@article{SteinbauerFerrein2016, author = {Steinbauer, Gerald and Ferrein, Alexander}, title = {20 Years of RoboCup}, series = {KI - K{\"u}nstliche Intelligenz}, volume = {30}, journal = {KI - K{\"u}nstliche Intelligenz}, number = {3-4}, publisher = {Springer}, address = {Berlin}, issn = {1610-1987}, doi = {10.1007/s13218-016-0442-z}, pages = {221 -- 224}, year = {2016}, language = {en} } @article{GossmannFrotscherLinderetal.2016, author = {Goßmann, Matthias and Frotscher, Ralf and Linder, Peter and Bayer, Robin and Epple, U. and Staat, Manfred and Temiz Artmann, Ayseg{\"u}l and Artmann, Gerhard}, title = {Mechano-pharmacological characterization of cardiomyocytes derived from human induced pluripotent stem cells}, series = {Cellular physiology and biochemistry}, volume = {38}, journal = {Cellular physiology and biochemistry}, number = {3}, publisher = {Karger}, address = {Basel}, issn = {1421-9778 (Online)}, doi = {10.1159/000443124}, pages = {1182 -- 1198}, year = {2016}, abstract = {Background/Aims: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. Methods: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS-CMs induced variations of the membrane deflection. The recorded contraction-relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca²⁺ channels (S-Bay K8644/verapamil) and Na⁺ channels (veratridine/lidocaine). Results: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose-response curves were highly accurate and consistent with reference data. Conclusion: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential.}, language = {en} } @article{FunkeBeckmannKeinzetal.2016, author = {Funke, Harald and Beckmann, Nils and Keinz, Jan and Abanteriba, Sylvester}, title = {Comparison of Numerical Combustion Models for Hydrogen and Hydrogen-Rich Syngas Applied for Dry-Low-NOx-Micromix-Combustion}, series = {ASME Turbo Expo 2016: Turbomachinery Technical Conference and Exposition Volume 4A: Combustion, Fuels and Emissions Seoul, South Korea, June 13-17, 2016}, journal = {ASME Turbo Expo 2016: Turbomachinery Technical Conference and Exposition Volume 4A: Combustion, Fuels and Emissions Seoul, South Korea, June 13-17, 2016}, publisher = {ASME}, address = {New York, NY}, isbn = {978-0-7918-4975-0}, doi = {10.1115/GT2016-56430}, pages = {12}, year = {2016}, abstract = {The Dry-Low-NOₓ (DLN) Micromix combustion technology has been developed as low emission combustion principle for industrial gas turbines fueled with hydrogen or syngas. The combustion process is based on the phenomenon of jet-in-crossflow-mixing. Fuel is injected perpendicular into the air-cross-flow and burned in a multitude of miniaturized, diffusion-like flames. The miniaturization of the flames leads to a significant reduction of NOₓ emissions due to the very short residence time of reactants in the flame. In the Micromix research approach, CFD analyses are validated towards experimental results. The combination of numerical and experimental methods allows an efficient design and optimization of DLN Micromix combustors concerning combustion stability and low NOₓ emissions. The paper presents a comparison of several numerical combustion models for hydrogen and hydrogen-rich syngas. They differ in the complexity of the underlying reaction mechanism and the associated computational effort. For pure hydrogen combustion a one-step global reaction is applied using a hybrid Eddy-Break-up model that incorporates finite rate kinetics. The model is evaluated and compared to a detailed hydrogen combustion mechanism derived by Li et al. including 9 species and 19 reversible elementary reactions. Based on this mechanism, reduction of the computational effort is achieved by applying the Flamelet Generated Manifolds (FGM) method while the accuracy of the detailed reaction scheme is maintained. For hydrogen-rich syngas combustion (H₂-CO) numerical analyses based on a skeletal H₂/CO reaction mechanism derived by Hawkes et al. and a detailed reaction mechanism provided by Ranzi et al. are performed. The comparison between combustion models and the validation of numerical results is based on exhaust gas compositions available from experimental investigation on DLN Micromix combustors. The conducted evaluation confirms that the applied detailed combustion mechanisms are able to predict the general physics of the DLN-Micromix combustion process accurately. The Flamelet Generated Manifolds method proved to be generally suitable to reduce the computational effort while maintaining the accuracy of detailed chemistry. Especially for reaction mechanisms with a high number of species accuracy and computational effort can be balanced using the FGM model.}, language = {en} } @article{AimenovaDigelEshibaev2016, author = {Aimenova, Zh. E. and Digel, Ilya and Eshibaev, А. А.}, title = {Dynamics of accumulation of lagochirzin in Lagochilus setulosus phytomass during the growing season and also features of its cultivation in the conditions of a typical sierozem}, series = {KazNU Bulletin. Biology series}, volume = {69}, journal = {KazNU Bulletin. Biology series}, number = {4}, publisher = {Al-Farabi Kazakh National University}, address = {Almaty}, issn = {1563-0218}, pages = {4 -- 11}, year = {2016}, abstract = {L.setulosus is offered for creation of biopreparation «Setulin», possesing he- mostatic action, the basic reactant of biopreparation is diterpen - lagochirzin. Results under the maintenance and dynamics of diterpen lagochirzin accumula- tion in various parts of L.setulosus are presented: in roots, stalks, leaves, flowers and calyx lobes during the growing season, and also results on conditions of cultivation L.setulosus in the conditions of a typical sierozem are resulted. From the obtained data is visible, that the given species of a plant is endemic. It is established, that dynamics of accumulation of lagochirzin in phytomass accrues from the beginning to the middle of the growing season. The chemical analysis of L.setulosus on a localization of lagochirzin in various organs of a plant, has shown, that the greatest quantity of lagochirzin collects in calyx lobes of the plants. Also it is established, that L.setulosus can be cultivated in the conditions of the typical sierozem, a mineral food is necessary for the given species of plants of Lagochilus genus, except nitric fertilizers. Comparative studying of wild-growing and cultural forms of L.setulosus has shown, that in the cultivated phytomass of plants the maintenance of lagochirzin on 17-20 \% higher than in the wild-growing species.