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The mission of the COMPASS-1 picosatellite is to take pictures of the earth, to validate a space-borne GPS receiver developed by the German Aerospace Center, and to verify the proper operation of the magnetic attitude control system in orbit. The spacecraft was launched on April 28, 2008 from the Indian space port Sriharikota, as part of the PSLV-C9 world record launch that simultaneously brought ten satellites into orbit. The mission operations were carried out from the ground stations in Aachen and Tainan. Arising difficulties in the communication link were overcome with the support of individuals from the amateur radio community. After several months of mission operation, abundant housekeeping and mission data has been commanded, received and analyzed and is presented in this paper.
Flight times to the heliopause using a combination of solar and radioisotope electric propulsion
(2011)
We investigate the interplanetary flight of a low-thrust space probe to the heliopause,located at a distance of about 200 AU from the Sun. Our goal was to reach this distance within the 25 years postulated by ESA for such a mission (which is less ambitious than the 15-year goal set by NASA). Contrary to solar sail concepts and combinations of allistic and electrically propelled flight legs, we have investigated whether the set flight time limit could also be kept with a combination of solar-electric propulsion and a second, RTG-powered upper stage. The used ion engine type was the RIT-22 for the first stage and the RIT-10 for the second stage. Trajectory optimization was carried out with the low-thrust optimization program InTrance, which implements the method of Evolutionary Neurocontrol,using Artificial Neural Networks for spacecraft steering and Evolutionary Algorithms to optimize the Neural Networks’ parameter set. Based on a parameter space study, in which the number of thrust units, the unit’s specific impulse, and the relative size of the solar power generator were varied, we have chosen one configuration as reference. The transfer time of this reference configuration was 29.6 years and the fastest one, which is technically
more challenging, still required 28.3 years. As all flight times of this parameter study were longer than 25 years, we further shortened the transfer time by applying a launcher-provided hyperbolic excess energy up to 49 km2/s2. The resulting minimal flight time for the reference configuration was then 27.8 years. The following, more precise optimization to a launch with the European Ariane 5 ECA rocket reduced the transfer time to 27.5 years. This is the fastest mission design of our study that is flexible enough to allow a launch every
year. The inclusion of a fly-by at Jupiter finally resulted in a flight time of 23.8 years,which is below the set transfer-time limit. However, compared to the 27.5-year transfer,this mission design has a significantly reduced launch window and mission flexibility if the
escape direction is restricted to the heliosphere’s “nose".
Flow visualization by means of PIV of an artificial aortic heart valve fixed into a mock aorta
(2005)
Rubber materials filled with reinforcing fillers display nonlinear rheological behavior at small strain amplitudes below γ0 < 0.1. Nevertheless, rheological data are analyzed mostly in terms of linear parameters, such as shear moduli (G′, G″), which loose their physical meaning in the nonlinear regime. In this work styrene butadiene rubber filled with carbon black (CB) under large amplitude oscillatory shear (LAOS) is analyzed in terms of the nonlinear parameter I3/1. Three different CB grades are used and the filler load is varied between 0 and 70 phr. It is found that I3/1(φ) is most sensitive to changes of the total accessible filler surface area at low strain amplitudes (γ0 = 0.32). The addition of up to 70 phr CB leads to an increase of I3/1(φ) by a factor of more than ten. The influence of the measurement temperature on I3/1 is pronounced for CB levels above the percolation threshold.
The development of new interfaces for (bio-)chemical sensors requires comprehensive analyses and testing. The light-addressable potentiometric sensor (LAPS) can be used as a platform to investigate the sensitivity of a newly developed interface towards (bio-)chemical agents. LAPS measurements are spatially resolved by utilisation of focused light beams to define individual measurement spots. In this work, a new digitally modulated LAPS set-up based on an FPGA design will be introduced to increase the number of measurement spots, to shorten the measurement time and to improve the measurement accuracy.
