@phdthesis{Saal2017, author = {Saal, Lena}, title = {Whole transcriptome profiling of compartmentalized motoneurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140006}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are the two most common devastating motoneuron diseases. The mechanisms leading to motoneuron degeneration are not resolved so far, although different hypotheses have been built on existing data. One possible mechanism is disturbed axonal transport of RNAs in the affected motoneurons. The underlying question of this study was therefore to characterize changes in transcript levels of distinct RNAs in cell culture models of spinal muscular atrophy and amyotrophic lateral sclerosis, especially in the axonal compartment of primary motoneurons. To investigate this in detail we first established compartmentalized cultures of Primary mouse motoneurons. Subsequently, total RNA of both compartments was extracted separately and either linearly amplified and subjected to microarray profiling or whole transcriptome amplification followed by RNA-Sequencing was performed. To make the whole transcriptome amplification method suitable for compartmentalized cultures, we adapted a double-random priming strategy. First, we applied this method for initial optimization onto serial dilutions of spinal cord RNA and later on to the compartmentalized motoneurons. Analysis of the data obtained from wildtype cultures already revealed interesting results. First, the RNA composition of axons turned out to be highly similar to the somatodendritic compartment. Second, axons seem to be particularly enriched for transcripts related to protein synthesis and energy production. In a next step we repeated the experiments by using knockdown cultures. The proteins depleted hereby are Smn, Tdp-43 and hnRNP R. Another experiment was performed by knocking down the non-coding RNA 7SK, the main interacting RNA of hnRNP R. Depletion of Smn led to a vast number of deregulated transcripts in the axonal and somatodendritic compartment. Transcripts downregulated in the axons upon Smn depletion were especially enriched for GOterms related to RNA processing and encode proteins located in neuron projections including axons and growth cones. Strinkingly, among the upregulated transcripts in the somatodendritic compartment we mainly found MHC class I transcripts suggesting a potential neuroprotective role. In contrast, although knockdown of Tdp-43 also revealed a large number of downregulated transcripts in the axonal compartment, these transcripts were mainly associated with functions in transcriptional regulation and RNA splicing. For the hnRNP R knockdown our results were again different. Here, we observed downregulated transcripts in the axonal compartment mainly associated with regulation of synaptic transmission and nerve impulses. Interestingly, a comparison between deregulated transcripts in the axonal compartment of both hnRNP R and 7SK knockdown presented a significant overlap of several transcripts suggesting some common mechanism for both knockdowns. Thus, our data indicate that a loss of disease-associated proteins involved in axonal RNA transport causes distinct transcriptome alterations in motor axons.}, subject = {Axon}, language = {en} } @phdthesis{Zimnol2017, author = {Zimnol, Anna}, title = {Relevance of angiotensin II type 1a receptor and NADPH oxidase for the formation of angiotensin II-mediated DNA damage}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137469}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Das Renin-Angiotensin-Aldosteron-System (RAAS) reguliert den Blutdruck sowie den Elektrolyt- und Wasserhaushalt. Das aktive Peptid, Angiotensin II (AngII), f{\"u}hrt dabei zur Vasokonstriktion und in h{\"o}heren Konzentrationen zu Bluthochdruck. Hypertensive Patienten haben ein erh{\"o}htes Risiko an Krebs zu erkranken, vor allem an Nierenkrebs. Wir konnten bereits in vivo zeigen, dass AngII in der Lage ist, den Blutdruck zu steigern und dosisabh{\"a}ngig zu DNA-Sch{\"a}den {\"u}ber den Angiotensin II Typ 1-Rezeptor (AT1R) f{\"u}hrt. Ein stimuliertes RAAS kann ferner {\"u}ber die Aktivierung der NADPH-Oxidase, einer Hauptquelle der Generierung reaktiver Sauerstoffspezies (ROS) in der Zelle, zu oxidativem Stress f{\"u}hren. Zielsetzung dieser Arbeit war es zum einen, mit Hilfe von AT1a-Rezeptor-defizienten M{\"a}usen in vivo zu pr{\"u}fen, ob die Bildung von ROS, sowie die Bildung von DNA-Sch{\"a}den in der Niere und im Herzen unabh{\"a}ngig von einem erh{\"o}hten Blutdruck auftreten. Zum anderen sollte, ebenfalls in vivo, untersucht werden, ob eine oder beide von zwei untersuchten Isoformen der NADPH-Oxidase (Nox) f{\"u}r die Ausl{\"o}sung oxidativen Stresses in der Niere verantwortlich ist. Zun{\"a}chst wurden f{\"u}r den Versuch zur {\"U}berpr{\"u}fung der Abh{\"a}ngigkeit AngII-induzierter DNA-Sch{\"a}den vom Blutdruck m{\"a}nnliche C57BL/6-M{\"a}use und AT1a-Knockout (KO)-M{\"a}use mit osmotischen Minipumpen ausgestattet, die AngII in einer Konzentrationen von 600 ng/kg min {\"u}ber einen Zeitraum von 28 Tagen abgaben. Zus{\"a}tzlich wurde eine Gruppe von AngII-behandelten Wildtyp (WT)-M{\"a}usen mit dem AT1-Rezeptor-Blocker Candesartan (Cand) behandelt. W{\"a}hrend des Versuchszeitraumes fanden regelm{\"a}ßige, nicht-invasive Blutdruckmessungen an den wachen M{\"a}usen statt. In WT-M{\"a}usen induzierte AngII Bluthochdruck, verursachte erh{\"o}hte Albumin-Level im Urin und f{\"u}hrte zur Bildung von ROS in Niere und im Herzen. Außerdem traten in dieser Gruppe DNA-Sch{\"a}den in Form von Einzel- und Doppelstrangbr{\"u}chen auf. All diese Reaktionen auf AngII konnten jedoch durch gleichzeitige Behandlung mit Cand verhindert werden. AT1a-KO-M{\"a}use hatten, verglichen mit WT-Kontrollm{\"a}usen, einen signifikant niedrigeren Blutdruck und normale Albumin-Level im Urin. In AT1a-KO-M{\"a}usen, die mit AngII behandelt wurden, konnte kein Anstieg des systolischen Blutdrucks sowie kein Einfluss auf die Nierenfunktion gefunden werden. Jedoch f{\"u}hrte AngII in dieser Gruppe zu einer Steigerung von ROS in der Niere und im Herzen. Zus{\"a}tzlich wurden genomische Sch{\"a}den, vor allem in Form von Doppelstrangbr{\"u}chen signifikant in dieser Gruppe induziert. Auch wenn AT1a-KO-Tiere, unabh{\"a}ngig von einer AngII-Infusion, keine eingeschr{\"a}nkte Nierenfunktion zeigten, so wiesen sie erhebliche histopathologische Sch{\"a}den im Hinblick auf die Glomeruli und das Tubulussystem auf. Diese Art von Sch{\"a}den deuten auf eine besondere Bedeutung des AT1aR im Hinblick auf die embryonale Entwicklung der Niere hin. Zusammenfassend beweisen die Ergebnisse dieses Experiments eindeutig, dass eine AngII-induzierte ROS-Produktion und die Induktion von DNA-Sch{\"a}den unabh{\"a}ngig von einem erh{\"o}hten Blutdruck auftreten. Da in der AngII-behandelten AT1a-KO-Gruppe eine signifikant h{\"o}here Expression des AT1b-Rezeptors zu finden war und die Blockade von beiden Rezeptorsubtypen mit Cand zu einer Verhinderung der sch{\"a}dlichen Effekte durch AngII f{\"u}hrte, scheint der AT1bR im Falle einer AT1aR-Defizienz f{\"u}r die Entstehung der Sch{\"a}den zust{\"a}ndig zu sein. Ziel des zweiten Experimentes war es, den Beitrag der Nox2 und Nox4 zum oxidativen DNA-Schaden in vivo zu untersuchen. Hierf{\"u}r wurden m{\"a}nnliche C57BL/6-M{\"a}use und Nox2- oder Nox4-defiziente M{\"a}use mit osmotischen Minipumpen ausgestattet, die AngII in einer Konzentration von 600 ng/kg min {\"u}ber einen Zeitraum von 28 Tagen abgaben. Im WT-Stamm und in beiden Nox-defizienten St{\"a}mmen induzierte AngII Bluthochdruck, verursachte erh{\"o}hte Albumin-Level im Urin und f{\"u}hrte zur Bildung von ROS in der Niere. Außerdem waren in allen AngII-behandelten Gruppen genomische Sch{\"a}den, vor allem in Form von Doppelstrangbr{\"u}chen, erh{\"o}ht. Auch in Abwesenheit von AngII wiesen Nox2- und Nox4-defiziente M{\"a}use mehr Doppelstrangbr{\"u}che im Vergleich zu WT-Kontrollm{\"a}usen auf. Interessanterweise kompensieren allerdings weder Nox2 noch Nox4 das Fehlen der jeweils anderen Isoform auf RNA-Basis. Aufgrund dieser Ergebnisse schließen wir, dass bislang keine Isoform alleine f{\"u}r die Generierung von oxidativen DNA-Sch{\"a}den in der Niere verantwortlich gemacht werden kann und dass eine Beteiligung einer weiteren Nox-Isoform sehr wahrscheinlich ist. M{\"o}glicherweise k{\"o}nnten aber auch andere ROS-generierende Enzyme, wie Xanthinoxidase oder Stickoxidsynthase involviert sein. Da genomische Sch{\"a}den in Nieren von Nox2- und Nox4-defizienten M{\"a}usen in Abwesenheit von AngII gegen{\"u}ber den Sch{\"a}den in WT-Kontrollm{\"a}usen erh{\"o}ht waren, k{\"o}nnten die beiden Isoformen auch eine sch{\"u}tzende Funktion im Bereich von Nierenkrankheiten {\"u}bernehmen. Da dies aber bislang nur f{\"u}r Nox4 beschrieben ist, ist es wahrscheinlicher, dass das Fehlen von einer der beiden Isoformen eher einen Einfluss auf die Embryonalentwicklung hat. Um dies jedoch abschließend zu kl{\"a}ren w{\"a}re es sinnvoll mit induzierbaren Knockout-Modellen zu arbeiten, bei denen m{\"o}gliche entwicklungsbedingte Effekte minimiert werden k{\"o}nnen.