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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.
The main objective of the BATIMASS project was to address how the energy balance in relatively lightweight steel buildings can be improved by building in ‘active thermal mass’ (ATM) into the building fabric. This was achieved through concept design, dynamic thermal modelling and testing of a number of potentially viable systems and concepts. A significant programme of thermal simulation modelling was undertaken utilising the thermally equivalent slab (TES) concept to model the passive thermal capacity effect of profiled, composite metal floor decks. It is apparent from the modelling results that thermal mass is a highly complex phenomenon which is highly dependent upon building type, occupancy patterns, climate and many other aspects of the building design and servicing strategy. The ATM systems developed, both conceptually and for prototype testing, focussed on water-cooled composite slabs, the Cofradal floor system and the phase change material (PCM) Energain. In addition to laboratory testing of prototypes, whole building monitoring was undertaken at the Kubik building in Spain and the RWTH test building in Germany. Advanced thermal modelling was also undertaken to estimate the likely benefits of the ATM concept designs developed and for comparison with the test results. In addition to thermal testing, structural tests were conducted on composite floor specimens incorporating embedded water pipes. This Final Report presents the results of the activities carried out under this RFCS contract RFSR CT 2012 00033. The work carried out is reported in six major sections corresponding to the technical Work Packages of the project. Only summaries of the work carried out are provided in this report; all work undertaken is fully reported in the formal project deliverables.
This work presents a basic forecast tool for predicting direct normal irradiance (DNI) in hourly resolution, which the Solar-Institut Jülich (SIJ) is developing within a research project. The DNI forecast data shall be used for a parabolic trough collector (PTC) system with a concrete thermal energy storage (C-TES) located at the company KEAN Soft Drinks Ltd in Limassol, Cyprus. On a daily basis, 24-hour DNI prediction data in hourly resolution shall be automatically produced using free or very low-cost weather forecast data as input. The purpose of the DNI forecast tool is to automatically transfer the DNI forecast data on a daily basis to a main control unit (MCU). The MCU automatically makes a smart decision on the operation mode of the PTC system such as steam production mode and/or C-TES charging mode. The DNI forecast tool was evaluated using historical data of measured DNI from an on-site weather station, which was compared to the DNI forecast data. The DNI forecast tool was tested using data from 56 days between January and March 2022, which included days with a strong variation in DNI due to cloud passages. For the evaluation of the DNI forecast reliability, three categories were created and the forecast data was sorted accordingly. The result was that the DNI forecast tool has a reliability of 71.4 % based on the tested days. The result fulfils SIJ’s aim to achieve a reliability of around 70 %, but SIJ aims to still improve the DNI forecast quality.
As part of the transnational research project EDITOR, a parabolic trough collector system (PTC) with concrete thermal energy storage (C-TES) was installed and commissioned in Limassol, Cyprus. The system is located on the premises of the beverage manufacturer KEAN Soft Drinks Ltd. and its function is to supply process steam for the factory's pasteurisation process [1]. Depending on the factory's seasonally varying capacity for beverage production, the solar system delivers between 5 and 25 % of the total steam demand. In combination with the C-TES, the solar plant can supply process steam on demand before sunrise or after sunset. Furthermore, the C-TES compensates the PTC during the day in fluctuating weather conditions. The parabolic trough collector as well as the control and oil handling unit is designed and manufactured by Protarget AG, Germany. The C-TES is designed and produced by CADE Soluciones de Ingeniería, S.L., Spain. In the focus of this paper is the description of the operational experience with the PTC, C-TES and boiler during the commissioning and operation phase. Additionally, innovative optimisation measures are presented.
Large scale central receiver systems typically deploy between thousands to more than a hundred thousand heliostats. During solar operation, each heliostat is aligned individually in such a way that the overall surface normal bisects the angle between the sun’s position and the aim point coordinate on the receiver. Due to various tracking error sources, achieving accurate alignment ≤1 mrad for all the heliostats with respect to the aim points on the receiver without a calibration system can be regarded as unrealistic. Therefore, a calibration system is necessary not only to improve the aiming accuracy for achieving desired flux distributions but also to reduce or eliminate spillage. An overview of current larger-scale central receiver systems (CRS), tracking error sources and the basic requirements of an ideal calibration system is presented. Leading up to the main topic, a description of general and specific terms on the topics heliostat calibration and tracking control clarifies the terminology used in this work. Various figures illustrate the signal flows along various typical components as well as the corresponding monitoring or measuring devices that indicate or measure along the signal (or effect) chain. The numerous calibration systems are described in detail and classified in groups. Two tables allow the juxtaposition of the calibration methods for a better comparison. In an assessment, the advantages and disadvantages of individual calibration methods are presented.