In order to efficiently convert lignocellulose, it is often necessary to conduct a pretreatment. The biomass considered in this study typically comprises of agricultural and horticultural residues, as well as beechwood. A very environmentally friendly method, namely, fungal pretreatment using white-rot fungi, leads to an enhanced enzymatic hydrolysis. In contrast to other processes presented, the energy input is extremely low. However, the fungal growth on the lignocellulosic substrates takes several weeks at least in order to be effective. Thus, the reduction of chemicals and energy for thermal processing is a target of our current research. Liquid hot water (LHW) and solvent-based pretreatment (OrganoSolv) require more complex equipment, as they depend on high temperatures (160 – 180 °C) and enhanced pressure (up to 20 bar). However, they prove to be promising processes in regard to the fractioning of lignocellulose. For optimal lignin recovery the parameters differ from those established in cellulose extraction. A novel screening system scaled down to a reaction volume of 100 mL has been developed and successfully tested for this purpose.
Useful market simulations are key to the evaluation of diferent market designs existing of multiple market mechanisms or rules. Yet a simulation framework which has a comparison of diferent market mechanisms in mind was not found. The need to create an objective view on different sets of market rules while investigating meaningful agent strategies concludes that such a simulation framework is needed to advance the research on this subject. An overview of diferent existing market simulation models is given which also shows the research gap and the missing capabilities of those systems. Finally, a methodology is outlined how a novel market simulation which can answer the research questions can be developed.
Light-addressable potentiometric sensors (LAPS) are semiconductor-based potentiometric sensors, with the advantage to detect the concentration of a chemical species in a liquid solution above the sensor surface in a spatially resolved manner. The addressing is achieved by a modulated and focused light source illuminating the semiconductor and generating a concentration-depending photocurrent. This work introduces a LAPS set-up that is able to monitor the electrical impedance in addition to the photocurrent. The impedance spectra of a LAPS structure, with and without illumination, as well as the frequency behaviour of the LAPS measurement are investigated. The measurements are supported by electrical equivalent circuits to explain the impedance and the LAPS-frequency behaviour. The work investigates the influence of different parameters on the frequency behaviour of the LAPS. Furthermore, the phase shift of the photocurrent, the influence of the surface potential as well as the changes of the sensor impedance will be discussed.
Frequency Dependent Impedance Analysis of the Foundation-Soil-Systems of Onshore Wind Turbines
(2018)
Frequency mixing magnetic detection (FMMD) has been explored for its applications in fields of magnetic biosensing, multiplex detection of magnetic nanoparticles (MNP) and the determination of core size distribution of MNP samples. Such applications rely on the application of a static offset magnetic field, which is generated traditionally with an electromagnet. Such a setup requires a current source, as well as passive or active cooling strategies, which directly sets a limitation based on the portability aspect that is desired for point of care (POC) monitoring applications. In this work, a measurement head is introduced that involves the utilization of two ring-shaped permanent magnets to generate a static offset magnetic field. A steel cylinder in the ring bores homogenizes the field. By variation of the distance between the ring magnets and of the thickness of the steel cylinder, the magnitude of the magnetic field at the sample position can be adjusted. Furthermore, the measurement setup is compared to the electromagnet offset module based on measured signals and temperature behavior.
Spontaneous language has rarely been subjected to neuroimaging studies. This study therefore introduces a newly developed method for the analysis of linguistic phenomena observed in continuous language production during fMRI.
Most neuroimaging studies investigating language have so far focussed on single word or — to a smaller extent — sentence processing, mostly due to methodological considerations. Natural language production, however, is far more than the mere combination of words to larger units. Therefore, the present study aimed at relating brain activation to linguistic phenomena like word-finding difficulties or syntactic completeness in a continuous language fMRI paradigm. A picture description task with special constraints was used to provoke hesitation phenomena and speech errors. The transcribed speech sample was segmented into events of one second and each event was assigned to one category of a complex schema especially developed for this purpose. The main results were: conceptual planning engages bilateral activation of the precuneus. Successful lexical retrieval is accompanied – particularly in comparison to unsolved word-finding difficulties – by the left middle and superior temporal gyrus. Syntactic completeness is reflected in activation of the left inferior frontal gyrus (IFG) (area 44). In sum, the method has proven to be useful for investigating the neural correlates of lexical and syntactic phenomena in an overt picture description task. This opens up new prospects for the analysis of spontaneous language production during fMRI.