}, subject = {Angiotensin II}, language = {de} } @phdthesis{Nashed2017, author = {Nashed, Alexander}, title = {Entwicklung spinnf{\"a}higer Precursorpolymere zur Herstellung nicht-oxidischer Keramikfasern}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138517}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Ausgehend von chlorhaltigem Oligosilan, erhalten durch Disproportionierung der „Disilan-Fraktion" der M{\"u}ller-Rochow-Synthese, wurde mit verschiedenen Aminen dechloriert bzw. strukturell modifiziert. Die auf diese Weise in das Oligosilan eingef{\"u}hrten Baugruppen wurden spektroskopisch und durch Vergleich mit geeigneten Modellverbindungen identifiziert. Vernetzungsgrad und keramische Ausbeute der erzeugten Materialen wurden bestimmt. Mit Ammoniak oder einwertigen Aminen wie Methylamin werden Produkte erhalten, die sich nicht zu Keramikfasern verarbeiten lassen. Letzteres scheitert daran, dass entweder keine signifikante Molekulargewichtserh{\"o}hung des Oligosilans erreicht wird, oder f{\"u}hrt dazu, dass das Oligomer vergelt und damit in Toluol unl{\"o}slich wird. Durch Umsetzung des Oligosilans mit zweiwertigen Aminen wie EDA oder TMDA als Vernetzungsreagenz gelang es, eine Syntheseroute zu entwickeln, die - anders als bei der am ISC etablierten Route - keinen thermischen Vernetzungsschritt erfordert, d.h. die gesamte Synthese findet bei Temperaturen ≤200 °C statt. Hierbei wird eine kontrollierbare Erh{\"o}hung des Molekulargewichts erreicht. Die Verwendung von TMDA hat gegen{\"u}ber EDA den Vorteil, dass aufgrund des Ausbleibens von Ringbildung ein h{\"o}her vernetztes Polymer erhalten wird. Dar{\"u}ber hinaus wurde gefunden, dass Gr{\"u}nfasern w{\"a}hrend der Pyrolyse durch radikalisch vernetzbare Gruppen (C=C-Doppelbindungen) im Polymer stabilisiert werden k{\"o}nnen. Diese Gruppen lassen sich entweder durch Dechlorierung mit Allylamin oder durch Umsetzung mit Vinyl-Grignard-Reagenzien einf{\"u}hren. Allylamin erwies sich hierbei als geeigneter, da es preiswerter und leichter handhabbar ist und außerdem - im Gegensatz zu Vinyl-Grignard-Reagenzien - eine vollst{\"a}ndige Dechlorierung des Polymers gestattet. Alle Polymere wurden auf ihre Verarbeitbarkeit zu Gr{\"u}n- und anschließend zu Keramikfasern untersucht. Hierbei wurde gefunden, dass die im Hinblick auf die Eigenschaften der resultierenden Keramikfasern g{\"u}nstigste Rezeptur in der Umsetzung eines zuvor mit DMA vollst{\"a}ndig dechlorierten Oligosilans mit 18,2 mol-\% TMDA und 40 mol-\% Allylamin (bezogen auf NMe2-Gruppen) besteht. Die aus diesem Polymer erhaltenen Keramikfasern zeigen die f{\"u}r noch nicht technisch ausgereifte, im Stadium der Entwicklung befindliche Fasern typischen Festigkeiten und entsprechen damit denjenigen, die auf der am ISC bereits etablierten Route erh{\"a}ltlich sind. Dies macht sie zu aussichtsreichen Kandidaten f{\"u}r die weitere Optimierung.}, subject = {Keramikfaser}, language = {de} } @phdthesis{Rueth2017, author = {R{\"u}th, Sebastian}, title = {Monetary Policy, Housing Market Dynamics, and the Propagation of Shocks}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137221}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {This dissertation studies the interrelations between housing markets and monetary policy from three different perspectives. First, it identifies housing finance specific shocks and analyzes their impact on the broader economy and, most importantly, the systematic monetary policy reaction to such mortgage sector disturbances. Second, it investigates the implications of the institutional arrangement of a currency union for the potential buildup of a housing bubble in a member country of the monetary union by, inter alia, fostering border-crossing capital flows and ultimately residential investment activity. This dissertation, third, quantifies the effects of autonomous monetary policy shifts on the macroeconomy and, in particular, on housing markets by conditioning on financial sector conditions. From a methodological perspective, the dissertation draws on time-series econometrics like vector autoregressions (VARs) or local projections models.}, subject = {Geldpolitik}, language = {en} } @phdthesis{Gabor2017, author = {Gabor, Sabine}, title = {Pr{\"a}klinische Evaluation von Aldosteronsynthaseinhibitoren als PET-Tracer f{\"u}r die Differentialdiagnostik des prim{\"a}ren Hyperaldosteronismus mit besonderem Fokus auf Cyanofluorphenylpyridinen und deren Derivate}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Zusammenfassend l{\"a}sst sich festhalten, dass in dieser Arbeit 15 neu entwickelte Substanzen zur selektiven und hochaffinen Blockade der Aldosteronsynthase untersucht werden konnten. Es wurden mehrere neue aufeinander aufbauende Testsysteme etabliert, um die neuen Substanzen auf ihre Selektivit{\"a}t und Affinit{\"a}t gegen{\"u}ber der Aldosteronsynthase zu untersuchen. Eine Testung der Inhibition der humanen Aldosteronsynthase und der 11β-Hydroxylase zuerst in getrennten Zellkulturans{\"a}tzen, die die humanen Enzyme stabil exprimieren, und anschließend in der NCI-h295 Zelllinie, die beide Enzyme und zus{\"a}tzlich die meisten anderen Enzyme der Steroidbiosynthese stabil exprimieren, ist eine gute Voraussetzung, um selektive und hochaffine Aldosteronsynthaseinhibitoren zu finden. Hier konnten sechs Inhibitoren ausgew{\"a}hlt werden, die hochaffin und selektiv an die Aldosteronsynthase binden und diese inhibieren. Die weitere Testung der [18F] markierten Substanzen zeigte f{\"u}r eine Substanz eine hochaffine und selektive Bindung an humanes adrenales Gewebe und keine unspezifische Bindung an andere humane Gewebe. Hier liegt die Voraussetzung vor, den Tracer weiteren in vivo Studien zuzuf{\"u}hren, um am humanisierten Mausmodell zu untersuchen, ob eine Bindung in vivo entsprechend den vielversprechenden Ergebnissen in vitro abl{\"a}uft. Auch die ex vivo Studie an Nebennieren einer gegen{\"u}ber der CYP11B2 humanisierten Maus bekr{\"a}ftigte diese Ergebnisse. Mit Hilfe dieser Untersuchungsmethoden lassen sich in Zukunft noch weiter entwickelte Substanzen umfangreich auf ihre Selektivit{\"a}t, Spezifit{\"a}t und Affinit{\"a}t testen. Dies dient als Grundlage f{\"u}r weitere Untersuchungen zur Entwicklung eines PET-Tracers f{\"u}r die Differentialdiagnostik bei prim{\"a}rem Hyperaldosteronismus. Eine Erkrankung, die h{\"a}ufiger ist als vermutet, und bei der die Differentialdiagnostik die entscheidende Voraussetzung f{\"u}r die Einleitung einer Therapie ist, die sich entweder operativ oder medikament{\"o}s darstellt. Bisherige differentialdiagnostische Vorgehensweisen beim prim{\"a}ren Hyperaldosteronismus bieten aktuell keine zufriedenstellenden Ergebnisse; dies kann sich mit der Einf{\"u}hrung eines neuen PET Tracers {\"a}ndern.}, subject = {Aldosteronsynthaseinhibitor}, language = {de} } @phdthesis{Rossi2017, author = {Rossi, Angela Francesca}, title = {Development of functionalized electrospun fibers as biomimetic artificial basement membranes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137618}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The basement membrane separates the epithelium from the stroma of any given barrier tissue and is essential in regulating cellular behavior, as mechanical barrier and as structural support. It further plays an important role for new tissue formation, homeostasis, and pathological processes, such as diabetes or cancer. Breakdown of the basement membrane is believed to be essential for tumor invasion and metastasization. Since the basement membrane is crucial for many body functions, the development of artificial basement membranes is indispensable for the ultimate formation of engineered functional tissue, however, challenging due to their complex structure. Electrospinning enables the production of fibers in the nano- or microscale range with morphological similarities to the randomly orientated collagen and elastic fibers in the basement membrane. However, electrospun fibers often lack the functional similarity to guide cells and maintain tissue-specific functions. Hence, their possible applications as matrix structure for tissue engineering are limited. Herein, the potential of polyester meshes, modified with six armed star-shaped pre-polymers and cell-adhesion-mediating peptides, was evaluated to act as functional