.
3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug–drug interactions as well as in human metabolite testing and risk assessment.
4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.
Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug–drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.
Nathan D. Lawson
; Nico Scheer
; Van N. Pham
; Ceol-Hee Kim
; Ajay B. Chitnis
; José A. Campos-Ortega
; Brant M. Weinstein
Stefan Hans
; Nico Scheer
; Iris Riedl
; Elisabeth von Weizäcker
; Patrick Blader
; José A. Campos-Ortega
Nico Scheer
; Yury Kapelyukh
; Jillian McEwan
; Vincent Beuger
; Lesley A. Stanley
; Anja Rode
; C. Roland Wolf
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.
Nico Scheer
; Jillian Ross
; Anja Rode
; Branko Zevnik
; Sandra Niehaves
; Nicole Faust
; C. Roland Wolf
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.
Jillian Ross
; Simon M. Plummer
; Anja Rode
; Nico Scheer
; Conrad C. Bower
; Ortwin Vogel
; Colin J. Henderson
; C. Roland Wolf
; Clifford R. Elcombe
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.
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.
Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line
(2012)
Nico Scheer
; Praveen Balimane
; Michael D. Hayward
; Sandra Buechel
; Gunther Kauselmann
; C. Roland Wolf
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.
Nico Scheer
; Lesley A. Mclaughlin
; Anja Rode
; Alastair Kenneth MacLeod
; Colin J. Henderson
; Roland C. Wolf
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.
Socio-technical scenarios for energy-intensive industries: the future of steel production in Germany
(2019)
R. Campen
; Julia Kowalski
; W.B. Lyons
; S. Tulaczyk
; Bernd Dachwald
; E. Pettit
; K. A. Welch
; J.A. Mikucki
W. Berry Lyons
; Jill A. Mikucki
; Laura A. German
; Kathleen A. Welch
; Susan A. Welch
; Christopher B. Gardener
; Slawek M. Tulaczyk
; Erin C. Pettit
; Julia Kowalski
; Bernd Dachwald
An overview on dry low NOx micromix combustor development for hydrogen-rich gas turbine applications
(2019)
Lars Breuer
; Johanna Pilas
; Eric Guthmann
; Michael Josef Schöning
; Ronald Thoelen
; Torsten Wagner
Nico Scheer
; Colin James Henderson
; Yury Kapelyukh
; Anja Rode
; Aileen W. Mclaren
; Alastair Kenneth MacLeod
; De Lin
; Jayne Wright
; Lesley Stanley
; C. Roland Wolf