@article{ChubanovFerioliWisnowskyetal.2016, author = {Chubanov, Vladimir and Ferioli, Silvia and Wisnowsky, Annika and Simmons, David G. and Leitzinger, Christin and Einer, Claudia and Jonas, Wenke and Shymkiv, Yuriy and Gudermann, Thomas and Bartsch, Harald and Braun, Attila and Akdogan, Banu and Mittermeier, Lorenz and Sytik, Ludmila and Torben, Friedrich and Jurinovic, Vindi and van der Vorst, Emiel P. C. and Weber, Christian and Yildirim, {\"O}nder A. and Sotlar, Karl and Sch{\"u}rmann, Annette and Zierler, Susanna and Zischka, Hans and Ryazanov, Alexey G.}, title = {Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival}, series = {eLife}, volume = {5}, journal = {eLife}, doi = {10.7554/eLife.20914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164987}, pages = {e19686}, year = {2016}, abstract = {Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.}, language = {en} } @phdthesis{Weber2020, author = {Weber, Christian}, title = {Evaluation eines Trainingsmodells f{\"u}r die perkutane Koronarintervention}, doi = {10.25972/OPUS-20012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200124}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Eine fundierte Ausbildung ist in der interventionellen Kardiologie essentiell, um die teilweise komplexen Prozeduren erfolgreich und sicher durchf{\"u}hren zu k{\"o}nnen. Bei der perkutanen Koronarintervention (PCI) k{\"o}nnen u.a. Fehler beim Handling des F{\"u}hrungsdrahtes auftreten. So kann es einerseits zum Drahtverlust, andererseits zur distalen Koronargef{\"a}ßperforation kommen. Daher ist es sinnvoll, die Technik des Katheterwechsels ohne inad{\"a}quate Drahtbewegung vor der ersten Intervention im Herzkatheterlabor am Modell zu trainieren. F{\"u}r diesen Zweck wurde der DACH-BOSS-Simulator entwickelt, an dem der Katheterwechsel trainiert werden kann. Die Validit{\"a}t des Modells wurde im Rahmen einer Studie bei 10 Medizinstudenten (S) sowie 10 angehenden interventionellen Kardiologen (F) untersucht. Jeder Teilnehmer f{\"u}hrte eine Trainingsreihe bestehend aus 25 Prozeduren durch. Um den Trainingseffekt zu ermitteln, wurden die mittleren Punktzahlen der ersten 3 und der letzten 3 Prozeduren jedes Probanden in der Studenten- und Fortgeschrittenengruppe verglichen. Zur Bestimmung der Konstruktvalidit{\"a}t f{\"u}hrte eine dritte Gruppe von 5 Experten (E, > 1000 PCIs) jeweils 3 Prozeduren durch. Ausmaß der Drahtbewegung und ben{\"o}tigte Zeit wurden mit Punkten bewertet und als Skills score dargestellt. Bei den ersten 3 Prozeduren erzielten die Experten signifikant h{\"o}here Werte als die Studenten oder die Fortgeschrittenengruppe (E: 12,9±1,0; S: 7,1±2,6, p = 0,001; F: 8,3±2,0; p = 0,001; Mann-Whitney-U). Anf{\"a}nger und Fortgeschrittene durchliefen w{\"a}hrend der 25 Trainingsprozeduren eine Lernkurve; im Mittel verbesserte sich die Studentengruppe von 7,1±2,6 auf 12,2±2 (p=0,007, Wilcoxon) und die Fortgeschrittenengruppe von 8,3±2,0 auf 13,2±1,0 (p = 0,005, Wilcoxon). Der DACH-BOSS-Simulator stellt somit ein valides Modell zum Training des Katheterwechsels ohne inad{\"a}quate Drahtbewegung dar. Angehende interventionelle Kardiologen k{\"o}nnen diesen wichtigen Schritt der Prozedur am Modell trainieren und erlernen. Ob die am Simulator erworbenen F{\"a}higkeiten auf die klinische Prozedur {\"u}bertragbar sind, muss in weiteren Studien untersucht werden.}, subject = {Simulation}, language = {de} } @article{SoehnleinDrechslerDoeringetal.2013, author = {Soehnlein, Oliver and Drechsler, Maik and D{\"o}ring, Yvonne and Lievens, Dirk and Hartwig, Helene and Kemmerich, Klaus and Ortega-G{\´o}mez, Almudena and Mandl, Manuela and Vijayan, Santosh and Projahn, Delia and Garlichs, Christoph D. and Koenen, Rory R. and Hristov, Mihail and Lutgens, Esther and Zernecke, Alma and Weber, Christian}, title = {Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes}, series = {EMBO Molecular Medicine}, volume = {5}, journal = {EMBO Molecular Medicine}, issn = {1757-4676}, doi = {10.1002/emmm.201201717}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122204}, pages = {471-481}, year = {2013}, abstract = {We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.}, language = {en} } @phdthesis{Weber2015, author = {Weber, Christian}, title = {Electrochemical Energy Storage: Carbon Xerogel-Manganese Oxide Composites as Supercapacitor Electrode Materials}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130748}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Electrochemical double layer capacitors (EDLC), most commonly referred to as "supercapacitors", have gained increasing scientific and commercial interest in recent years. Purely electrostatic charge storage processes allow charge- and discharge cycles in the second-time scale, exhibiting a theoretical capacitance in the order of 100 F per gram of electrode material, thereby providing efficient recuperation devices for electromechanical processes, for example. Introducing electrochemically active materials such as manganese oxides into the supercapacitor electrode, allows to combine the double-layer storage with a battery-like storage process, leading to capacitance that can be up to two orders of magnitude larger than those in EDLC. In the present work, an electroless deposition approach of manganese oxide on a carbon scaffold is adapted and further investigated. The carbon material is derived from an organic xerogel, which in turn is prepared via a sol-gel process, allowing tailoring of the structural properties of the carbon, making it an ideal model system to study the relation between morphology and electrochemical performance in the carbon-manganese oxide hybrid electrode. In the first part of this thesis, a variation of manganese oxide deposition time at a low concentration of precursor solution is analyzed. Mass uptakes reach up to 58 wt.