isotropic and bipolar artificial basement membranes. Thereby, the meshes were shown to be biocompatible and stable including under dynamic conditions, and the degradation profile to correlate with the rate of new tissue formation. The different peptide sequences did not influence the morphology and integrity of the fibers. The modified membranes exhibited protein-repellent properties over 12 months, indicating the long-term stability of the cross-linked star-polymer surfaces. Cell culture experiments with primary fibroblasts and a human keratinocyte cell line (HaCaT) revealed that cell adhesion and growth strongly depends on the peptide sequences and their combinations employed. HaCaT cells grew to confluence on membranes modified with a combination of laminin/collagen type IV derived binding sequences and with a combination of fibronectin/laminin/collagen type IV derived peptide sequences. Fibroblasts strongly adhered to the fibronectin derived binding sequence and to membranes containing a combination of fibronectin/laminin/collagen type IV derived peptide sequences. The adhesion and growth of fibroblasts and HaCaT cells were significantly reduced on membranes modified with laminin, as well as collagen IV derived peptide sequences. HaCaT cells and fibroblasts barely adhered onto meshes without peptide sequences. Co-culture experiments at the air-liquid interface with fibroblasts and HaCaT cells confirmed the possibility of creating biocompatible, biofunctional and biomimetic isotropic and bipolar basement membranes, based on the functionalized fibers. HaCaT cells grew in several layers, differentiating towards the surface and expressing cytokeratin 10 in the suprabasal and cytokeratin 14 in the basal layers. Migration of fibroblasts into the electrospun membrane was shown by vimentin staining. Moreover, specific staining against laminin type V, collagen type I, III, IV and fibronectin illustrated that cells started to remodel the electrospun membrane and produced new extracellular matrix proteins following the adhesion to the synthetic surface structures. The culturing of primary human skin keratinocytes proved to be difficult on electrospun fibers. Cells attached to the membrane, but failed to form a multilayered, well-stratified, and keratinized epidermal layer. Changing the fiber composition and fixation methods did not promote tissue development. Further investigations of the membrane demonstrated the tremendous influence of the pore size of the membrane on epithelial formation. Furthermore, primary keratinocytes reacted more sensitive to pH changes in the medium than HaCaT cells did. Since primary keratinocytes did not adequately develop on the functionalized meshes, polycarbonate membranes were used instead of electrospun meshes to establish oral mucosa models. The tissue-engineered models represented important features of native human oral mucosa. They consisted of a multilayered epithelium with stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. The models formed a physical barrier and the expression of characteristic cell markers was comparable with that in native human oral mucosa. The results from the ET-50 assay and the irritation study reflected the reproducibility of the tissue equivalents. Altogether, electrospinning enables the production of fibers with structural similarity to the basement membrane. Incorporating extracellular matrix components to mimic the functional composition offers a safe and promising way to modify the fibers so that they can be used for different tissue engineering applications. The resultant biomimetic membranes that can be functionalized with binding sequences derived from widely varying proteins can be used as a toolbox to study the influence of isotropic and bipolar basement membranes on tissue formation and matrix remodeling systematically, with regards to the biochemical composition and the influence and importance of mono- and co-culture. The oral mucosa models may be useful for toxicity and permeation studies, to monitor the irritation potential of oral health care products and biomaterials or as a disease model.}, subject = {Tissue Engineering}, language = {en} } @phdthesis{Kunz2017, author = {Kunz, Meik}, title = {Systembiologische Analysen von Interaktionen: Zytokinine (Pflanzenpathogene), 3D-Zellkulturen (Krebstherapie) und Drugtargets}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134911}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Der Einsatz von computergest{\"u}tzten Analysen hat sich zu einem festen Bestandteil der biowissenschaftlichen Forschung etabliert. Im Rahmen dieser vorliegenden Arbeit wurden systembiologische Untersuchungen auf verschiedene biologische Themengebiete und Organismen angewendet. In diesem Zusammenhang liefert die Arbeit einen innovativen und interdisziplin{\"a}ren methodischen Ansatz. Die grundlegende Frage lautet: Wie verstehe und beschreibe ich Signalwege und wie kann ich sie beeinflussen? Der Ansatz verkn{\"u}pft verschiedene biologische Datens{\"a}tze und Datenebenen miteinander, beginnend vom Genom und Interaktionskontext {\"u}ber semiquantitative Simulationen hin zu neuen Interventionen und Experimenten, welche therapeutisch und biotechnologisch genutzt werden k{\"o}nnen. Die Analysen k{\"o}nnen auf diese Weise - zu einem besseren Verst{\"a}ndnis experimenteller Daten und biologischer Fragestellungen beitragen und erm{\"o}glichen ein systematisches Verst{\"a}ndnis der zugrunde liegenden Signalwege und Netzwerkeffekte (z.B. in Pflanzen). - Dar{\"u}ber hinaus erm{\"o}glichen sie die Identifizierung wichtiger funktioneller Hubproteine und die Entwicklung neuer therapeutischer Strategien f{\"u}r weitere experimentelle Testungen (z.B. Tumormodelle), - stellen zudem einen hilfreichen Schritt auf dem Weg zur personalisierten Medizin (z.B. lncRNAs und Tumormodelle) und Medikamentenentwicklung (z.B. Datenbank DrumPID) dar. (i) Als Grundlage wurde hierzu eine integrierte systembiologische Methode entwickelt, welche experimentelle Daten (z.B. Transkriptomdaten) hinsichtlich ihrer biologischen Funktionen untersucht und die Identifizierung relevanter funktioneller Cluster und Hubproteine erm{\"o}glicht. In einem ersten Teil wurden Analysen zum pflanzlichen Immunsystem durchgef{\"u}hrt. Mithilfe der entwickelten Methode wurden Genexpressionsdatens{\"a}tze von A. thaliana, die mit dem Pathogen Pst DC3000 infiziert wurden, untersucht, um den Einfluss verschiedener Virulenzfaktoren auf das Interaktom der Wirtspflanze zu untersuchen und neue Modulatoren einer CK-vermittelten Immunabwehr zu finden. In diesem Zusammenhang konnte gezeigt werden, dass die von Pst DC3000 sekretierten Abwehrstoffe wichtige pflanzliche Hormonsignalwege f{\"u}r die Immunabwehr in A. thaliana beeinflussen. Die Ergebnisse zeigen zudem, dass sich der Einfluss auf das Netzwerkverhalten der Effektorproteine und COR-Phytotoxine von dem der PAMPs unterscheidet, sich jedoch auch eine Regulierung gemeinsamer Signalwege und eine {\"U}berlappung der beiden Phasen der Immunantwort (PTI und ETI) in A. thaliana finden lassen. Die komplexe Immunantwort auf eine Infektion spiegelt sich zudem in einer h{\"o}heren Anzahl an funktionellen Clustern und Hubproteinen in Pst DC3000 gegen{\"u}ber den beiden untersuchten Mutanten wider, wobei sich f{\"u}r Pst DC3000 insbesondere ein stark vernetztes immunrelevantes Cluster um den JA-Signalweg zeigt. Weiterhin wurden anhand der entwickelten Methode wichtige Hubproteine f{\"u}r die Immunabwehr identifiziert. Als bedeutende Vertreter sind AHK2 und AAR14 zu nennen, welche Teil des Zweikomponentensystems der Signal{\"u}bertragung von CK sind und hierbei wichtige Modulatoren f{\"u}r eine CK-vermittelte Immunabwehr darstellen. (ii) Im zweiten Teil der Arbeit schließen sich Untersuchungen an einem in vitro-Experiment einer 2D- und 3D-Zellkultur einer HSP90-Behandlung in einem Lungentumormodell an. In diesem Zusammenhang wurden mithilfe der entwickelten Methode Unterschiede zwischen den beiden Zellkultursystemen gefunden, die das unterschiedliche Behandlungsansprechen erkl{\"a}ren, und f{\"u}r die beiden KRAS-mutierten Zelllinien A549 und H441 des 3D-Testsystems neue prognostische und therapeutische Kandidaten identifiziert. Hierbei haben die durchgef{\"u}hrten Analysen zwei funktionelle Cluster von Protein-Interaktionen um p53 und die STAT-Familie gefunden, welche eine Verbindung zu HSP90 haben und die entsprechenden Behandlungsunterschiede nach einer HSP90-Inhibierung zwischen den beiden Zellkultursystemen erkl{\"a}ren k{\"o}nnen. Unter Ber{\"u}cksichtigung des zelllinien-spezifischen Mutationshintergrunds wurde eine prognostische Markersignatur und daraus abgeleitet HIF1A f{\"u}r die H441-Zelllinie und AMPK f{\"u}r die