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Schmidt, Katharina ; Forkmann, Katarina ; Schultz, Heidrun ; Gratz, Marcel ; Bitz, Andreas ; Wiech, Katja ; Bingel, Ulrike
Improved efficiency prediction of a molten salt receiver based on dynamic cloud passage simulation
(2019)
Schwager, Christian ; Teixeira Boura, Cristiano José ; Flesch, Robert ; Alexopoulos, Spiros ; Herrmann, Ulf
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.
Schöning, Michael Josef ; Wagner, Torsten ; Poghossian, Arshak ; Miyamoto, K.I. ; Werner, C.F. ; Krause, S. ; Yoshinobu, T.
Capri, Miriam ; Morsiani, Cristina ; Santoro, Aurelia ; Moriggi, Manuela ; Conte, Maria ; Martucci, Morena ; Bellavista, Elena ; Fabbri, Cristina ; Giampieri, Enrico ; Albracht, Kirsten ; Flück, Martin ; Ruoss, Severin ; Brocca, Lorenza ; Canepari, Monica ; Longa, Emanuela ; Giulio, Irene Di ; Bottinelli, Roberto ; Cerretelli, Paolo ; Salvioli, Stefano ; Gelfi, Cecilia ; Franceschi, Claudio ; Narici, Marco ; Rittweger, Jörn
Bartella, Alexander K. ; Kamal, Mohammad ; Scholl, Ingrid ; Schiffer, Stefan ; Steegmann, Julius ; Ketelsen, Dominik ; Hölzle, Frank W. ; Lethaus, Bernd
Waldmann, Christoph ; Vera, Jean-Pierre de ; Dachwald, Bernd ; Strasdeit, Henry ; Sohl, Frank ; Hanff, Hendrik ; Kowalski, Julia ; Heinen, Dirk ; Macht, Sabine ; Bestmann, Ulf ; Meckel, Sebastian ; Hildebrandt, Marc ; Funke, Oliver ; Gehrt, Jan-Jöran
The quest for life on other planets is closely connected with the search for water in liquid state. Recent discoveries of deep oceans on icy moons like Europa and Enceladus have spurred an intensive discussion about how these waters can be accessed. The challenge of this endeavor lies in the unforeseeable requirements on instrumental characteristics both with respect to the scientific and technical methods. The TRIPLE/nanoAUV initiative is aiming at developing a mission concept for exploring exo-oceans and demonstrating the achievements in an earth-analogue context, exploring the ocean under the ice shield of Antarctica and lakes like Dome-C on the Antarctic continent.
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)
Iken, Heiko ; Bronder, Thomas ; Goretzki, Alexander ; Kriesel, Jana ; Ahlborn, Kristina ; Gerlach, Frank ; Vonau, Winfried ; Zander, Willi ; Schubert, Jürgen ; Schöning, Michael Josef
Dantism, Shahriar ; Röhlen, Desiree ; Selmer, Thorsten ; Wagner, Torsten ; Wagner, Patrick ; Schöning, Michael Josef
Schalung und Gerüste
(2019)
Die grundsätzliche Planung von Schalungsaufgaben wird heute in der Regel im Rahmen der Arbeitsvorbereitung von den entsprechenden Stabsabteilungen oder als Serviceleistung von den Schalungsherstellern mit Anwendung von spezieller Software und den technischen Unterlagen für die jeweiligen Schalungsgeräte durchgeführt. Diese Programme und technischen Unterlagen stehen in der Regel auch den Mitarbeitern in der Bauleitung zur Verfügung, werden dort aber eher seltener genutzt. Zur Anwendung auf der Baustelle stellen die Schalungshersteller neben den technischen Unterlagen Bemessungstabellen zur Verfügung, welche die Auswahl und Dimensionierung einzelner Schalungen wesentlich erleichtern.
