TY - JOUR A1 - Scheer, Nico A1 - Wilson, Ian D. T1 - A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity JF - Drug Discovery Today N2 - 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. Y1 - 2016 U6 - https://doi.org/10.1016/j.drudis.2015.09.002 SN - 1359-6446 VL - 21 IS - 2 SP - 250 EP - 263 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Paulßen, Elisabeth A1 - Lengkeek, Nigel A. A1 - Le, Van So A1 - Pellegrini, Paul A. A1 - Greguric, Ivan A1 - Weiner, Ron T1 - The role of additives in moderating the influence of Fe(III) and Cu(II) on the radiochemical yield of [⁶⁸Ga(DOTATATE)] JF - Applied Radiation and Isotopes N2 - [⁶⁸Ga(DOTATATE)] has demonstrated its clinical usefulness. Both Fe³⁺ and Cu²⁺, potential contaminants in Gallium-68 generator eluent, substantially reduce the radiochemical (RC) yield of [⁶⁸Ga(DOTATATE)] if the metal/ligand ratio of 1:1 is exceeded. A variety of compounds were examined for their potential ability to reduce this effect. Most had no effect on RC yield. However, addition of phosphate diminished the influence of Fe³⁺ by likely forming an insoluble iron salt. Addition of ascorbic acid reduced Cu²⁺ and Fe³⁺ to Cu⁺ and Fe²⁺ respectively, both of which have limited impact on RC yields. At low ligand amounts (5 nmol DOTATATE), the addition of 30 nmol phosphate (0.19 mM) increased the tolerance of Fe3⁺ from 4 nmol to 10 nmol (0.06 mM), while the addition of ascorbic acid allowed high RC yields (>95%) in the presence of 40 nmol Fe³⁺ (0.25 mM) and 100 nmol Cu²⁺ (0.63 mM). The effect of ascorbic acid was highly pH-dependant, and gave optimal results at pH 3. Y1 - 2016 U6 - https://doi.org/10.1016/j.apradiso.2015.09.008 SN - 1872-9800 VL - 107 SP - 13 EP - 16 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Infantino, Angelo A1 - Paulßen, Elisabeth A1 - Mostacci, Domiziano A1 - Schaffer, Paul A1 - Trinczek, Michael A1 - Hoehr, Cornelia T1 - Assessment of the production of medical isotopes using the Monte Carlo code FLUKA: Simulations against experimental measurements JF - Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms N2 - The Monte Carlo code FLUKA is used to simulate the production of a number of positron emitting radionuclides, ¹⁸F, ¹³N, ⁹⁴Tc, ⁴⁴Sc, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ⁵²Mn, ⁶¹Cu and ⁵⁵Co, on a small medical cyclotron with a proton beam energy of 13 MeV. Experimental data collected at the TR13 cyclotron at TRIUMF agree within a factor of 0.6 ± 0.4 with the directly simulated data, except for the production of ⁵⁵Co, where the simulation underestimates the experiment by a factor of 3.4 ± 0.4. The experimental data also agree within a factor of 0.8 ± 0.6 with the convolution of simulated proton fluence and cross sections from literature. Overall, this confirms the applicability of FLUKA to simulate radionuclide production at 13 MeV proton beam energy. Y1 - 2016 U6 - https://doi.org/10.1016/j.nimb.2015.10.067 SN - 1872-9584 VL - 366 SP - 117 EP - 123 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Bernecker, Andreas T1 - Divided we reform? Evidence from US welfare policies JF - Journal of Public Economics N2 - Divided government is often thought of as causing legislative deadlock. I investigate the link between divided government and economic reforms using a novel data set on welfare reforms in US states between 1978 and 2010. Panel data regressions show that, under divided government, a US state is around 25% more likely to adopt a welfare reform than under unified government. Several robustness checks confirm this counter-intuitive finding. Case study evidence suggests an explanation based on policy competition between governor, senate, and house. Y1 - 2016 U6 - https://doi.org/10.1016/j.jpubeco.2016.08.003 SN - 0047-2727 VL - 142 SP - 24 EP - 38 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Beckenbach, Isabel A1 - Scheidweiler, Robert T1 - Perfect ƒ-Matchings and ƒ-Factors in Hypergraphs - A Combinatorial Approach JF - Discrete Mathematics N2 - We prove