ECG is corrupted by magneto-hydrodynamic effects at higher magnetic field strength. Artifacts in the ECG trace and severe T-wave elevation might be mis-interpreted as R-waves. MHD being inherently sensitive to blood flow and blood velocity provides an alternative approach for cardiac gating, even in peripheral target areas far away from the commonly used upper torso positions of ECG electrodes. This feature would be very beneficial to address traveling time induced motion artifacts and trigger latency related issues raised by ECG-gated peripheral MR angiography. For all those reasons, this work proposes the use of MHD-trigger for cardiac gated MR.
We consider recent reports on small-world topologies of interaction networks derived from the dynamics of spatially extended systems that are investigated in diverse scientific fields such as neurosciences, geophysics, or meteorology. With numerical simulations that mimic typical experimental situations, we have identified an important constraint when characterizing such networks: indications of a small-world topology can be expected solely due to the spatial sampling of the system along with the commonly used time series analysis based approaches to network characterization.
Messenger apps like WhatsApp and Telegram are frequently used for everyday communication, but they can also be utilized as a platform for illegal activity. Telegram allows public groups with up to 200.000 participants. Criminals use these public groups for trading illegal commodities and services, which becomes a concern for law enforcement agencies, who manually monitor suspicious activity in these chat rooms. This research demonstrates how natural language processing (NLP) can assist in analyzing these chat rooms, providing an explorative overview of the domain and facilitating purposeful analyses of user behavior. We provide a publicly available corpus of annotated text messages with entities and relations from four self-proclaimed black market chat rooms. Our pipeline approach aggregates the extracted product attributes from user messages to profiles and uses these with their sold products as features for clustering. The extracted structured information is the foundation for further data exploration, such as identifying the top vendors or fine-granular price analyses. Our evaluation shows that pretrained word vectors perform better for unsupervised clustering than state-of-the-art transformer models, while the latter is still superior for sequence labeling.
We study the novel possibilities computer aided design and production open up for the design of building systems. Such systems today can, via individualized mass production, consist of a larger number and more complex parts than previously and therefore be assembled into more complex wholes. This opens up the possibility of designing specialized systems specifically for single buildings. The common order of starting with a building system and designing a building using this system can be reversed to designing a building first and then developing a system specifically for that building. We present and discuss research that incorporates students design projects into research work and fosters links between research and teaching.
In the last decades, several hundred exoplanets could be detected thanks to space-based observatories, namely CNES’ COROT and NASA’s Kepler. To expand this quest ESA plans to launch CHEOPS as the f irst small class mission in the cosmic visions program (S1) and PLATO as the 3rd medium class mission, so called M3 . PLATO’s primary objective is the detection of Earth like Exoplanets orbiting solar type stars in the habitable zone and characterisation of their bulk properties. This is possible by precise lightcurve measurement via 34 cameras. That said it becomes obvious that accurate pointing is key to achieve the required signal to noise ratio for positive transit detection. The paper will start with a comprehensive overview of PLATO’s mission objectives and mission architecture. Hereafter, special focus will be devoted to PLATO’s pointing requirements. Understanding the very nature of PLATO’s pointing requirements is essential to derive a design baseline to achieve the required performance. The PLATO frequency domain is of particular interest, ranging from 40 mHz to 3 Hz. Due to the very different time-scales involved, the spectral pointing requirement is decomposed into a high frequency part dominated by the attitude control system and the low frequency part dominated by the thermo-elastic properties of the spacecraft’s configuration. Both pose stringent constraints on the overall design as well as technology properties to comply with the derived requirements and thus assure a successful mission.