Die nachfolgend aufgeführten Beispiele aus dem Bereich Schalung und Gerüste beschreiben Aufgaben, die im Baustellenbetrieb auf die Bauleitung zu kommen können und auch ohne Unterstützung einer Stabsabteilung gelöst werden können.
Boden, Baugrube, Verbau
(2019)
Im folgenden Kapitel werden die wichtigsten geotechnischen Nachweise sowie praxisnahe Beispiele für den Baubetrieb aufgeführt. Es wird im Wesentlichen auf die Bodenbeschreibung und Klassifikation nach DIN 18196 sowie nach DIN 18300 eingegangen, welche sowohl für die weiteren Berechnungen als auch für die Kalkulation von großer Bedeutung sind.
Die aus der Praxis aufgeführten Beispiele verdeutlichen verschiedene Untersuchungs- und Auswertungsmethoden für direkte und indirekte Aufschlüsse, diese enthalten Labor- und Feldversuche, mit denen man die Verdichtbarkeit von Böden auswertet und quantifiziert, sowie viele andere Themenbereiche wie Erddruckberechnungen sowie Spannungs- und Setzungsberechnungen.
Darüber hinaus werden exemplarisch bestimmte Verbauarten bezüglich ihrer Bemessung erläutert. Es wird ebenfalls auf das Thema Wasserhaltung eingegangen und die erforderlichen Maßnahmen beschrieben, um bestimmte Versagensmechanismen - wie z.B. den hydraulischen Grundbruch - zu verhindern.
Der baurechtliche Vertrag
(2019)
Anhand von kurzen theoretischen Einführungen werden anhand von Beispielen die wesentlichen Aspekte des baurechtlichen Vertrages erläutert. Nach einer Einführung über das Zustandekommen von (Bau-) Verträgen wird die für Streitfälle unerlässliche Dokumentation auf Baustellen erläutert. Hierbei werden Hinweise zur Erstellung von Protokollen, zum E-Mail bei Großprojekten und zur Dokumentation von Stundenlohnarbeiten gegeben. Des Weiteren wird eine Schriftverkehrsliste vorgestellt, die zur Nachverfolgung des Schriftverkehrs bei Großprojekten unerlässlich ist.
Anschließend werden die typischen Vertragsarten vorgestellt, die bei der Abwicklung von Großprojekten zu beachten sind und die Unterschiede werden durch Fallbeispiele erläutert.
Einen Schwerpunkt des Kapitels bilden auftragsnehmerseitige Verzüge sowie mangelbehaftete Leistungen. Hier werden Hinweise gegeben, wie in den entsprechenden Situationen zu reagieren ist.
Übungsaufgaben und Berechnungen für den Baubetrieb: Klausurvorbereitung mit ausführlichen Lösungen
(2019)
Noureddine, Yacine ; Kraff, Oliver ; Ladd, Mark E. ; Wrede, Karsten ; Chen, Bixia ; Quick, Harald H. ; Schaefers, Georg ; Bitz, Andreas
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)
Gorzalka, Philip ; Dahlke, Dennis ; Göttsche, Joachim ; Israel, Martin ; Patel, Dhruvkumar ; Prahl, Christoph ; Schmiedt, Jacob Estevam ; Frommholz, Dirk ; Hoffschmidt, Bernhard ; Linkiewicz, Magdalena
Reger, Vitali ; Kuhnhenne, Markus ; Hachul, Helmut ; Döring, Bernd ; Blanke, Tobias ; Göttsche, Joachim
Clearance of blood components and fluid drainage play a crucial role in subarachnoid hemorrhage (SAH) and post hemorrhagic hydrocephalus (PHH). With the involvement of interstitial fluid (ISF) and cerebrospinal fluid (CSF), two pathways for the clearance of fluid and solutes in the brain are proposed. Starting at the level of capillaries, flow of ISF follows along the basement membranes in the walls of cerebral arteries out of the parenchyma to drain into the lymphatics and CSF [1]–[3]. Conversely, it is shown that CSF enters the parenchyma between glial and pial basement membranes of penetrating arteries [4]–[6]. Nevertheless, the involved structures and the contribution of either flow pathway to fluid balance between the subarachnoid space and interstitial space remains controversial. Low frequency oscillations in vascular tone are referred to as vasomotion and corresponding vasomotion waves are modeled as the driving force for flow of ISF out of the parenchyma [7]. Retinal vessel analysis (RVA) allows non-invasive measurement of retinal vessel vasomotion with respect to diameter changes [8]. Thus, the aim of the study is to investigate vasomotion in RVA signals of SAH and PHH patients.