A549-Zelllinie als neue therapeutische Targets gefunden, wobei die anschließend durchgef{\"u}hrten in silico-Simulationen einen potentiellen therapeutischen Effekt aufzeigen konnten. Weiterhin wurden wichtige experimentelle Readout-Parameter in ein in silico-Lungentumormodell integriert, wobei unter Einbeziehung des Mutationshintergrunds f{\"u}r die verwendeten Zelllinien die HSP90-Behandlung des 3D-Testsystems computergest{\"u}tzt abgebildet werden konnte. Im weiteren Verlauf wurden im in silico-Lungentumormodell Resistenzmechanismen nach einer Gefitinib-Behandlung mit bekanntem Mutationsstatus f{\"u}r die Zelllinien HCC827 und A549 untersucht und daraus folgend neue Therapieans{\"a}tze abgeleitet, die von potentieller klinischer Bedeutung sein k{\"o}nnen. Die durchgef{\"u}hrten in silico-Simulationen f{\"u}r HCC827 konnten hierbei zeigen, dass eine EGFR- und c-MET-Koaktivierung zu einer Gefitinib-Resistenz f{\"u}hren kann, wohingegen bei den A549 eine Komutation von KRAS und IGF-1R zu einem geringen Behandlungsansprechen beitr{\"a}gt. Die Simulationen lassen zudem erkennen, dass eine direkte Inhibierung der an der Resistenzentwicklung beteiligten Rezeptoren c-MET und IGF-1R in beiden F{\"a}llen nicht die bestm{\"o}gliche Therapiestrategie darstellt. In beiden Zelllinien konnte gezeigt werden, dass eine kombinierte Inhibierung von PI3K und MEK den bestm{\"o}glichen therapeutischen Effekt liefert, was demnach einen vielversprechenden Therapieansatz bei Gefitinib-resistenten Lungentumorpatienten darstellt. In einem weiteren Schritt wurde das therapeutische Potential der miRNA-21 im in silico-Modell f{\"u}r die HCC827-Zelllinie untersucht. Die durchgef{\"u}hrten Simulationen zeigen, dass eine miRNA-21-{\"U}berexpression zu einer Resistenzentwickung nach Gefitinib-Behandlung beitragen kann, wobei eine Inhibierung der miRNA-21 diesen Effekt umkehren kann. Die Ergebnisse lassen zudem erkennen, dass eine PTEN-Aktivierung als potentieller Marker einer erfolgreichen therapeutischen Inhibierung der miRNA-21 fungieren kann, wohingegen eine reduzierte miRNA-21-Expression als m{\"o}glicher Marker f{\"u}r eine erfolgreiche Gefitinib-Behandlung dienen kann. (iii) Im dritten Teil der Arbeit wurden systematisch RNA- und Protein-Interaktionen untersucht. Hierzu wurden integrierte systembiologische Analysen an neu identifizierten und funktionell bislang unbekannten lncRNAs durchgef{\"u}hrt. Die Analysen f{\"u}r die infolge einer Herzhypertrophie hochregulierte lncRNA Chast haben umfassend gezeigt, dass diese Proteine und Transkriptionsfaktoren regulieren und binden kann, welche die Signal{\"u}bertragung und Genexpression regulieren, aber auch eine Verbindung zum kardiovaskul{\"a}ren System und stressinduzierter Herzhypertrophie besitzt. Anhand der Ergebnisse l{\"a}sst sich schlussfolgern, dass Chast direkt und indirekt (a) Proteine binden und die Translation beeinflussen kann, zudem eine Chromatin-modifizierende Funktion besitzt und so die Transkription, z.B. f{\"u}r herz- und stress-assoziierte Gene, reguliert, und/oder (b) in einem negativen Feedbackloop seine eigene Transkription reguliert. Obwohl lncRNAs meist eine geringe Konservierung aufweisen, konnten die durchgef{\"u}hrten Analysen f{\"u}r Chast eine Sequenz-Struktur-Konservierung in S{\"a}ugetieren aufzeigen. Weiterhin haben die Untersuchungen an zwei hypoxie-induzierten lncRNAs in Endothelzellen gezeigt, dass die lncRNA MIR503HG eine hohe Sequenz-Struktur-Konservierung in S{\"a}ugetieren besitzt, wohingegen die LINC00323-003 eine geringe Konservierung aufzeigt. Dies untermauert die Tatsache, dass lncRNAs h{\"a}ufig eine geringe Konservierung aufweisen, was Untersuchungen in Modellorganismen hinsichtlich einer therapeutischen Nutzung schwierig machen. Da sich zahlreiche Untersuchungen auf Interaktionen und Signalwege konzentriert haben, wurde abschließend eine Datenbank entwickelt, welche Analysen von Protein-Interaktionen und Signalwegen nachhaltig voranbringt. Die entwickelte DrumPID-Datenbank stellt insbesondere die Interaktion zwischen einem Medikament und seinem Target in den Fokus und erm{\"o}glicht Analysen einzelner Interaktionen und beteiligter Signalwege, bietet zus{\"a}tzlich aber auch verschiedene Links zu anderen Datenbanken f{\"u}r individuelle weiterf{\"u}hrende Analysen. DrumPID erm{\"o}glicht ein geeignetes Medikament u. a. f{\"u}r ein vorgegebenes Zielprotein zu finden und dessen Wirkmechanismus und Interaktionskontext zu untersuchen, was zu einem besseren experimentellen Verst{\"a}ndnis beitragen kann. Zudem erlaubt DrumPID eine potentielle chemische Leitstruktur f{\"u}r ein Zielprotein zu entwickeln, was z.B. spezifisch ein parasitisches Protein inhibiert, ohne dabei einen toxischen Effekt im Menschen zu haben. Zahlreiche weitere Pharmakabeispiele belegen, dass DrumPID f{\"u}r den t{\"a}glichen wissenschaftlichen Gebrauch auf dem Gebiet der Analyse von Protein-Pharmaka-Interaktionen und der Medikamentenentwicklung geeignet ist. Die beschriebenen Ergebnisse der Promotionsarbeit wurden in f{\"u}nf Originalarbeiten, zwei {\"U}bersichtsartikeln und einem Buchteil, u. a. in Science Translational Medicine, ver{\"o}ffentlicht, sechs dieser Publikationen erfolgten im Rahmen von Erstautorschaften.}, subject = {Systembiologie}, language = {de} } @phdthesis{Gehring2017, author = {Gehring, Jennifer}, title = {Functional analysis of the latrophilin homolog dCirl in Drosophila melanogaster}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-101061}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Latrophilin, alternatively named calcium-independent receptor of α-latrotoxin (CIRL), resembles a prototype of the adhesion class G-protein coupled receptors (GPCRs). Initially identified as a high-affinity receptor for α-latrotoxin, a component of the black widow spider, latrophilins are now associated with various distinct functions, such as synaptic exocytosis, tissue polarity and fertility (Tobaben et al., 2002; Langenhan et al., 2009; Promel et al., 2012). Despite these exploratory efforts the precise subcellular localisation as well as the endogenous ligand of CIRL still remains elusive. In this work genetic experiments, imaging approaches and behavioural studies have been used to unravel the localisation and physiological function of the latrophilin homolog dCirl in Drosophila melanogaster. Containing only one latrophilin homolog together with its genetic accessibility and well-established transgenic approaches, Drosophila seemed an ideally suited model organism. The present study showed that dCirl is widely expressed in the larval central nervous system including moto- and sensory neurons. Further, this work revealed that removal of the latrophilin homolog does not greatly affect synaptic transmission but it seems that aspects of the postsynaptic structural layout are controlled by dCIRL in the fruit fly. Additionally, dCirl expression at the transcriptional level was confirmed in larval and adult chordotonal organs, specialised mechanosensors implicated in proprioception (Eberl, 1999). Expression of dCIRL at the protein level could not yet been confirmed in moto- and sensory neurons likely due to low endogenous expression. However, behavioural studies using dCirl knockout mutant larvae indicated a putative mechanosensory function of dCIRL regarding touch sensitivity and locomotion behaviour. The second part of this thesis presents a strategy to examine interactions between several presynaptic proteins in living cells. The attempt described in this work is based on the discovery that GFP when split into two non-fluorescent fragments can form a fluorescent complex. The association of the fragments can be facilitated by fusing them to two proteins that interact with each other. Therefore, the split GFP method enables direct visualization of synaptic protein interactions in living cells. In initial experiments I could show that full length reporter protein fusions with n-Synaptobrevin (n-Syb), Synaptotagmin (Syt) and Syntaxin (Syx) allow expression in Drosophila and confirmed that fusion to either end of each synaptic protein did not impair expression or influence the viability of transgenic flies. Further, transgenes containing protein fusions of Syx, Syt, and n-Syb with split GFP fragments were established in previous studies (Gehring, 2010). The present work characterises the interaction of these protein fusions during different stages of synaptic vesicle turnover at active zones such as synaptic vesicle docking at the presynaptic membrane and vesicle fusion. These results suggest that the spGFP assay seems only partly suitable for resolving fast and transient protein-protein interactions at larval Drosophila active zones in vivo.