\%, leading to an increase of volumetric capacitance by a factor 5, however reducing the dynamic performance of the electrode. The structural characterization gives hints on the deposition location of the active material either in the intra-particular pores of the carbon backbone or on the enveloping surface area of the particles forming the backbone. In order to comprehensively answer the question of the location of the active material within the hybrid electrode, the particle size of the carbon backbone and therefore the enveloping surface area of the carbon particles was varied. For samples with high mass uptakes, scanning electron microscopy (SEM) images show a layer thickness of 27 nm of active material around the carbon particles. In order to quantitatively investigate this layer morphology, even for low mass uptakes where no layer is visible in SEM images, a model interpreting data from anomalous small angle X-ray scattering (ASAXS) measurements was developed. The results confirm the presence of a layer around the carbon particles, exhibiting a layer thickness ranging from 3 to 26 nm. From an electrochemical point of view, carbon backbones with a large enveloping surface area will lead to high mass uptakes in the electroless deposition process and therefore lead to high capacitance of the electrode. However, for future application, electrodeposition approaches should be investigated in detail, since no deposits will form on the interface between carbon backbone and current collector, leading to a better dynamic performance of the hybrid electrode. Furthermore, the ASAXS-method should be promoted and applied on other material systems, since this technique allows to draw important conclusions and allows to deduce integral and quantitative information towards a rational design of high performance electrodes.}, subject = {Superkondensator}, language = {en} } @article{ProjahnSimsekyilmazSinghetal.2014, author = {Projahn, Delia and Simsekyilmaz, Sakine and Singh, Smriti and Kanzler, Isabella and Kramp, Birgit K. and Langer, Marcella and Burlacu, Alexandrina and Bernhagen, J{\"u}rgen and Klee, Doris and Zernecke, Alma and Hackeng, Tilman M. and Groll, J{\"u}rgen and Weber, Christian and Liehn, Elisa A. and Koenen, Roy R.}, title = {Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction}, series = {Journal of Cellular and Molecular Medicine}, volume = {18}, journal = {Journal of Cellular and Molecular Medicine}, number = {5}, issn = {1582-4934}, doi = {10.1111/jcmm.12225}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116597}, pages = {790-800}, year = {2014}, abstract = {Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies.}, language = {en} } @article{TilstamGijbelsHabbeddineetal.2014, author = {Tilstam, Pathricia V. and Gijbels, Marion J. and Habbeddine, Mohamed and Cudejko, Celine and Asare, Yaw and Theelen, Wendy and Zhou, Baixue and D{\"o}ring, Yvonne and Drechsler, Maik and Pawig, Lukas and Simsekyilmaz, Sakine and Koenen, Rory R. and de Winther, Menno P. J. and Lawrence, Toby and Bernhagen, J{\"u}rgen and Zernecke, Alma and Weber, Christian and Noels, Heidi}, title = {Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {2}, doi = {10.1371/journal.pone.0087452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117450}, pages = {e87452}, year = {2014}, abstract = {Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach.}, language = {en} } @phdthesis{Weber2005, author = {Weber, Christian}, title = {Bedeutung des Her-2/neu beim Ovarialkarzinom - Korrelation und Vergleich mit klinischen Prognosefaktoren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-15611}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {In der vorgelegten Arbeit werden klinische Prognosefaktoren des Ovarialkarzinoms an einem Kollektiv von 105 Patientinnen untersucht, die in den Jahren 1996 bis 1998 in der Universit{\"a}ts-Frauenklinik W{\"u}rzburg behandelt wurden. Zudem wird eine immunhistochemische Bestimmung des Her-2/neu - Status vorgenommen, der beim Mamma-Karzinom als unabh{\"a}ngiger Prognosefaktor bekannt ist und mit einer schlechteren Prognose einhergeht. Zusammenfassend ließ sich in dieser Arbeit keine {\"U}berexpression des Her-2/neu am Ovar feststellen, eine unabh{\"a}ngige prognostische Relevanz muß aus unserer Sicht verneint werden.}, language = {de} } @article{SimsekyilmazLiehnWeinandyetal.2016, author = {Simsekyilmaz, Sakine and Liehn, Elisa A. and Weinandy, Stefan and Schreiber, Fabian and Megens, Remco T. A. and Theelen, Wendy and Smeets, Ralf and Jockenh{\"o}vel, Stefan and Gries, Thomas and M{\"o}ller, Martin and Klee, Doris and Weber, Christian and Zernecke, Alma}, title = {Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179745}, year = {2016}, abstract = {Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE\(^{-/-}\) carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.}, language = {en} } @article{ButtStempfleListeretal.2020, author = {Butt, Elke and Stempfle, Katrin and Lister, Lorenz and Wolf, Felix and Kraft, Marcella and Herrmann, Andreas B. and Viciano, Cristina Perpina and Weber, Christian and Hochhaus, Andreas and Ernst, Thomas and Hoffmann, Carsten and Zernecke, Alma and Frietsch, Jochen J.}, title = {Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia}, series = {Cells}, volume = {9}, journal = {Cells}, number = {2}, issn = {2073-4409}, doi = {10.3390/cells9020444}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200638}, year = {2020}, abstract = {The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.}, language = {en} }