Recognition of subjects with mild cognitive impairment (MCI) by the use of retinal arterial vessels.
(2019)
Zingsheim, Jonas ; Grimmer, Timo ; Ortner, Marion ; Schmaderer, Christoph ; Hauser, Christine ; Kotliar, Konstantin
Hypertension describes the pathological increase of blood pressure, which is most commonly associated with the increase of vascular wall stiffness [1]. Referring to the “Deutsche Bluthochdruck Liga” this pathology shows a growing trend in our aging society. In order to find novel pharmacological and probably personalized treatments, we want to present a functional approach to study biomechanical properties of a human aortic vascular model.
In this method review we will give an overview of recent studies which were carried out with the CellDrum technology [2] and underline the added value to already existing standard procedures known from the field of physiology.
Herein described CellDrum technology is a system to measure functional mechanical properties of cell monolayers and thin tissue constructs in-vitro. Additionally, the CellDrum enables to elucidate the mechanical response of cells to pharmacological drugs, toxins and vasoactive agents. Due to its highly flexible polymer support, cells can also be mechanically stimulated by steady and cyclic biaxial stretching.
Production and Characterization of Porous Fibroin Scaffolds for Regenerative Medical Application
(2019)
Kopp, Alexander ; Schmeets, Ralf ; Gosau, Martin ; Friedrich, Reinhard E. ; Fuest, Sandra ; Behbahani, Mehdi ; Barbeck, Mike ; Rutkowski, Rico ; Burg, Simon ; Kluwe, Lan ; Henningsen, Anders
Donner, Ralf ; Rabel, Matthias ; Scholl, Ingrid ; Ferrein, Alexander ; Donner, Marc ; Geier, Andreas ; John, André ; Köhler, Christian ; Varga, Sebastian
The potential of near infrared spectroscopy (NIRS) for the environmental biomonitoring of plants
(2019)
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.
Human induced pluripotent stem cells (hiPSCs) have shown to be promising in disease studies and drug screenings [1]. Cardiomyocytes derived from hiPSCs have been extensively investigated using patch-clamping and optical methods to compare their electromechanical behaviour relative to fully matured adult cells. Mathematical models can be used for translating findings on hiPSCCMs to adult cells [2] or to better understand the mechanisms of various ion channels when a drug is applied [3,4]. Paci et al. (2013) [3] developed the first model of hiPSC-CMs, which they later refined based on new data [3]. The model is based on iCells® (Fujifilm Cellular Dynamics, Inc. (FCDI), Madison WI, USA) but major differences among several cell lines and even within a single cell line have been found and motivate an approach for creating sample-specific models. We have developed an optimisation algorithm that parameterises the conductances (in S/F=Siemens/Farad) of the latest Paci et al. model (2018) [5] using current-voltage data obtained in individual patch-clamp experiments derived from an automated patch clamp system (Patchliner, Nanion Technologies GmbH, Munich).
The discovery of human induced pluripotent stem cells reprogrammed from somatic cells [1] and their ability to differentiate into cardiomyocytes (hiPSC-CMs) has provided a robust platform for drug screening [2]. Drug screenings are essential in the development of new components, particularly for evaluating the potential of drugs to induce life-threatening pro-arrhythmias. Between 1988 and 2009, 14 drugs have been removed from the market for this reason [3]. The microelectrode array (MEA) technique is a robust tool for drug screening as it detects the field potentials (FPs) for the entire cell culture. Furthermore, the propagation of the field potential can be examined on an electrode basis. To analyze MEA measurements in detail, we have developed an open-source tool.