}, subject = {Taufliege}, language = {en} } @phdthesis{Beinicke2017, author = {Beinicke, Andrea}, title = {Career Construction Across the Life Span: Career Choice and Career Development}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117447}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {This dissertation contributes to deepen our understanding of constructs that play a key role in individuals' vocational career construction. In this regard, many previous studies have focused exclusively on a specific phase of an individual's career. Yet, modern societies require continuous investments in one's career to adapt to changing Environments throughout the life span. Consequently, this dissertation takes a broad approach to capture a wide spectrum of career construction processes. According to Super's (1990) developmental stage framework, individuals have to manage vocational developmental tasks corresponding to each of the developmental life stages in order to be career mature across the life span. As the two stages exploration and maintenance set the stage for individuals' future career pathways, they are especially important in individuals' vocational career construction. Therefore, both of them are addressed in this dissertation. By answering open research questions relevant to career choice in early career stages and to career development in later career stages, this dissertation contributes to the overarching goal of shedding more light on constructs relevant to individuals' vocational career construction processes across the life span. Beyond the results presented within each study's horizon, this dissertation aimed at offering practical guidance to career counselors, trainees, and training and development (T\&D) professionals. Career counselors and T\&D professionals are involved in guiding vocational career construction processes of individuals across the life span. Thus, on the one hand, this dissertation supports career counselors' work so that they can help deliberating individuals make optimal and effective career choices. On the other hand, this dissertation facilitates T\&D professionals' work so that they can effectively design and evaluate e-learning and classroom trainings in corporate educational settings. Identifying individuals' vocational interests combined with cognitive abilities through adequate test measures and maximizing success of learning and success of transfer through fostering evidence-based transfer support actions will help individuals adapt quickly to the changing nature of work environments in the 21st century and to continue to successfully construct careers across the life span.}, subject = {Karriere}, language = {en} } @phdthesis{Gao2017, author = {Gao, Shiqiang}, title = {Characterizing new photoreceptors to expand the Optogenetic toolbox}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112941}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Optogenetics is a method to control the cell activity with light by expression of a natural or engineered photoreceptor via genetic modification technology. Optogenetics early success came with the light-gated cation channel "Channelrhodopsin-2" in neurons and expanded from neuroscience to other research fields such as cardiac research and cell signaling, also due to the enrichment by new photoreceptors. In this study, I focus on searching and characterizing new photoreceptors to expand the optogenetic tool box. In this work I characterize three newly discovered microbial rhodopsins and some engineered mutants of them. The first rhodopsin is a proton pump from the diatom Fragilariopsis cylindrus, Fragilariopsis Rhodopsin or abbreviated: FR. I cloned the full-length FR and proved it to be a light-activated proton pump with high efficacy in comparison to Bacteriorhodopsin (BR). During this study, I also developed a new method to improve the plasma membrane targeting of several microbial rhodopsins. I also obtained a FR mutant (channel-like FR or chFR) which behaves like a light-gated proton channel. FR can be used for optogenetic hyperpolarization or alkalization of a cell while the chFR could be used for depolarization or lowering of the cellular pH. The induction of FR expression under iron-limited conditions in the diatom indicated an alternative energy generation mechanism of F. cylindrus when iron-containing enzymes are scarce. I then characterized a new microbial rhodopsin with novel light-regulated Guanylyl Cyclase (GC) activity. This rhodopsin guanylyl cyclase from the fungus Blastocladiella emersonii (B.e. CyclaseOpsin or BeCyclOp) has been proven by me to be an efficient light-gated GC with high specificity and fast kinetics. BeCyclOp also has a novel structure with eight transmembrane helices, containing a long cytosolic N-terminus which participates in the tight regulation of the GC activity. In collaboration with Prof. Alexander Gottschalk (Univ. Frankfurt/M.), BeCyclOp has been tested in muscle cells and sensory neurons of Caenorhabditis elegans and proven to be a powerful optogenetic tool in a living animal. I also generated a BeCyclOp mutant with enhanced light sensitivity. Already more than ten years ago, guanylyl cyclase rhodopsins were suggested to exist in Chlamydomonas reinhardtii by analyzing genomic sequence data. But until now no functional proof existed. By further cloning and sequencing I discovered such a rhodopsin with light-regulated guanylyl cyclase activity. This functional Cyclaseopsin (COP6c) is quite different to BeCyclOp, as it was proven to be a light-inhibited GC. Cop6c is much larger than BeCyclOp with a His-Kinase and a response regulator domain between the rhodopsin and the cyclase domain. I also introduced a new strategy for generating optogenetic tools by fusing the photoactivated adenylyl cyclase bPAC to two different CNG channels. These new tools function via light-gated cAMP production and subsequent CNG channel activation. These tools combined the properties of bPAC (highly sensitive to blue light) and CNG channels (high single-channel conductance and high Ca2+ permeability), as demonstrated by expression in Xenopus oocytes. As a further benefit the fusing of bPAC to CNG channels leads to a bPAC with a more than tenfold reduced dark activity which is a valuable improvement for bPAC itself as an optogenetic tool.}, subject = {Photorezeptor}, language = {en} } @article{Kraft2017, author = {Kraft, Stephan}, title = {Vom Kopf auf die F{\"u}ße gestellt, auf dass die Welt kopfsteht. B{\"u}rgerliches Trauerspiel und Kom{\"o}die in Karl von Holteis Trauerspiel in Berlin und Johann Nestroys Die verh{\"a}ngnißvolle Faschings-Nacht}, series = {Nestroyana}, volume = {37}, journal = {Nestroyana}, publisher = {Lehner}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257900}, pages = {39-50}, year = {2017}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @incollection{Kraft2017, author = {Kraft, Stephan}, title = {Hans Staden}, series = {Fr{\"u}he Neuzeit in Deutschland 1520-1620. Literaturwissenschaftliches Verfasserlexikon}, booktitle = {Fr{\"u}he Neuzeit in Deutschland 1520-1620. Literaturwissenschaftliches Verfasserlexikon}, publisher = {Walter de Gruyter}, address = {Berlin u.a.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257226}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {Sp. 112-117}, year = {2017}, abstract = {Kein Abstract verf{\"u}gbar.}, subject = {Staden, Hans}, language = {de} } @article{SyperekAndrzejewskiRudnoRudzińskietal.2017, author = {Syperek, M. and Andrzejewski, J. and Rudno-Rudziński, W. and Maryński, A. and Sȩk, G. and Misiewicz, J. and Reithmaier, J. P. and Somers, A. and H{\"o}fling, S.}, title = {The issue of 0D-like ground state isolation in GaAs- and InP-based coupled quantum dots-quantum well systems}, series = {Journal of Physics: Conference Series}, volume = {906}, journal = {Journal of Physics: Conference Series}, number = {1}, issn = {1742-6588}, doi = {10.1088/1742-6596/906/1/012019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262876}, year = {2017}, abstract = {The issue of quantum mechanical coupling between a semiconductor quantum dot and a quantum well is studied in two families of GaAs- and InP- based structures at cryogenic temperatures. It is shown that by tuning the quantum well parameters one can strongly disturb the 0D-character of the coupled system ground state, initially located in a dot. The out-coupling of either an electron or a hole state from the quantum dot confining potential is viewed by a significant elongation of the photoluminescence decay time constant. Band structure calculations show that in the GaAs-based coupled system at its ground state a hole remains isolated in the dot, whereas an electron gets delocalized towards the quantum well. The opposite picture is built for the ground state of a coupled system based on InP.