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An overview on dry low NOx micromix combustor development for hydrogen-rich gas turbine applications
(2019)
Breuer, Lars ; Pilas, Johanna ; Guthmann, Eric ; Schöning, Michael Josef ; Thoelen, Ronald ; Wagner, Torsten
Scheer, Nico ; Henderson, Colin James ; Kapelyukh, Yury ; Rode, Anja ; Mclaren, Aileen W. ; MacLeod, Alastair Kenneth ; Lin, De ; Wright, Jayne ; Stanley, Lesley ; Wolf, C. Roland
Jan Thimo, Grundmann ; Bauer, Waldemar ; Biele, Jens ; Boden, Ralf ; Ceriotti, Matteo ; Cordero, Federico ; Dachwald, Bernd ; Dumont, Etienne ; Grimm, Christian D. ; Hercik, David
Salpati, Laurent ; Chu, Xiaoyan ; Chen, Liangfu ; Prasad, Bhagwat ; Dallas, Shannon ; Evers, Raymond ; Mamaril-Fishman, Donna ; Geier, Ethan G. ; Kehler, Jonathan ; Kunta, Jeevan ; Mezler, Mario ; Laplanche, Loic ; Pang, Jodie ; Soars, Matthew G. ; Unadkat, Jashvant D. ; van Waterschoot, Robert A.B. ; Yabut, Jocelyn ; Schinkel, Alfred H. ; Scheer, Nico ; Rode, Anja
Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography–tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans.
Luisier, Raphaëlle ; Lempiäinen, Harri ; Scherbichler, Nina ; Braeuning, Albert ; Geissler, Miriam ; Dubost, Valerie ; Müller, Arne ; Scheer, Nico ; Chibout, Salah-Dine ; Hara, Hisanori ; Picard, Frank ; Theil, Diethilde ; Couttet, Philippe ; Vitobello, Antonio ; Grenet, Olivier ; Grasl-Kraupp, Bettina ; Ellinger-Ziegelbauer, Heidrung ; Thomson, John P. ; Meehan, Richard R. ; Elcombe, Clifford R. ; Henderson, Colin J. ; Wolf, C. Roland ; Schwarz, Michael ; Moulin, Pierre ; Terranova, Remi ; Moggs, Jonathan G.
The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
Cytochrome b5 Is a Major Determinant of Human Cytochrome P450 CYP2D6 and CYP3A4 Activity In Vivo s
(2015)
Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms
(2015)
Scheer, Nico ; Kapelyukh, Yury ; Rode, Anja ; Oswald, Stefan ; Busch, Diana ; Mclaughlin, Lesley A. ; Lin, De ; Henderson, Colin J. ; Wolf, C. Roland
Dallas, Shannon ; Salphati, Laurent ; Gomez-Zepeda, David ; Wanek, Thomas ; Chen, Liangfu ; Chu, Xiaoyan ; Kunta, Jeevan ; Mezler, Mario ; Menet, Marie-Claude ; Chasseigneaux, Stephanie ; Declèves, Xavier ; Langer, Oliver ; Pierre, Esaie ; DiLoreto, Karen ; Hoft, Carolin ; Laplanche, Loic ; Pang, Jodie ; Pereira, Tony ; Andonian, Clara ; Simic, Damir ; Rode, Anja ; Yabut, Jocelyn ; Zhang, Xiaolin ; Scheer, Nico
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.
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.
The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice
(2017)
Wilson, Ian D. ; Wilson, Claire E. ; Scheer, Nico ; Dickie, A.P. ; Schreiter, K. ; Wilson, E. M. ; Riley, R. J. ; Wehr, R. ; Bial, J.
Leschinger, Tim ; Birgel, Stefan ; Hackl, Michael ; Staat, Manfred ; Müller, Lars Peter ; Wegmann, Kilian
The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice
(2018)
Wilson, C. E. ; Dickie, A. P. ; Schreiter, K. ; Wehr, R. ; Wilson, E. M. ; Bial, J. ; Scheer, Nico ; Wilson, I. D. ; Riley, R. J.
The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.
Raupp, Sebastian M. ; Schmitt, Marcel ; Walz, Anna-Lena ; Diehm, Ralf ; Hummel, Helga ; Scharfer, Philip ; Schabel, Wilhelm
Slot die coating is applied to deposit thin and homogenous films in roll-to-roll and sheet-to-sheet applications. The critical step in operation is to choose suitable process parameters within the process window. In this work, we investigate an upper limit for stripe coatings. This maximum film thickness is characterized by stripe merging which needs to be avoided in a stable process. It is shown that the upper limit reduces the process window for stripe coatings to a major extent. As a result, stripe coatings at large coating gaps and low viscosities are only possible for relatively thick films. Explaining the upper limit, a theory of balancing the side pressure in the gap region in the cross-web direction has been developed.