Searching optimal continuous-thrust trajectories is usually a difficult and time-consuming task. The solution quality of traditional optimal-control methods depends strongly on an adequate initial guess because the solution is typically close to the initial guess, which may be far from the (unknown) global optimum. Evolutionary neurocontrol attacks continuous-thrust optimization problems from the perspective of artificial intelligence and machine learning, combining artificial neural networks and evolutionary algorithms. This chapter describes the method and shows some example results for single- and multi-phase continuous-thrust trajectory optimization problems to assess its performance. Evolutionary neurocontrol can explore the trajectory search space more exhaustively than a human expert can do with traditional optimal-control methods. Especially for difficult problems, it usually finds solutions that are closer to the global optimum. Another fundamental advantage is that continuous-thrust trajectories can be optimized without an initial guess and without expert supervision.
Die urbane Mobilität ist im Wandel und insbesondere neue innovative Geschäftsmodelle werden einen wesentlichen Teil zur Lösung von künftigen Mobilitätsbedürfnissen beitragen. Die sogenannte „Shared Mobility“ gilt aktuell neben der Elektrifizierung des Antriebes und autonomem Fahrzeugtechnologien als einer der wichtigsten Trendthemen in der Automobilindustrie. Neue Mobilitätsdienstleistungen verlangen dabei verstärkt auch neue Fahrzeugkonzepte.
Wind loads have great impact on many engineering structures. Wind storms often cause irreparable damage to the buildings which are exposed to it. Along with the earthquakes, wind represents one of the most common environmental load on structures and is relevant for limit state design. Modern wind codes indicate calculation procedures allowing engineers to deal with structural systems, which are susceptible to conduct wind-excited oscillations. In the codes approximate formulas for wind buffeting are specified which relate the dynamic problem to rather abstract parameter functions. The complete theory behind is not visible in order to simplify the applicability of the procedures. This chapter derives the underlying basic relations of the spectral method for wind buffeting and explains the main important applications of it in order to elucidate part of the theoretical background of computations after the new codes. The stochasticity of the wind processes is addressed, and the analysis of analytical as well as measurement based power spectra is outlined. Short MATLAB codes are added to the Appendix 3 which carry out the computation of a single sided auto-spectrum from a statistically stationary, discrete stochastic process. Two examples are presented.
Cornelis, Peter ; Givanoudi, Stella ; Yongabi, Derick ; Iken, Heiko ; Duwé, Sam ; Deschaume, Olivier ; Robbens, Johan ; Dedecker, Peter ; Bartic, Carmen ; Wübbenhorst, Michael ; Schöning, Michael Josef ; Heyndrickx, Marc ; Wagner, Patrick
Kyphoplasty of Osteoporotic Fractured Vertebrae: A Finite Element Analysis about Two Types of Cement
(2019)
Meyer, Carolin ; Gaalen, Kerstin van ; Leschinger, Tim ; Scheyerer, Max J. ; Neiss, Wolfram F. ; Staat, Manfred ; Müller, Lars P. ; Wegmann, Kilian
System und Verfahren zur Durchführung von Messungen biaxialer und kreuzförmiger Zugversuche, wobei ein Weg oder eine Kraft auf eine Materialprobe über mindestens zwei Nadelarme mit Nadeln geleitet wird, die in einem Gehäuse gelagert sind, wobei die Arme und/oder Nadelarme für eine ungehinderte Querkontraktion bei gleichmäßiger Lasteinleitung um eine Achse drehbar gelagert und seitlich auslenkbar sind.