}, language = {en} } @article{PaxtonSmolanBoecketal.2017, author = {Paxton, Naomi and Smolan, Willi and B{\"o}ck, Thomas and Melchels, Ferry and Groll, J{\"u}rgen and Jungst, Tomasz}, title = {Proposal to assess printability of bioinks for extrusion-based bioprinting and evaluation of rheological properties governing bioprintability}, series = {Biofabrication}, volume = {9}, journal = {Biofabrication}, number = {4}, doi = {10.1088/1758-5090/aa8dd8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254061}, year = {2017}, abstract = {The development and formulation of printable inks for extrusion-based 3D bioprinting has been a major challenge in the field of biofabrication. Inks, often polymer solutions with the addition of crosslinking to form hydrogels, must not only display adequate mechanical properties for the chosen application but also show high biocompatibility as well as printability. Here we describe a reproducible two-step method for the assessment of the printability of inks for bioprinting, focussing firstly on screening ink formulations to assess fibre formation and the ability to form 3D constructs before presenting a method for the rheological evaluation of inks to characterise the yield point, shear thinning and recovery behaviour. In conjunction, a mathematical model was formulated to provide a theoretical understanding of the pressure-driven, shear thinning extrusion of inks through needles in a bioprinter. The assessment methods were trialled with a commercially available cr{\`e}me, poloxamer 407, alginate-based inks and an alginate-gelatine composite material. Yield stress was investigated by applying a stress ramp to a number of inks, which demonstrated the necessity of high yield for printable materials. The shear thinning behaviour of the inks was then characterised by quantifying the degree of shear thinning and using the mathematical model to predict the window of printer operating parameters in which the materials could be printed. Furthermore, the model predicted high shear conditions and high residence times for cells at the walls of the needle and effects on cytocompatibility at different printing conditions. Finally, the ability of the materials to recover to their original viscosity after extrusion was examined using rotational recovery rheological measurements. Taken together, these assessment techniques revealed significant insights into the requirements for printable inks and shear conditions present during the extrusion process and allow the rapid and reproducible characterisation of a wide variety of inks for bioprinting.}, language = {en} } @article{TemmeAdamAhnenetal.2017, author = {Temme, Fabian and Adam, Jan and Ahnen, Max L. and Baack, Dominik and Balbo, Matteo and Bergmann, Matthias and Biland, Adrian and Blank, Michael and Bretz, Thomas and Br{\"u}gge, Kai A. and Buss, Jens and Dmytriiev, Anton and Dorner, Daniela and Einecke, Sabrina and Hempfling, Christina and Hildebrand, Dorothee and Hughes, Gareth and Linhoff, Lena and Mannheim, Karl and M{\"u}ller, Sebastian and Neise, Dominik and Neronov, Andrii and N{\"o}the, Max and Paravac, Aleksander and Pauss, Felicitas and Rhode, Wolfgang and Shukla, Amit and Thaele, Julia and Walter, Roland}, title = {Long-Term monitoring of bright blazars in the multi-GeV to TeV range with FACT}, series = {Galaxies}, volume = {5}, journal = {Galaxies}, number = {1}, publisher = {MDPI}, issn = {2075-4434}, doi = {10.3390/galaxies5010018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198088}, pages = {18}, year = {2017}, abstract = {Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.}, language = {en} } @phdthesis{LyTung2017, author = {Ly Tung, Nam}, title = {Toward an Intelligent Long-Term Assistance for People with Dementia In the Context of Navigation in Indoor Environments}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155235}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Dementia is a complex neurodegenerative syndrome that by 2050 could affect about 135 Million people worldwide. People with dementia experience a progressive decline in their cognitive abilities and have serious problems coping with activities of daily living, including orientation and wayfinding tasks. They even experience difficulties in finding their way in a familiar environment. Being lost or fear of getting lost may consequently develop into other psychological deficits such as anxiety, suspicions, illusions, and aggression. Frequent results are social isolation and a reduced quality of life. Moreover, the lives of relatives and caregivers of people with dementia are also negatively affected. Regarding navigation and orientation, most existing approaches focus on outdoor environment and people with mild dementia, who have the capability to use mobile devices. However, Rasquin (2007) observe that even a device with three buttons may be too complicated for people with moderate to severe dementia. In addition, people who are living in care homes mainly perform indoor activities. Given this background, we decided to focus on designing a system for indoor environments for people with moderate to severe dementia, who are unable or reluctant to use smartphone technology. Adopting user-centered design approach, context and requirements of people with dementia were gathered as a first step to understand needs and difficulties (especially in spatial disorientation and wayfinding problems) experienced in dementia care facilities. Then, an "Implicit Interactive Intelligent (III) Environment" for people with dementia was proposed emphasizing implicit interaction and natural interface. The backbone of this III Environment is based on supporting orientation and navigation tasks with three systems: a Monitoring system, an intelligent system, and a guiding system. The monitoring system and intelligent system automatically detect and interpret the locations and activities performed by the users i.e. people with dementia. This approach (implicit input) reduces cognitive workload as well as physical workload on the user to provide input. The intelligent system is also aware of context, predicts next situations (location, activity), and decides when to provide an appropriate service to the users. The guiding system with intuitive and dynamic environmental cues (lighting with color) has the responsibility for guiding the users to the places they need to be. Overall, three types of a monitoring system with Ultra-Wideband and iBeacon technologies, different techniques and algorithms were implemented for different contexts of use. They showed a high user acceptance with a reasonable price as well as decent accuracy and precision. In the intelligent system, models were built to recognize the users' current activity, detect the erroneous activity, predict the next location and activity, and analyze the history data, detect issues, notify them and suggest solutions to caregivers via visualized web interfaces. About the guiding systems, five studies were conducted to test and evaluate the effect of lighting with color on people with dementia. The results were promising. Although several components of III Environment in general and three systems, in particular, are in place (implemented and tested separately), integrating them all together and employing this in the dementia context as a fully properly evaluation with formal stakeholders (people with dementia and caregivers) are needed for the future step.}, language = {en} } @phdthesis{Wirth2017, author = {Wirth, Robert}, title = {Consequences of bending and breaking the rules}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155075}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Social life is organized around rules and norms. The present experiments investigate the cognitive architecture of rule violations. To do so, a setting with arbitrary rules that had to be followed or broken was developed, and breaking these rules did not have any negative consequences. Removed from any social influences that might further encourage or hinder the rule breaker, results suggest that simply labeling a behavior as a rule violation comes with specific costs: They are more difficult to plan and come with specific behavioral markers during execution. In essence, rule violations resemble rule negations, but they also trigger additional processes. The question of what makes rule violations more difficult than rule inversions is the major focus of the remaining experiments. These experiments revealed negative affective consequences of rule violation and rule inversions alike, while rule violations additionally prime authority-related concepts, thus sensitizing towards authority related stimuli. Next, the question how these burdens of non-conformity can be mitigated was investigated, and the influence of having executed the behavior in question frequently and recently was tested in both negations and rule violations. The burdens of non-conformity can best be reduced by a combination of having violated/negated a rule very frequently and very recently. Transfer from another task, however, could not be identified. To conclude, a model that accounts for the data that is currently presented is proposed. As a variant of a task switching model, it describes the cognitive processes that were investigated and highlights unique processing steps that rule violations seem to require.