The concept of an injective affine embedding of the quantum states into a set of classical states, i.e., into the set of the probability measures on some measurable space, as well as its relation to statistically complete observables is revisited, and its limitation in view of a classical reformulation of the statistical scheme of quantum mechanics is discussed. In particular, on the basis of a theorem concerning a non-denseness property of a set of coexistent effects, it is shown that an injective classical embedding of the quantum states cannot be supplemented by an at least approximate classical description of the quantum mechanical effects. As an alternative approach, the concept of quasi-probability representations of quantum mechanics is considered.
The network approach towards the analysis of the dynamics of complex systems has been successfully applied in a multitude of studies in the neurosciences and has yielded fascinating insights. With this approach, a complex system is considered to be composed of different constituents which interact with each other. Interaction structures can be compactly represented in interaction networks. In this contribution, we present a brief overview about how interaction networks are derived from multivariate time series, about basic network characteristics, and about challenges associated with this analysis approach.
Researching the field of business intelligence and analytics (BI & A) has a long tradition within information systems research. Thereby, in each decade the rapid development of technologies opened new room for investigation. Since the early 1950s, the collection and analysis of structured data were the focus of interest, followed by unstructured data since the early 1990s. The third wave of BI & A comprises unstructured and sensor data of mobile devices. The article at hand aims at drawing a comprehensive overview of the status quo in relevant BI & A research of the current decade, focusing on the third wave of BI & A. By this means, the paper’s contribution is fourfold. First, a systematically developed taxonomy for BI & A 3.0 research, containing seven dimensions and 40 characteristics, is presented. Second, the results of a structured literature review containing 75 full research papers are analyzed by applying the developed taxonomy. The analysis provides an overview on the status quo of BI & A 3.0. Third, the results foster discussions on the predicted and observed developments in BI & A research of the past decade. Fourth, research gaps of the third wave of BI & A research are disclosed and concluded in a research agenda.
The paper presents the derivation of a new equivalent skin friction coefficient for estimating the parasitic drag of short-to-medium range fixed-wing unmanned aircraft. The new coefficient is derived from an aerodynamic analysis of ten different unmanned aircraft used on surveillance, reconnaissance, and search and rescue missions. The aircraft are simulated using a validated unsteady Reynolds-averaged Navier Stokes approach. The UAV's parasitic drag is significantly influenced by the presence of miscellaneous components like fixed landing gears or electro-optical sensor turrets. These components are responsible for almost half of an unmanned aircraft's total parasitic drag. The new equivalent skin friction coefficient accounts for these effects and is significantly higher compared to other aircraft categories. It is used to initially size an unmanned aircraft for a typical reconnaissance mission. The improved parasitic drag estimation yields a much heavier unmanned aircraft when compared to the sizing results using available drag data of manned aircraft.
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.
The treatment of septic wounds with curative dressings based on biocomposites containing sage and marigold phytoextracts was effective in in vitro and in vivo experiments. These dressings caused the purification of the wound surface from purulent-necrotic masses three days earlier than in the other experimental groups. The consequence of an increase in incidents of severe course of the wound and the observed tendency to increase the number of adverse effects is the development of long-term recurrent wound processes. To treat purulent wounds, the following tactics were used: The purulent wounds of animals were covered with the examined wound dressing, and then the next day samples were taken, the procedure was performed once in 2 days. To obtain the active nanostructured sorbents such as carbonized rice husks, they are functionalized with biologically active components possessing antimicrobial, anti-inflammatory, antitoxic, immunomodulating, antiallergic and other types of properties.
Biotechnological downstream processing is usually an elaborate procedure, requiring a multitude of unit operations to isolate the target component. Besides the disadvantageous space-time yield, the risks of cross-contaminations and product loss grow fast with the complexity of the isolation procedure. A significant reduction of unit operations can be achieved by application of magnetic particles, especially if these are functionalized with affinity ligands. As magnetic susceptible materials are highly uncommon in biotechnological processes, target binding and selective separation of such particles from fermentation or reactions broths can be done in a single step. Since the magnetizable particles can be produced from iron salts and low priced polymers, a single-use implementation of these systems is highly conceivable. In this article, the principles of magnetizable particles, their synthesis and functionalization are explained. Furthermore, applications in the area of reaction engineering, microfluidics and downstream processing are discussed focusing on established single-use technologies and development potential.