In this work, three patent pending calibration methods for heliostat fields of central receiver systems (CRS) developed by the Solar-Institut Jülich (SIJ) of the FH Aachen University of Applied Sciences are presented. The calibration methods can either operate in a combined mode or in stand-alone mode. The first calibration method, method A, foresees that a camera matrix is placed into the receiver plane where it is subjected to concentrated solar irradiance during a measurement process. The second calibration method, method B, uses an unmanned aerial vehicle (UAV) such as a quadrocopter to automatically fly into the reflected solar irradiance cross-section of one or more heliostats (two variants of method B were tested). The third calibration method, method C, foresees a stereo central camera or multiple stereo cameras installed e.g. on the solar tower whereby the orientations of the heliostats are calculated from the location detection of spherical red markers attached to the heliostats. The most accurate method is method A which has a mean accuracy of 0.17 mrad. The mean accuracy of method B variant 1 is 1.36 mrad and of variant 2 is 1.73 mrad. Method C has a mean accuracy of 15.07 mrad. For method B there is great potential regarding improving the measurement accuracy. For method C the collected data was not sufficient for determining whether or not there is potential for improving the accuracy.
Activated carbons are known as excellent adsorbents. Their applications include the adsorptive removal of color, odor, taste, undesirable organic and inorganic pollutants from drinking and waste water; air purification in inhabited spaces; purification of many chemicals, pharmaceutical products and many others. This chapter elucidates the role of normal microflora in the maintenance of human health and presents materials on possible clinical displays of microecological infringements and ways of their correction. It presents new developments concerning new probiotics with immobilized Lactobacillus and Bacillus. The chapter considers the mechanisms of the intestine disbacteriosis correction by sorbed probiotics. It demonstrates the advantages and creation prospects of immobilized probiotics developed on the basis of carbonized rice husk. There are great prospects for the development of medical biotechnology due to use of carbon sorbents with a nanostructured surface. Microbial communities form a biocenosis of the biotope and together with the host organism create permanent or temporary ecosystems.
This study describes the development of a new combined polysaccharide-matrix-based technology for the immobilization of Lactobacillus rhamnosus GG (LGG) bacteria in biofilm form. The new composition allows for delivering the bacteria to the digestive tract in a manner that improves their robustness compared with planktonic cells and released biofilm cells. Granules consisting of a polysaccharide matrix with probiotic biofilms (PMPB) with high cell density (>9 log CFU/g) were obtained by immobilization in the optimized nutrient medium. Successful probiotic loading was confirmed by fluorescence microscopy and scanning electron microscopy. The developed prebiotic polysaccharide matrix significantly enhanced LGG viability under acidic (pH 2.0) and bile salt (0.3%) stress conditions. Enzymatic extract of feces, mimicking colon fluid in terms of cellulase activity, was used to evaluate the intestinal release of probiotics. PMPB granules showed the ability to gradually release a large number of viable LGG cells in the model colon fluid. In vivo, the oral administration of PMPB granules in rats resulted in the successful release of probiotics in the colon environment. The biofilm-forming incubation method of immobilization on a complex polysaccharide matrix tested in this study has shown high efficacy and promising potential for the development of innovative biotechnologies.
Multimodal bioimage sensor
(2014)
To visualize the biochemical distribution two-dimensionally, we invented a solid-state-type ion image sensor that indicates the chemical activity of solutions and cells. The device, which consists of a CCD array covered with a functionalized membrane to detect charge accumulation, is highly sensitive to changes in the concentration and two-dimensional distribution of ions and biomaterials.
Solar-electric propulsion (SEP) is superior with
respect to payload capacity, flight time and
flexible launch window to the conventional
interplanetary transfer method using chemical
propulsion combined with gravity assists. This fact
results from the large exhaust velocities of electric
low–thrust propulsion and is favourable also for
missions to the giant planets, Kuiper-belt objects
and even for a heliopause probe (IHP) as shown in
three studies by the authors funded by DLR. They
dealt with a lander for Europa and a sample return
mission from a mainbelt asteroid [1], with the
TANDEM mission [2]; the third recent one
investigates electric propulsion for the transfer to
the edge of the solar system.
All studies are based on triple-junction solar arrays,
on rf-ion thrusters of the qualified RIT-22 type and
they use the intelligent trajectory optimization
program InTrance [3].
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.
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.
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.
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.
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.
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.
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.
We present a new Min-Max theorem for an optimization problem closely connected to matchings and vertex covers in balanced hypergraphs. The result generalizes Kőnig’s Theorem (Berge and Las Vergnas in Ann N Y Acad Sci 175:32–40, 1970; Fulkerson et al. in Math Progr Study 1:120–132, 1974) and Hall’s Theorem (Conforti et al. in Combinatorica 16:325–329, 1996) for balanced hypergraphs.