}, subject = {Soziale Norm}, language = {en} } @article{ApostolidisGkarpousisKoch2017, author = {Apostolidis -Gkarpousis, Alexandros and Koch, Christian}, title = {Convergences et divergences dans les articles «Langage» de Louis de Jaucourt et «Langue» de Nicolas Beauz{\´e}e. Une comparaison de deux articles de l'Encyclop{\´e}die de Diderot et D'Alembert}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {3}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2510-2613}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172843}, pages = {19-36}, year = {2017}, abstract = {The two articles of «Langage» and «Langue», published in 1765 in the 9th volume of the great French Encyclop{\´e}die by Diderot and D'Alembert, treat some essential philosophical questions on the human ability of communication with linguistic signs. Nevertheless, as the two authors Jaucourt and Beauz{\´e}e did not share completely identic points of view, the comparative lecture of both articles reveals a complementary perspective, particularly relating to the origin of language as a divine gift or humans' creation for communicative needs. A further aspect of divergence concerns the textual composition of the article « Langage » as a structured informative text, and the article « Langue » as a long and freely composed writing including personal remarks by the author. The following article deals with the potential of approaches to the Encyclop{\´e}die in modern linguistics, concretely demonstrated in the comparative analysis of these two articles.}, language = {fr} } @article{KraftFleischerWiedmannetal.2017, author = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {159}, doi = {10.1186/s12883-017-0937-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081}, year = {2017}, abstract = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.}, language = {en} } @article{LaglerElMeseryKuebleretal.2017, author = {Lagler, Charlotte and El-Mesery, Mohamed and K{\"u}bler, Alexander Christian and M{\"u}ller-Richter, Urs Dietmar Achim and St{\"u}hmer, Thorsten and Nickel, Joachim and M{\"u}ller, Thomas Dieter and Wajant, Harald and Seher, Axel}, title = {The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {10}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158993}, pages = {e0185720}, year = {2017}, abstract = {Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.}, language = {en} } @article{BellingerAltenmuellerVolkmann2017, author = {Bellinger, Daniel and Altenm{\"u}ller, Eckart and Volkmann, Jens}, title = {Perception of time in music in patients with Parkinson's disease - The processing of musical syntax compensates for rhythmic deficits}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2017.00068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171805}, year = {2017}, abstract = {Objective: Perception of time as well as rhythm in musical structures rely on complex brain mechanisms and require an extended network of multiple neural sources. They are therefore sensitive to impairment. Several psychophysical studies have shown that patients with Parkinson's disease (PD) have deficits in perceiving time and rhythms due to a malfunction of the basal ganglia (BG) network. Method: In this study we investigated the time perception of PD patients during music perception by assessing their just noticeable difference (JND) in the time perception of a complex musical Gestalt. We applied a temporal discrimination task using a short melody with a clear beat-based rhythm. Among the subjects, 26 patients under L-Dopa administration and 21 age-matched controls had to detect an artificially delayed time interval in the range between 80 and 300 ms in the middle of the musical period. We analyzed the data by (a) calculating the detection threshold directly, (b) by extrapolating the JNDs, (c) relating it to musical expertise. Results: Patients differed from controls in the detection of time-intervals between 220 and 300 ms (*p = 0.0200, n = 47). Furthermore, this deficit depended on the severity of the disease (*p = 0.0452; n = 47). Surprisingly, PD patients did not show any deficit of their JND compared to healthy controls, although the results showed a trend (*p = 0.0565, n = 40). Furthermore, no significant difference of the JND was found according to the severity of the disease. Additionally, musically trained persons seemed to have lower thresholds in detecting deviations in time and syntactic structures of music (*p = 0.0343, n = 39). Conclusion: As an explanation of these results, we would like to propose the hypothesis of a time-syntax-congruency in music perception suggesting that processing of time and rhythm is a Gestalt process and that cortical areas involved in processing of musical syntax may compensate for impaired BG circuits that are responsible for time processing and rhythm perception. This mechanism may emerge more strongly as the deficits in time processing and rhythm perception progress. Furthermore, we presume that top-down-bottom-up-processes interfere additionally and interact in this context of compensation.}, language = {en} } @phdthesis{LehmanngebHofmann2017, author = {Lehmann [geb. Hofmann], Anna}, title = {Entwicklung potenzieller Inhibitoren der Hitzeschockkomponenten HSF1 und HSP70 am Modell des Multiplen Myeloms}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153477}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Krebs geh{\"o}rt zu einem der zentralen Leiden der 21. Jahrhunderts und ist in den einkommensstarken L{\"a}ndern die zweith{\"a}ufigste Todesursache. Die Erkrankung Multiples Myleom (MM) geh{\"o}rt mit 1.3 \% aller Krebserkrankungen zwar zu den seltenen Formen, verl{\"a}uft jedoch meist t{\"o}dlich und zeichnet sich durch eine unkontrollierte Entartung der monoklonaler Plasmazellen im Knochenmark aus. Da maligne Zellen dauerhaft internen und externen Stressfaktoren ausgesetzt sind und auf die Hitzeschutzantwort angewiesen sind, stellen die Komponenten des Hitzeschocksystems wie z.B. Chaperone HSP70 und HSP90 bzw. der Hitzeschockfaktor HSF1 ein attraktives therapeutisches Ziel dar. Nachweislich f{\"u}hrt die Inhibition des Chaperons HSP90 zur HSF1-vermittelten Hochregulation des Proteins HSP70, sodass die Hitzeschutzantwort der zytotoxischen Aktivit{\"a}t der Inhibitoren entgegenwirkt und die Therapieerfolgschancen mindert. Die vorliegende Doktorarbeit, die im Rahmen der Klinischen Forschergruppe 216 (CRU216) ausgearbeitet wurde, befasste sich einerseits mit der Erweiterung der bereits vorhandenen Substanzbibliotheken sowohl zur Inhibition des Proteins HSP70 als auch des Transkriptionsfaktors HSF1. Hierdurch sollten detailliertere Struktur-Wirkungs-Bezeugungen evaluiert werden. Weiterhin wurden die kooperierenden Arbeitsgruppen des Forschungsprojektes durch die Entwicklung und Herstellung von Substanzen unterst{\"u}tzt, um mit Hilfe vielseitiger Methoden die exakten Wirkmechanismen beider Verbindungsklassen zu verstehen und aufzukl{\"a}ren. Die bereits bestehende Substanzbibliothek der 3,4-Dihydroisochinolin-1(2H)-on-Derivate aus der vorangehenden Arbeit wurde erfolgreich um neue Carbons{\"a}ure- ((±) 6a-j) und Carbons{\"a}ureamidverbindungen ((±) 7b-e) erweitert. Durch die Substitution phenolischer Seitengruppen der Isoquinolinone gelang es, S{\"a}urederivate herzustellen, die eine h{\"o}here Zytotoxizit{\"a}t auf den INA-6-Zellen als die Leitstruktur AH073t aufwiesen. Dabei handelt es sich um die monobromierte Verbindung (±) 6c (EC50 = 0.17 µM) oder das Derivat mit einem kurzem Bromoethoxylinker (±) 6j (EC50 = 0.18 µM). Parallel hierzu wurde festgestellt, dass die Substitution aromatischer Seitengruppen durch aliphatische Reste ((±) 6h-i) zum kompletten Aktivit{\"a}tsverlust f{\"u}hrte. Durch dir fortf{\"u}hrende Umsetzung zu den Amiden gelang die Herstellung des Derivates (±) 7c (EC50 = 0.47 µM), welches eine {\"a}hnliche Aktivit{\"a}t im Vergleich zu der Struktur AH122t ((±) 7a) zeigte. Weiterhin wurde Verbindung (±) 7d identifiziert, die eine