characterizations of the existence of perfect ƒ-matchings in uniform mengerian and perfect hypergraphs. Moreover, we investigate the ƒ-factor problem in balanced hypergraphs. For uniform balanced hypergraphs we prove two existence theorems with purely combinatorial arguments, whereas for non-uniform balanced hypergraphs we show that the ƒ-factor problem is NP-hard. Y1 - 2016 U6 - https://doi.org/10.1016/j.disc.2017.05.005 SN - 2192-7782 N1 - Als Volltext auch bei ZIB (Zuse Institute Berlin) VL - 240 IS - 10 SP - 2499 EP - 2506 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Weber, Tobias A1 - Arent, Jan-Christoph A1 - Münch, Lukas A1 - Duhovic, Miro A1 - Balvers, Johannes M. T1 - A fast method for the generation of boundary conditions for thermal autoclave simulation JF - Composites Part A N2 - Manufacturing process simulation enables the evaluation and improvement of autoclave mold concepts early in the design phase. To achieve a high part quality at low cycle times, the thermal behavior of the autoclave mold can be investigated by means of simulations. Most challenging for such a simulation is the generation of necessary boundary conditions. Heat-up and temperature distribution in an autoclave mold are governed by flow phenomena, tooling material and shape, position within the autoclave, and the chosen autoclave cycle. This paper identifies and summarizes the most important factors influencing mold heat-up and how they can be introduced into a thermal simulation. Thermal measurements are used to quantify the impact of the various parameters. Finally, the gained knowledge is applied to develop a semi-empirical approach for boundary condition estimation that enables a simple and fast thermal simulation of the autoclave curing process with reasonably high accuracy for tooling optimization. Y1 - 2016 U6 - https://doi.org/10.1016/j.compositesa.2016.05.036 SN - 1359-835X VL - 88 SP - 216 EP - 225 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Schmidt, K. A1 - Forkmann, K. A1 - Sinke, C. A1 - Gratz, M. A1 - Bitz, Andreas A1 - Bingel, U. T1 - The differential effect of trigeminal vs. peripheral pain stimulation on visual processing and memory encoding is influenced by pain-related fear JF - NeuroImage N2 - Compared to peripheral pain, trigeminal pain elicits higher levels of fear, which is assumed to enhance the interruptive effects of pain on concomitant cognitive processes. In this fMRI study we examined the behavioral and neural effects of trigeminal (forehead) and peripheral (hand) pain on visual processing and memory encoding. Cerebral activity was measured in 23 healthy subjects performing a visual categorization task that was immediately followed by a surprise recognition task. During the categorization task subjects received concomitant noxious electrical stimulation on the forehead or hand. Our data show that fear ratings were significantly higher for trigeminal pain. Categorization and recognition performance did not differ between pictures that were presented with trigeminal and peripheral pain. However, object categorization in the presence of trigeminal pain was associated with stronger activity in task-relevant visual areas (lateral occipital complex, LOC), memory encoding areas (hippocampus and parahippocampus) and areas implicated in emotional processing (amygdala) compared to peripheral pain. Further, individual differences in neural activation between the trigeminal and the peripheral condition were positively related to differences in fear ratings between both conditions. Functional connectivity between amygdala and LOC was increased during trigeminal compared to peripheral painful stimulation. Fear-driven compensatory resource activation seems to be enhanced for trigeminal stimuli, presumably due to their exceptional biological relevance. Y1 - 2016 U6 - https://doi.org/10.1016/j.neuroimage.2016.03.026 SN - 1053-8119 VL - 134 SP - 386 EP - 395 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Molinnus, Denise A1 - Sorich, Maren