Fundamentals and ignition of a microplasma at 2.45 GHZ / Holtrup, Stephan ; Heuermann, Holger
(2009)
Different analytical approaches exist to describe the structural substance or wear reserve of sewer systems. The aim is to convert engineering assessments of often complex defect patterns into computational algorithms and determine a substance class for a sewer section or manhole. This analytically determined information is essential for strategic rehabilitation planning processes up to network level, as it corresponds to the most appropriate rehabilitation type and can thus provide decision-making support. Current calculation methods differ clearly from each other in parts, so that substance classes determined by the different approaches are only partially comparable with each other. The objective of the German R&D cooperation project ‘SubKanS’ is to develop a methodology for classifying the specific defect patterns resulting from the interaction of all the individual defects, and their severities and locations. The methodology takes into account the structural substance of sewer sections and manholes, based on real data and theoretical considerations analogous to the condition classification of individual defects. The result is a catalogue of defect patterns and characteristics, as well as associated structural substance classifications of sewer systems (substance classes). The methodology for sewer system substance classification is developed so that the classification of individual defects can be transferred into a substance class of the sewer section or manhole, eventually taking into account further information (e.g. pipe material, nominal diameter, etc.). The result is a validated methodology for automated sewer system substance classification.
Future evolution of risk management for structures : Advancement for the future IEC 62305-2 Ed3
(2011)
In the RoboCup@Home domestic service robot competition, complex tasks such as "get the cup from the kitchen and bring it to the living room" or "find me this and that object in the apartment" have to be accomplished. At these competitions the robots may only be instructed by natural language. As humans use qualitative concepts such as "near" or "far", the robot needs to cope with them, too. For our domestic robot, we use the robot programming and plan language Readylog, our variant of Golog. In previous work we extended the action language Golog, which was developed for the high-level control of agents and robots, with fuzzy concepts and showed how to embed fuzzy controllers in Golog. In this paper, we demonstrate how these notions can be fruitfully applied to two domestic service robotic scenarios. In the first application, we demonstrate how qualitative fluents based on a fuzzy set semantics can be deployed. In the second program, we show an example of a fuzzy controller for a follow-a-person task.
A Gamified Information System (GIS) implements game concepts and elements, such as affordances and game design principles to motivate people. Based on the idea to develop a GIS to increase the motivation of software developers to perform software quality tasks, the research work at hand aims at investigating relevant requirements from that target group. Therefore, 14 interviews with software development experts are conducted and analyzed. According to the results, software developers prefer the affordances points, narrative storytelling in a multiplayer and a round-based setting. Furthermore, six design principles for the development of a GIS are derived.
Virtual Reality (VR) offers novel possibilities for remote training regardless of the availability of the actual equipment, the presence of specialists, and the training locations. Research shows that training environments that adapt to users' preferences and performance can promote more effective learning. However, the observed results can hardly be traced back to specific adaptive measures but the whole new training approach. This study analyzes the effects of a combined point and leveling VR-based gamification system on assembly training targeting specific training outcomes and users' motivations. The Gamified-VR-Group with 26 subjects received the gamified training, and the Non-Gamified-VR-Group with 27 subjects received the alternative without gamified elements. Both groups conducted their VR training at least three times before assembling the actual structure. The study found that a level system that gradually increases the difficulty and error probability in VR can significantly lower real-world error rates, self-corrections, and support usages. According to our study, a high error occurrence at the highest training level reduced the Gamified-VR-Group's feeling of competence compared to the Non-Gamified-VR-Group, but at the same time also led to lower error probabilities in real-life. It is concluded that a level system with a variable task difficulty should be combined with carefully balanced positive and negative feedback messages. This way, better learning results, and an improved self-evaluation can be achieved while not causing significant impacts on the participants' feeling of competence.