Dotzauer, Martin ; Pfeiffer, Diana ; Lauer, Markus ; Pohl, Marcel ; Mauky, Eric ; Bär, Katharina ; Sonnleitner, Matthias ; Zörner, Wilfried ; Hudde, Jessica ; Schwarz, Björn ; Faßauer, Burkhardt ; Dahmen, Markus ; Rieke, Christian ; Herbert, Johannes ; Thrän, Daniela
Mit modernen nicht invasiven bildgebenden Verfahren lassen sich anhand der Fundusfotografie bzw. der optischen Verfilmung Aspekte der funktionellen und strukturellen retinalen Gefäßveränderungen objektiv untersuchen. Der Zustand und das Verhalten retinaler Gefäße beeinflussen im prä-, post- und kapillaren Bereich den Blutfluss und strömungsbedingte Stoffwechselverhältnisse passiv und aktiv über den Gefäßdurchmesser. Retinale Gefäße gleichen von Aufbau und Funktion den zerebralen Gefäßen und spiegeln den Zustand der Mikrozirkulation wider. Mithilfe von aus den Gefäßweiten berechneten Biomarkern soll eine Aussage über die Prognose von systemischen vaskulär bedingten Erkrankungen getroffen werden. Die statische retinale Gefäßanalyse befasst sich mit der Untersuchung des Zustandes der prä- und postkapillaren Gefäßdurchmesser der retinalen Mikrozirkulation anhand einer optischen Fundusaufnahme. Bei der dynamischen retinalen Gefäßanalyse wird der Längsschnitt eines retinalen Gefäßes nicht invasiv funktionell und strukturell über einen Zeitraum vor, während und nach einer spezifischen vaskulären Stimulation untersucht. Die genaue Methodologie der Auswertung und die Bezeichnung der Parameter variieren bei unterschiedlichen Ansätzen. Mittels retinaler Gefäßanalyse wurden bislang mehrere klinische Querschnitts- und Interventionsstudien in der Augenheilkunde und anderen Fachgebieten, inkl. Kardiologie, Neurologie, Neurochirurgie, Nephrologie, Gynäkologie, Sportmedizin, Diabetologie, Hypertensiologie usw. durchgeführt. Mit der statischen retinalen Gefäßanalyse steht eine kostengünstige, reproduzierbare, nicht invasive Screeningtechnik zur Verfügung, um eine prognostische Aussage über die Gefäßgesundheit eines individuellen Patienten zu treffen. Die dynamische retinale Gefäßanalyse besitzt ein weiteres diagnostisches Anwendungsspektrum als die statische, da sie das Verhalten retinaler Gefäße zeitkontinuierlich untersucht. Die Evaluation vaskulärer Erkrankungen sowie zerebro- bzw. kardiovaskulärer Morbidität und Mortalität mittels mehrerer methodologischer Modalitäten retinaler Gefäßanalyse mit ihren jeweiligen quantitativen Biomarkern bietet eine zukunftsträchtige diagnostische Perspektive. Die interdisziplinäre klinische Anwendung dieser vaskulären Biomarker gewinnt zunehmend an Bedeutung, sowohl in der Augenheilkunde als auch in anderen Fachgebieten.
Bleilevens, Christian ; Hill, Aileen ; Grzanna, Tim ; Fechter, Tamara ; Bohnen, Melanie ; Weber, Hans-Joachim ; Beckers, Christian ; Borosch, Sebastian ; Zayat, Rashad ; Benstoem, Carin ; Rossaint, Rolf ; Goetzenich, Andreas
BACKGROUND: Muscle stretch reflexes are widely considered to beneficially influence joint stability and power generation in the lower limbs. While in the upper limbs and especially in the muscles surrounding the shoulder joint such evidence is lacking. OBJECTIVE: To quantify the electromyographical response in the muscles crossing the shoulder of specifically trained overhead athletes to an anterior perturbation force. METHODS: Twenty healthy male participants performed six sets of different external shoulder rotation stretches on an isokinetic dynamometer over a range of amplitudes and muscle pre-activation moment levels. All stretches were applied with a dynamometer acceleration of 10,000∘/s2 and a velocity of 150∘/s. Electromyographical response was measured via sEMG. RESULTS: Consistent reflexes were not observed in all experimental conditions. The reflex latencies revealed a significant muscle main effect (F (2,228) = 99.31, p< 0.001; η2= 0.466; f= 0.934) and a pre-activation main effect (F (1,228) = 142.21, p< 0.001; η2= 0.384; f= 1.418). The stretch reflex amplitude yielded a significant pre-activation main effect (F (1,222) = 470.373, p< 0.001; η2= 0.679; f= 1.454). CONCLUSION: Short latency muscle reflexes showed a tendency to an anterior to posterior muscle recruitment whereby the main internal rotator muscles of the shoulder revealed the most consistent results.