}, language = {en} } @article{DiktaReisselHarlass2016, author = {Dikta, Gerhard and Reißel, Martin and Harlaß, Carsten}, title = {Semi-parametric survival function estimators deduced from an identifying Volterra type integral equation}, series = {Journal of multivariate analysis}, journal = {Journal of multivariate analysis}, number = {147}, publisher = {Elsevier}, address = {Amsterdam}, doi = {10.1016/j.jmva.2016.02.008}, pages = {273 -- 284}, year = {2016}, abstract = {Based on an identifying Volterra type integral equation for randomly right censored observations from a lifetime distribution function F, we solve the corresponding estimating equation by an explicit and implicit Euler scheme. While the first approach results in some known estimators, the second one produces new semi-parametric and pre-smoothed Kaplan-Meier estimators which are real distribution functions rather than sub-distribution functions as the former ones are. This property of the new estimators is particular useful if one wants to estimate the expected lifetime restricted to the support of the observation time. Specifically, we focus on estimation under the semi-parametric random censorship model (SRCM), that is, a random censorship model where the conditional expectation of the censoring indicator given the observation belongs to a parametric family. We show that some estimated linear functionals which are based on the new semi-parametric estimator are strong consistent, asymptotically normal, and efficient under SRCM. In a small simulation study, the performance of the new estimator is illustrated under moderate sample sizes. Finally, we apply the new estimator to a well-known real dataset.}, language = {en} } @article{FrotscherMuanghongDursunetal.2016, author = {Frotscher, Ralf and Muanghong, Danita and Dursun, G{\"o}zde and Goßmann, Matthias and Temiz Artmann, Ayseg{\"u}l and Staat, Manfred}, title = {Sample-specific adaption of an improved electro-mechanical model of in vitro cardiac tissue}, series = {Journal of Biomechanics}, volume = {49}, journal = {Journal of Biomechanics}, number = {12}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0021-9290 (Print)}, doi = {10.1016/j.jbiomech.2016.01.039}, pages = {2428 -- 2435}, year = {2016}, abstract = {We present an electromechanically coupled computational model for the investigation of a thin cardiac tissue construct consisting of human-induced pluripotent stem cell-derived atrial, ventricular and sinoatrial cardiomyocytes. The mechanical and electrophysiological parts of the finite element model, as well as their coupling are explained in detail. The model is implemented in the open source finite element code Code_Aster and is employed for the simulation of a thin circular membrane deflected by a monolayer of autonomously beating, circular, thin cardiac tissue. Two cardio-active drugs, S-Bay K8644 and veratridine, are applied in experiments and simulations and are investigated with respect to their chronotropic effects on the tissue. These results demonstrate the potential of coupled micro- and macroscopic electromechanical models of cardiac tissue to be adapted to experimental results at the cellular level. Further model improvements are discussed taking into account experimentally measurable quantities that can easily be extracted from the obtained experimental results. The goal is to estimate the potential to adapt the presented model to sample specific cell cultures.}, language = {en} } @article{ZhangHeimbachScheeretal.2016, author = {Zhang, Jin and Heimbach, Tycho and Scheer, Nico and Barve, Avantika and Li, Wenkui and Lin, Wen and He, Handan}, title = {Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling}, series = {Journal of Pharmaceutical Sciences}, volume = {Volume 105}, journal = {Journal of Pharmaceutical Sciences}, number = {Issue 4}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0022-3549}, doi = {doi.org/10.1016/j.xphs.2016.01.021}, pages = {1398 -- 1404}, year = {2016}, abstract = {NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.}, language = {en} } @article{DallasSalphatiGomezZepedaetal.2016, author = {Dallas, Shannon and Salphati, Laurent and Gomez-Zepeda, David and Wanek, Thomas and Chen, Liangfu and Chu, Xiaoyan and Kunta, Jeevan and Mezler, Mario and Menet, Marie-Claude and Chasseigneaux, Stephanie and Decl{\`e}ves, Xavier and Langer, Oliver and Pierre, Esaie and DiLoreto, Karen and Hoft, Carolin and Laplanche, Loic and Pang, Jodie and Pereira, Tony and Andonian, Clara and Simic, Damir and Rode, Anja and Yabut, Jocelyn and Zhang, Xiaolin and Scheer, Nico}, title = {Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model}, series = {Molecular Pharmacology}, volume = {89}, journal = {Molecular Pharmacology}, number = {5}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.115.102079}, pages = {492 -- 504}, year = {2016}, abstract = {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.}, language = {en} }