A1 - Bartz, Alexander A1 - Siegert, Petra A1 - Willenberg, Holger S. A1 - Lisdat, Fred A1 - Poghossian, Arshak A1 - Keusgen, Michael A1 - Schöning, Michael Josef T1 - Towards an adrenaline biosensor based on substrate recycling amplification in combination with an enzyme logic gate JF - Sensors and Actuators B: Chemical N2 - An amperometric biosensor using a substrate recycling principle was realized for the detection of low adrenaline concentrations (1 nM) by measurements in phosphate buffer and Ringer’s solution at pH 6.5 and pH 7.4, respectively. In proof-of-concept experiments, a Boolean logic-gate principle has been applied to develop a digital adrenaline biosensor based on an enzyme AND logic gate. The obtained results demonstrate that the developed digital biosensor is capable for a rapid qualitative determination of the presence/absence of adrenaline in a YES/NO statement. Such digital biosensor could be used in clinical diagnostics for the control of a correct insertion of a catheter in the adrenal veins during adrenal venous-sampling procedure. Y1 - 2016 U6 - https://doi.org/10.1016/j.snb.2016.06.064 SN - 0925-4005 VL - 237 SP - 190 EP - 195 PB - Elsevier CY - Amsterdam ER - TY - CHAP A1 - Poghossian, Arshak A1 - Bronder, Thomas A1 - Scheja, S. A1 - Wu, Chunsheng A1 - Metzger-Boddien, C. A1 - Keusgen, M. A1 - Schöning, Michael Josef T1 - Label-free Electrostatic Detection of DNA Amplification by PCR Using Capacitive Field-effect Devices T2 - Procedia Engineering N2 - A capacitive field-effect EIS (electrolyte-insulator-semiconductor) sensor modified with a positively charged weak polyelectrolyte of poly(allylamine hydrochloride) (PAH)/single-stranded probe DNA (ssDNA) bilayer has been used for a label-free electrostatic detection of pathogen-specific DNA amplification via polymerase chain reaction (PCR). The sensor is able to distinguish between positive and negative PCR solutions, to detect the existence of target DNA amplicons in PCR samples and thus, can be used as tool for a quick verification of DNA amplification and the successful PCR process. Y1 - 2016 U6 - https://doi.org/10.1016/j.proeng.2016.11.512 SN - 1877-7058 N1 - Proceedings of the 30th anniversary Eurosensors Conference – Eurosensors 2016, 4-7. Sepember 2016, Budapest, Hungary VL - Vol. 168 SP - 514 EP - 517 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Wu, Chunsheng A1 - Poghossian, Arshak A1 - Bronder, Thomas A1 - Schöning, Michael Josef T1 - Sensing of double-stranded DNA molecules by their intrinsic molecular charge using the light-addressable potentiometric sensor JF - Sensors and Actuators B: Chemical N2 - A multi-spot light-addressable potentiometric sensor (LAPS), which belongs to the family of semiconductor field-effect devices, was applied for label-free detection of double-stranded deoxyribonucleic acid (dsDNA) molecules by their intrinsic molecular charge. To reduce the distance between the DNA charge and sensor surface and thus, to enhance the electrostatic coupling between the dsDNA molecules and the LAPS, the negatively charged dsDNA molecules were electrostatically adsorbed onto the gate surface of the LAPS covered with a positively charged weak polyelectrolyte layer of PAH (poly(allylamine hydrochloride)). The surface potential changes in each spot of the LAPS, induced by the layer-by-layer adsorption of a PAH/dsDNA bilayer, were recorded by means of photocurrent-voltage and constant-photocurrent measurements. In addition, the surface morphology of the gate surface before and after consecutive electrostatic adsorption of PAH and dsDNA layers was studied by atomic force microscopy measurements. Moreover, fluorescence microscopy was used to verify the successful adsorption of dsDNA molecules onto the PAH-modified LAPS surface. A high sensor signal of 25 mV was registered after adsorption of 10 nM dsDNA molecules. The lower detection limit is down to 0.1 nM dsDNA. The obtained results demonstrate that the PAH-modified LAPS device provides a convenient