After a liver tumor intervention the medical doctor has to compare both pre and postoperative CT acquisitions to ensure that all carcinogenic cells are destroyed. A correct assessment of the intervention is of vital importance, since it will reduce the probability of tumor recurrence. Some methods have been proposed to support the medical doctors during the assessment process, however, all of them focus on secondary tumors. In this paper a tool is presented that enables the outcome validation for both primary and secondary tumors. Therefore, a multiphase registration (preoperative arterial and portal phases) followed by a registration between the pre and postoperative CT images is carried out. The first registration is in charge of the primary tumors that are only visible in the arterial phase. The secondary tumors will be incorporated in the second registration step. Finally, the part of the tumor that was not covered by the necrosis is quantified and visualized. The method has been tested in 9 patients, with an average registration error of 1.41 mm.
This Research Briefing, issued in July 2010, concluded that:
- Small and medium-sized enterprises (SMEs) in Europe have long called for a matching legal form valid across the EU (similar to that of the European company (SE) for large firms)
- The main benefits would be the availability of uniform Europe-wide company structures, significant cost reductions for businesses and further integration of the internal market
- Given the differing national views regarding the concrete features of the new legal form there is currently no sign of an agreement being reached at the European level in the short term; however, it is possible that progress will be made in negotiations during the year
- The key issues being discussed in depth are company formation, transnationality and employee participation rights in the new European private company (SPE).
Wenn durch innovative, automatisierte Güterwagen betriebswirtschaftliche Vorteile nutzbar gemacht werden sollen, muss die Migration auf das neue System in sinnvollen Teilschritten unter Berücksichtigung der organisationellen und betrieblichen Vereinbarkeit vorgenommen werden. Eine stufenweise Migration mit Nachrüstbarkeit und Kompatibilität kann die optimale Ausstattungsvariante für die unterschiedlichen Betriebsszenarien sowie eine Steigerung der Wirtschaftlichkeit des Gesamtsystems bieten.
For smaller railway operators or those with a diverse fleet, it can be difficult to collect sufficient data to improve maintenance programs. At the same time, new rules such as entity in charge of maintenance – ECM – regulations impose an additional workload by requiring a dedicated maintenance management system and specific reports. The RailCrowd platform sets out to facilitate compliance with ECM and similar regulations while at the same time pooling anonymised fleet data across operators to form virtual fleets, providing greater data insights.
Vor dem Hintergrund zunehmender gesellschaftlicher Veränderungen bei den Lebens- und Familienformen hat es sich die Commission on European Family Law (CEFL) seit 2001 zum Ziel gesetzt, unverbindliche Regelungsvorschläge für ein europaweit einheitliches Familienrecht zu schaffen. Die Vorstellung und Diskussion dieser auf rechtsvergleichender Basis erstellten Principles erfolgt auf den regelmäßig veranstalteten Tagungen der CEFL. Die nunmehr fünfte Konferenz zum Thema „Family Law and Culture in Europe – Developments, Challenges and Opportunities“ fand erstmals in Deutschland statt. Ausgerichtet wurde die Veranstaltung, zu der ca. 200 Teilnehmerinnen und Teilnehmern aus Wissenschaft und Praxis aus insgesamt 33 Ländern angereist waren, von Nina Dethloff (Direktorin des Instituts für Deutsches, Europäisches und Internationales Familienrecht an der Universität Bonn), Katharina Boele-Woelki (Direktorin des Utrecht Centre for European Research into Family Law und Preisträgerin des Anneliese Maier-Forschungspreises der Alexander von Humboldt-Stiftung) und Werner Gephart (Direktor des Käte Hamburger Kollegs „Recht als Kultur“).
Bereits 2015 wurde in der Zeitschrift „Qualität in der Wissenschaft“ (QiW) über das Kooperationsprojekt „Guter Studienstart im Ingenieurbereich“, das Orientierungssemester von RWTH und FH Aachen, berichtet. In diesem Artikel legen wir den Schwerpunkt auf die Entwicklung des Projekts in den Jahren 2015 bis 2018 und geben eine Rückschau sowie einen Ausblick auf die Entwicklungsperspektiven nach dem offiziellen Projektende.
Does stiffer electoral competition reduce political shirking? For a micro-analysis of this question, I construct a new data set spanning the years 2005 to 2012 covering biographical and political information about German Members of Parliament (MPs), including their attendance rates in voting sessions. For the parliament elected in 2009, I show that indeed opposition party MPs who expect to face a close race in their district show significantly and relevantly lower absence rates in parliament beforehand. MPs of governing parties seem not to react significantly to electoral competition. These results are confirmed by an analysis of the parliament elected in 2005, by several robustness checks, and also by employing an instrumental variable strategy exploiting convenient peculiarities of the German electoral system. The study also shows how MPs elected via party lists react to different levels of electoral competition.
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.
Kearney, D. ; Herrmann, Ulf ; Nava, P. ; Kelly, B. ; Mahoney, R. ; Pacheco, J. ; Cable, R. ; Potrovitza, N. ; Blake, D. ; Price, H.