The invention pertains to a CellDrum electrode arrangement for measuring mechanical stress, comprising a mechanical holder (1 ) and a non-conductive membrane (4), whereby the membrane (4) is at least partially fixed at its circumference to the mechanical holder (1), keeping it in place when the membrane (4) may bend due to forces acting on the membrane (4), the mechanical holder (1) and the membrane (4) forming a container, whereby the membrane (1) within the container comprises an cell- membrane compound layer or biological material (3) adhered to the deformable membrane 4 which in response to stimulation by an agent may exert mechanical stress to the membrane (4) such that the membrane bending stage changes whereby the container may be filled with an electrolyte, whereby an electric contact (2) is arranged allowing to contact said electrolyte when filled into to the container, whereby within a predefined geometry to the fixing of the membrane (4) an electrode (7) is arranged, whereby the electrode (7) is electrically insulated with respect to the electric contact (2) as well as said electrolyte, whereby mechanical stress due to an agent may be measured as a change in capacitance.
Puppe, Michael ; Giuliano, Stefano ; Frantz, Cathy ; Uhlig, Ralf ; Schumacher, Ralph ; Ibraheem, Wagdi ; Schmalz, Stefan ; Waldmann, Barbara ; Guder, Christoph ; Peter, Dennis ; Schwager, Christian ; Teixeira Boura, Cristiano José ; Alexopoulos, Spiros ; Spiegel, Michael ; Wortmann, Jürgen ; Hinrichs, Matthias ; Engelhard, Manfred ; Aust, Michael
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.
Albanna, Walid ; Lüke, Jan Niklas ; Schubert, Gerrit Alexander ; Dibué-Adjei, Maxine ; Kotliar, Konstantin ; Hescheler, Jürgen ; Clusmann, Hans ; Steiger, Hans-Jakob ; Hänggi, Daniel ; Kamp, Marcel A. ; Schneider, Toni ; Neumaier, Felix
Rietsch, Stefan H. G. ; Brunheim, Sascha ; Orzada, Stephan ; Voelker, Maximilian N. ; Maderwald, Stefan ; Bitz, Andreas ; Gratz, Marcel ; Ladd, Mark E. ; Quick, Harald H.
Lempiäinen, Harri ; Couttet, Philippe ; Bolognani, Federico ; Müller, Arne ; Dubost, Valérie ; Luisier, Raphaëlle ; Rio-Espinola, Alberto del ; Vitry, Veronique ; Unterberger, Elif B. ; Thomson, John P. ; Treindl, Fridolin ; Metzger, Ute ; Wrzodek, Clemens ; Hahne, Florian ; Zollinger, Tulipan ; Brasa, Sarah ; Kalteis, Magdalena ; Marcellin, Magali ; Giudicelli, Fanny ; Braeuning, Albert ; Morawiec, Laurent ; Zamurovic, Natasa ; Längle, Ulrich ; Scheer, Nico ; Schübeler, Dirk ; Goodman, Jay ; Chibout, Salah-Dine ; Marlowe, Jennifer ; Theil, Dietlinde ; Heard, David J. ; Grenet, Olivier ; Zell, Andreas ; Templin, Markus F. ; Meehan, Richard R. ; Wolf, Roland C. ; Elcombe, Clifford R. ; Schwarz, Michael ; Moulin, Pierre ; Terranova, Rémi ; Moggs, Jonathan G.
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.
Morais, Paulo V. ; Silva, Anielle C. A. ; Dantas, Noelio O. ; Schöning, Michael Josef ; Siqueira, José R., Jr.
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.
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.
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.
Lawson, Nathan D. ; Scheer, Nico ; Pham, Van N. ; Kim, Ceol-Hee ; Chitnis, Ajay B. ; Campos-Ortega, José A. ; Weinstein, Brant M.
Hans, Stefan ; Scheer, Nico ; Riedl, Iris ; Weizäcker, Elisabeth von ; Blader, Patrick ; Campos-Ortega, José A.
Scheer, Nico ; Kapelyukh, Yury ; McEwan, Jillian ; Beuger, Vincent ; Stanley, Lesley A. ; Rode, Anja ; Wolf, C. Roland
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.