and rapid platform for the direct label-free electrical detection of in-solution hybridized dsDNA molecules. KW - Layer-by-layer adsorption KW - Poly(allylamine hydrochloride) KW - Label-free detection KW - DNA biosensor KW - LAPS KW - Field effect Y1 - 2016 U6 - https://doi.org/10.1016/j.snb.2016.02.004 SN - 0925-4005 IS - 229 SP - 506 EP - 512 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Rösch, C. A1 - Kratz, F. A1 - Hering, T. A1 - Trautmann, S. A1 - Umanskaya, N. A1 - Tippkötter, Nils A1 - Müller-Renno, C.M. A1 - Ulber, Roland A1 - Hannig, M. A1 - Ziegler, C. T1 - Albumin-lysozyme interactions: cooperative adsorption on titanium and enzymatic activity JF - Colloids and Surfaces B: Biointerfaces N2 - The interplay of albumin (BSA) and lysozyme (LYZ) adsorbed simultaneously on titanium was analyzed by gel electrophoresis and BCA assay. It was found that BSA and lysozyme adsorb cooperatively. Additionally, the isoelectric point of the respective protein influences the adsorption. Also, the enzymatic activity of lysozyme and amylase (AMY) in mixtures with BSA was considered with respect to a possible influence of protein-protein interaction on enzyme activity. Indeed, an increase of lysozyme activity in the presence of BSA could be observed. In contrast, BSA does not influence the activity of amylase. Y1 - 2016 U6 - https://doi.org/10.1016/j.colsurfb.2016.09.048 VL - 149 IS - 1 SP - 115 EP - 121 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Wulfhorst, Helene A1 - Duwe, Anna-Maria A1 - Merseburg, Johannes A1 - Tippkötter, Nils T1 - Compositional analysis of pretreated (beech) wood using differential scanning calorimetry and multivariate data analysis JF - Tetrahedron N2 - The composition of plant biomass varies depending on the feedstock and pre-treatment conditions and influences its processing in biorefineries. In order to ensure optimal process conditions, the quantitative proportion of the main polymeric components of the pre-treated biomass has to be determined. Current standard procedures for biomass compositional analysis are complex, the measurements are afflicted with errors and therefore often not comparable. Hence, new powerful analytical methods are urgently required to characterize biomass. In this contribution, Differential Scanning Calorimetry (DSC) was applied in combination with multivariate data analysis (MVA) to detect the cellulose content of the plant biomass pretreated by Liquid Hot Water (LHW) and Organosolv processes under various conditions. Unlike conventional techniques, the developed analytic method enables the accurate quantification of monosaccharide content of the plant biomass without any previous sample preparation. It is easy to handle and avoids errors in sample preparation. Y1 - 2016 U6 - https://doi.org/10.1016/j.tet.2016.04.029 VL - 72 IS - 46 SP - 7329 EP - 7334 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Valero, Daniel A1 - Bung, Daniel Bernhard T1 - Sensitivity of turbulent Schmidt number and turbulence model to simulations of jets in crossflow JF - Environmental Modelling and Software N2 - Environmental discharges have been traditionally designed by means of cost-intensive and time-consuming experimental studies. Some extensively validated models based on an integral approach have been often employed for water quality problems, as recommended by USEPA (i.e.: CORMIX). In this study, FLOW-3D is employed for a full 3D RANS modelling of two turbulent jet-to-crossflow cases, including free surface jet impingement. Results are compared to both physical modelling and CORMIX to better assess model performance. Turbulence measurements have been collected for a better understanding of turbulent diffusion's parameter sensitivity. Although both studied models are generally able to reproduce jet trajectory, jet separation downstream of the impingement has been reproduced only by RANS modelling. Additionally, concentrations are better reproduced by FLOW-3D when the proper turbulent Schmidt number