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Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction.
Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line
(2012)
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.
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.
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.
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.
Gas sensor investigation based on a catalytically activated thin-film thermopile for H2O2 detection
(2010)
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.
Future evolution of risk management for structures : Advancement for the future IEC 62305-2 Ed3
(2011)
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.