Biodiversity and the coexistence of species have puzzled and fascinated biologists since decades and is a hotspot in todays’ natural sciences. Preserving this biodiversity is a great challenge as habitats and environments underlying tremendous changes like climate change and the loss of natural habitats, which are mainly due to anthropogenic influences. The coexistence of numerous species even in homogeneous environments is a stunning feature of natural communities and has been summarized under the term ‘paradox of plankton’. Up to now, there are several mechanisms discussed, which may contribute to local and global diversity of organisms. Several interspecific trade offs have been identified maintaining the coexistence of species like their abilities regarding competition and predator avoidance, their capability to disperse in space and time, and their ability to exploit variable resources. Further, micro-evolutionary dynamics supporting the coexistence of species have been added to our knowledge, and deriving from theoretical deterministic models, non-linear dynamics which describe the temporal fluctuation of abundances of organisms. Whereas competition and predation seem to be clue structural elements within interacting organisms, the intrinsic dynamic behavior – by means of temporal changes in abundance - plays an important role regarding coexistence within a community. The present work sheds light on different factors affecting the coexistence of species using experimental microbial model systems consisting of a bacterivorous ciliate as the predator and two bacteria strains as prey organism. Additionally, another experimental setup consisting of two up to five bacteria species competing for one limiting resource was investigated. Highly controllable chemostat systems were established to exclude extrinsic disturbances. According to theoretical analyses I was able to show - experimentally and theoretically - that phenotypic plasticity of one species within a microbial one-predator-two-prey food web enlarges the range of possible coexistence of all species under different dynamic conditions, compared to a food web without phenotypic plasticity. This was accompanied by non-linear (chaotic) population dynamics within all experimental systems showing phenotypic plasticity. The experiments on the interplay of competition, predation and invasion showed that all aspects have an influence on species coexistence. Under undisturbed controlled conditions all aspects were analyzed in detail and in combination. Populations showed oscillations which were shown by quasi-chaotic attractors in phase space diagrams. Competition experiments with two up to five bacteria species competing for one limiting resource showed that all organisms were able to coexist which was mediated by species oscillations entering a regime of chaos. Besides that fact it was found, that the productivity (biomass) as well as the total cell numbers – under the same nutrition supply – increased by an increasing number of species in the experimental systems. Up to now, the occurrence of non-linear dynamics in well controlled experimental studies has been recognized several times and this phenomenon seemed to be more common in natural systems than generally assumed.
In this paper we present an extension of the action language Golog that allows for using fuzzy notions in non-deterministic argument choices and the reward function in decision-theoretic planning. Often, in decision-theoretic planning, it is cumbersome to specify the set of values to pick from in the non-deterministic-choice-of-argument statement. Also, even for domain experts, it is not always easy to specify a reward function. Instead of providing a finite domain for values in the non-deterministic-choice-of-argument statement in Golog, we now allow for stating the argument domain by simply providing a formula over linguistic terms and fuzzy uents. In Golog’s forward-search DT planning algorithm, these formulas are evaluated in order to find the agent’s optimal policy. We illustrate this in the Diner Domain where the agent needs to calculate the optimal serving order.
In this work, we report on our attempt to design and implement an early introduction to basic robotics principles for children at kindergarten age. One of the main challenges of this effort is to explain complex robotics contents in a way that pre-school children could follow the basic principles and ideas using examples from their world of experience. What sets apart our effort from other work is that part of the lecturing is actually done by a robot itself and that a quiz at the end of the lesson is done using robots as well. The humanoid robot Pepper from Softbank, which is a great platform for human–robot interaction experiments, was used to present a lecture on robotics by reading out the contents to the children making use of its speech synthesis capability. A quiz in a Runaround-game-show style after the lecture activated the children to recap the contents they acquired about how mobile robots work in principle. In this quiz, two LEGO Mindstorm EV3 robots were used to implement a strongly interactive scenario. Besides the thrill of being exposed to a mobile robot that would also react to the children, they were very excited and at the same time very concentrated. We got very positive feedback from the children as well as from their educators. To the best of our knowledge, this is one of only few attempts to use a robot like Pepper not as a tele-teaching tool, but as the teacher itself in order to engage pre-school children with complex robotics contents.
Reasoning with Qualitative Positional Information for Domestic Domains in the Situation Calculus
(2011)
In this paper we present CAESAR, an intelligent domestic service robot. In domestic settings for service robots complex tasks have to be accomplished. Those tasks benefit from deliberation, from robust action execution and from flexible methods for human–robot interaction that account for qualitative notions used in natural language as well as human fallibility. Our robot CAESAR deploys AI techniques on several levels of its system architecture. On the low-level side, system modules for localization or navigation make, for instance, use of path-planning methods, heuristic search, and Bayesian filters. For face recognition and human–machine interaction, random trees and well-known methods from natural language processing are deployed. For deliberation, we use the robot programming and plan language READYLOG, which was developed for the high-level control of agents and robots; it allows combining programming the behaviour using planning to find a course of action. READYLOG is a variant of the robot programming language Golog. We extended READYLOG to be able to cope with qualitative notions of space frequently used by humans, such as “near” and “far”. This facilitates human–robot interaction by bridging the gap between human natural language and the numerical values needed by the robot. Further, we use READYLOG to increase the flexible interpretation of human commands with decision-theoretic planning. We give an overview of the different methods deployed in CAESAR and show the applicability of a system equipped with these AI techniques in domestic service robotics
The impact of wake model effects is investigated for two highly
non-planar lifting systems. Dependent on the geometrical
arrangement of the configuration, the wake model shape is found
to considerably affect the estimation. Particularly at higher angles
of attack, an accurate estimation based on the common linear wake
model approaches is involved.