is used. This study provides a recommendation on the selection of the turbulence model and the turbulent Schmidt number for future outfall structures design studies. Y1 - 2016 U6 - https://doi.org/10.1016/j.envsoft.2016.04.030 SN - 1364-8152 (electronic) VL - 82 SP - 218 EP - 228 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Dikta, Gerhard A1 - Reißel, Martin A1 - Harlaß, Carsten T1 - Semi-parametric survival function estimators deduced from an identifying Volterra type integral equation JF - Journal of multivariate analysis N2 - 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. KW - Volterra integral equation KW - Product-integration KW - Asymptotic efficiency KW - Semi-parametric random censorship model KW - Censored data KW - Survival analysis Y1 - 2016 U6 - https://doi.org/10.1016/j.jmva.2016.02.008 IS - 147 SP - 273 EP - 284 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Frotscher, Ralf A1 - Muanghong, Danita A1 - Dursun, Gözde A1 - Goßmann, Matthias A1 - Temiz Artmann, Aysegül A1 - Staat, Manfred T1 - Sample-specific adaption of an improved electro-mechanical model of in vitro cardiac tissue JF - Journal of Biomechanics N2 - 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. KW - hiPS cardiomyocytes KW - Homogenization KW - Hodgkin–Huxley models KW - Frequency adaption KW - Electromechanical modeling KW - Drug simulation KW - Computational biomechanics KW - Cardiac tissue Y1 - 2016 U6 - https://doi.org/10.1016/j.jbiomech.2016.01.039 SN - 0021-9290 (Print) SN - 1873-2380 (Online) VL - 49 IS - 12 SP - 2428 EP - 2435 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Zhang, Jin A1 - Heimbach, Tycho A1 - Scheer, Nico A1 - Barve, Avantika A1 - Li, Wenkui A1 - Lin, Wen A1 - He, Handan T1 - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling JF - Journal of Pharmaceutical Sciences N2 - 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. Y1 - 2016 U6 - https://doi.org/doi.org/10.1016/j.xphs.2016.01.021 SN - 0022-3549 VL - Volume 105 IS - Issue 4 SP - 1398 EP - 1404 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Murib, M. S. A1 - Yeap, W. S. A1 - Eurlings, Y. A1 - Grinsven, B. van A1 - Boyen, H.-G. A1 - Conings, B. A1 - Michiels, L. A1 - Ameloot, Marcel A1 - Carleer, R. A1 - Warmer, J. A1 - Kaul, P. A1 - Haenen, K. A1 - Schöning, Michael Josef A1 - Ceuninck, W. de A1 - Wagner, P. T1 - Heat-transfer based characterization of DNA on synthetic sapphire chips JF - Sensors and Actuators B: Chemical N2 - In this study, we show that synthetic sapphire (Al₂O₃), an established implant material, can also serve as a platform material for biosensors comparable to nanocrystalline diamond. Sapphire chips, beads, and powder were first modified with (3-aminopropyl) triethoxysilane (APTES), followed by succinic anhydride (SA), and finally single-stranded probe DNA was EDC coupled to the functionalized layer. The presence of the APTES-SA layer on sapphire powders was confirmed by thermogravimetric analyis and Fourier-transform infrared spectroscopy. Using planar sapphire chips as substrates and X-ray photoelectron spectroscopy (XPS) as surface-sensitive tool, the sequence of individual layers was analyzed with respect to their chemical state, enabling the quantification of areal densities of the involved molecular units. Fluorescence microscopy was used to demonstrate the hybridization of fluorescently tagged target DNA to the probe DNA, including denaturation- and re-hybridization experiments. Due to its high thermal conductivity, synthetic sapphire is especially suitable as a chip material for the heat-transfer method, which was employed to distinguish complementary- and non-complementary DNA duplexes containing single-nucleotide polymorphisms. These results indicate that it is possible to detect mutations electronically with a chemically resilient and electrically insulating chip material. Y1 - 2016 U6 - https://doi.org/10.1016/j.snb.2016.02.027 SN - 0925-4005 VL - 230 IS - 230 SP - 260 EP - 271 PB - Elsevier CY - Amsterdam ER -