Gamification and gamified information systems (GIS) apply video game elements to encourage the work on boring and everyday tasks. Meanwhile, several research works provide evidence that gamification increases efficiency and effectivity of such tasks. The paper at hand investigates the health care sector, which is challenged with cost pressure and suffers in process efficiency. We hypothesize that GIS may improve the efficiency and quality of care processes. By applying an interview-based content analysis, the paper at hand evaluates gamification elements in an assisted living environment and provides three research contributions. First, insights into relevant GIS affordances and application examples for assisted living facilities are given. Second, assisted living experts evaluate GIS design guidelines. Both the relevant affordances and design principles comprise a basis for the development of a GIS for social workers in assisted living facilities. Third, potential adoption barriers and design guidelines for GIS in assisted living are presented.
Gas sensor investigation based on a catalytically activated thin-film thermopile for H2O2 detection
(2010)
In aseptic filling systems, hydrogen peroxide vapour is commonly used for the reduction of microbial contaminations in carton packages. In this process, the germicidal efficiency of the vapour depends especially on the H₂O₂ concentration. To monitor the H₂O₂ concentration, a calorimetric H₂O₂ gas sensor based on a catalytically activated thin-film thermopile is investigated. Two different sensor layouts, namely a circular and a linear form, as well as two various material pairs such as tungsten/nickel and gold/nickel, have been examined for the realization of a thin-film thermopile. Additionally, manganese oxide and palladium particles have been compared as responsive catalysts towards H₂O₂. The thin-film sensors have been investigated at various H₂O₂ concentrations, gas temperatures and flow rates.
Rehabilitative body weight supported gait training aims at restoring walking function as a key element in activities of daily living. Studies demonstrated reductions in muscle and joint forces, while kinematic gait patterns appear to be preserved with up to 30% weight support. However, the influence of body weight support on muscle architecture, with respect to fascicle and series elastic element behavior is unknown, despite this having potential clinical implications for gait retraining. Eight males (31.9 ± 4.7 years) walked at 75% of the speed at which they typically transition to running, with 0% and 30% body weight support on a lower-body positive pressure treadmill. Gastrocnemius medialis fascicle lengths and pennation angles were measured via ultrasonography. Additionally, joint kinematics were analyzed to determine gastrocnemius medialis muscle–tendon unit lengths, consisting of the muscle's contractile and series elastic elements. Series elastic element length was assessed using a muscle–tendon unit model. Depending on whether data were normally distributed, a paired t-test or Wilcoxon signed rank test was performed to determine if body weight supported walking had any effects on joint kinematics and fascicle–series elastic element behavior. Walking with 30% body weight support had no statistically significant effect on joint kinematics and peak series elastic element length. Furthermore, at the time when peak series elastic element length was achieved, and on average across the entire stance phase, muscle–tendon unit length, fascicle length, pennation angle, and fascicle velocity were unchanged with respect to body weight support. In accordance with unchanged gait kinematics, preservation of fascicle–series elastic element behavior was observed during walking with 30% body weight support, which suggests transferability of gait patterns to subsequent unsupported walking.
With a steady increase of regulatory requirements for business processes, automation support of compliance management is a field garnering increasing attention in Information Systems research. Several approaches have been developed to support compliance checking of process models. One major challenge for such approaches is their ability to handle different modeling techniques and compliance rules in order to enable widespread adoption and application. Applying a structured literature search strategy, we reflect and discuss compliance-checking approaches in order to provide an insight into their generalizability and evaluation. The results imply that current approaches mainly focus on special modeling techniques and/or a restricted set of types of compliance rules. Most approaches abstain from real-world evaluation which raises the question of their practical applicability. Referring to the search results, we propose a roadmap for further research in model-based business process compliance checking.
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.
Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line
(2012)
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.
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.