sechsfach h{\"o}here Zytotoxizit{\"a}t von 34.8 nM im Vergleich zu der Leitstruktur (±) 7a (EC50 = 200 nM) aufwies. Die Trennung der trans-Enantiomere der Leitstruktur AH073t wurde erfolgreich mit Hilfe einer chiralen chromatographischen Methode durchgef{\"u}hrt und die Absolutkonfiguration mit Hilfe der Circulardichroismus-Spektroskopie (Arbeitskreis Bringmann) bestimmt. Durch die biologische Untersuchung an den MM-INA-6-Zellen (Arbeitskreis Chatterjee) wurde die enantiospezifische Aktivit{\"a}t des 3R,4R-Enantiomers best{\"a}tigt, wohingegen das 3S,4S-Isomer hingegen nicht aktiv war. Die angestrebte Amidierung zu enantiomerenreinen Substanzen f{\"u}hrte gegen die Erwartung zu einem Diastereomerengemisch, da aufgrund des aciden Protons am Kohlenstoff C-4 die Carbons{\"a}uren im Laufe der Synthese epimerisierten. Um die Epimerisierung an der aciden Position zu vermeiden, wurden neuartige Isochinolinoncarbons{\"a}ure-Derivate hergestellt, die erstmalig an dem Kohlenstoff C 4 substituiert wurden. Mit Hilfe einer Schutzgruppentechnik wurden in drei Syntheseschritten erfolgreich drei neue Derivate, n{\"a}mlich eine fluorierte ((±) 11), methylierte ((±) 15) und ethylierte Verbindung ((±) 16), erhalten. Die Bestimmung der Absolutkonfiguration der fluorierten und ethylierten Spezies gelang durch die R{\"o}ntgenstrukturanalyse der Einkristalle (Arbeitskreis Braunschweig). Dabei wurde festgestellt, dass die Alkylierungsreaktion stereospezifisch verliefen und ausschließlich cis-Derivate erhalten wurden. Die biologische Untersuchung dieser Substanzen best{\"a}tigte die Konfiguration, da alle drei Verbindungen keine Aktivit{\"a}t auf MM-INA-6-Zellen zeigten (EC50 >100 µM). Weiterhin wurde mit Hilfe einer UV-metrischen Messung die S{\"a}ttigungskonzentration der neuen Derivate untersucht. Hierbei wurde festgestellt, dass die Substitution am Kohlenstoff C-4 zur Senkung der L{\"o}slichkeit gef{\"u}hrt hat. Anhand der Proteinkristallstruktur des bHSC70 (C.Grimm) wurde ein TMAO-Molek{\"u}l in der N{\"a}he der der Interface-Oberfl{\"a}che identifiziert. Basierend auf diesem Ergebnis wurde eine Methode zur Herstellung eines TMAO-Isochinolinonhybrides entwickelt, welches sich an der Leitstruktur AH073t orientierte. W{\"a}hrend der Synthesesequenz ist es zu der Decarboxylierung des angestrebten 3,4-Dihydroisochinolin-1(2H)-on-Derivates gekommen, wodurch das neue Derivat 17 erhalten wurde. Nachdem die Reaktionsbedinungen variiert und die gew{\"u}nschte Verbindung nicht erhalten wurde, wurde 17 im darauffolgenden Syntheseschritt erfolgreich zum TMAO-Hybrid 18 umgesetzt. Der Szintillationsn{\"a}henachweis (SPA) ist eine etablierte Methode, um mit Hilfe von radioaktivmarkierten Liganden Bindungsstudien im Hochdurchsatzformat durchzuf{\"u}hren und hier die Bindungsposition der Isochinolinon-Derivate zu untersuchen. Die Substanz AH122t diente hierbei als Leitstruktur zur Entwicklung einer Methode zur Radioaktivmarkierung der potentiellen HSP70-Inhibitoren, sodass die aktivierte Stanylverbindung (±) 19 erhalten wurde. Diese Verbindung konnte in der Gegenwart von Chloramin T und des NaI-Salzes innerhalb von wenigen Sekunden zum Radioliganden (±) 7d* umgesetzt werden. Die Herstellung des Radioliganden wurde mittels einer entwickelten HPLC-Methode analysiert und validiert. Eine weitere M{\"o}glichkeit zur Evaluieren der potentiellen Bindungspartner der hergestellten Isochinolinon-Verbindungen bietet die Affinit{\"a}tschromatographie gekoppelt mit der proteomischen Analyse mittels quantitativer Massenspektrometrie (Arbeitskreis Schlosser). Es gelang die Herstellung der Biotin-markierter Liganden (±) 23, der sich an der Leitstruktur AH073t orientierte, und (±) 25, der sich an AH081t orientierte. Die ersten Analysen mittels Affinit{\"a}tschromatographie zeigten, dass mit dem Liganden (±) 23 {\"u}berraschenderweise keine Proteine signifikant angereichert wurden, w{\"a}hrend mit dem Liganden (±) 25 zwar keine HSP70-Proteine angereichert, aber einige Komponenten der Hitzeschutzantwort wie die Phosphatidylinositol-Kinasen DNA-PK und ATM, und die Untereinheiten des Chaperons HSP90 identifiziert werden konnten. Die bereits bestehende Substanzbibliothek der -Acylaminocarboxamide wurde erfolgreich mit Hilfe der Ugi-Multikomponentenreaktion um die Derivate (±) 38c-g erweitert. Die Evaluierung der biologischen Aktivit{\"a}t erfolgte semiquantitativ mittels Westernblot und quantitativ mittels ELISA-Assay (Arbeitskreis Chatterjee), wobei die Beurteilung indirekt anhand des HSF1-vermittelten Regulationslevels des Chaperons HSP72 erfolgte. Hierbei wurden neue Verbindungen (±) 38c und (±) 38g mit dem ,-ges{\"a}ttigten Carbonylsystem identifiziert, die eine vergleichbare inhibitorische Aktivit{\"a}t wie die bereits bekannten unges{\"a}ttigten Derivaten (±) 37l oder (±) 37m zeigten, was darauf hinweist, dass die inhibitorische Aktivit{\"a}t der  Acylaminocarboxamide nicht von der kovalenten Bindung des Michael-Systems verursacht wird. Um das Target der -Acylaminocarboxamide zu evaluieren, wurde auch hier die Durchf{\"u}hrung der Affinit{\"a}tschromatographie gekoppelt mit der Analyse mittels der quantitativer Massenspektrometrie angestrebt (Arbeitskreis Schlosser). In Anlehnung an die Synthesemethodik f{\"u}r die HSP70-Liganden wurden hierf{\"u}r die Biotin-markierten Liganden (±) 42, (±) 44 und (±) 46 erfolgreich hergestellt, die sich durch die Position des Biotinlinkers unterscheiden. Die proteomische Untersuchung wurde erfolgreich mit den Liganden (±) 44 und (±) 46 durchgef{\"u}hrt und es wurden 68 Proteine signifikant angereichert. Viele dieser Proteine tragen die sogenannte Armadillo-Dom{\"a}ne, die eine wichtige Rolle in der Protein-Protein-Interaktion spielt und eine hochkonservierte Bindungstasche aufweist. Unter den angereicherten Proteinen befanden sich mitunter der MICOS-Komplex, der CCR4-NOT-Komplex und die Kinasen des Phosphatidylinositol-Signalwegs. Von den letzteren konnten explizit die Kinasen DNA-PK, ATM, ATR und mTOR identifiziert werden, die m{\"o}glicherweise die HSF1-regulierte HSP70-Expression beeinflussen. Weiterhin wurde festgestellt, dass die Position des Linkers die Bindung an zwei unterschiedliche Proteingruppen beeinflusst. W{\"a}hrend der Ligand (±) 44 ausschließlich mit den Proteinen des CCR4-NOT-Komplexes interagierte, wurden f{\"u}r den Liganden (±) 46 die Komponenten des COG Komplexes identifiziert.}, subject = {Plasmozytom}, language = {de} } @phdthesis{ElBashir2017, author = {ElBashir, Rasha}, title = {Development of New Mass Spectrometry-based Methods for the Analysis of Posttranslational Modifications}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153731}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Posttranslational modifications (PTMs) play a crucial role in many cellular processes. They are reversible, dynamic, and highly regulated events that alter the properties of proteins and increase their functional diversity. The identification and quantification of PTMs are critical for deciphering the molecular mechanisms of PTMs-related biological processes and disease treatment and prevention. Two of the most common and important PTMs that regulate many protein functions are acetylation and phosphorylation. An important role of acetylation is the regulation of DNA/RNA-protein interactions. A prominent example for this are histones, whose tail regions are lysine-rich and can be highly acetylated at their N-terminal domain. In spite of the utmost importance of this PTM, methods that allow the accurate measuring the site-specific acetylation degree are missing. One of the challenges in quantifying the acetylation degree at an individual lysine residue of the histones N-termini is the occurrence of multiple lysines in close proximity. Herein, we describe the development of the "Fragment Ion Patchwork Quantification," a new mass spectrometry-based approach for the highly accurate quantification of sites-pecific acetylation degrees. This method combines 13C1-acetyl derivatization on the protein level, proteolysis by low-specificity proteases and quantification on the fragment ion level. Acetylation degrees are determined from the isotope patterns of acetylated b and y ions. We have shown that this approach allows determining the site-specific acetylation degrees of all lysine residues for all core histones of Trypanosoma brucei. In addition, we demonstrate the use of this approach to identify the substrate sites of histone acetyltransferases and to monitor the changes in acetylation of the histones of canonical nucleosome and transcription start site nucleosomes. Phosphorylation is one of the most common and most important PTMs. The analysis of the human genome showed that there are about 518 kinases and more than 500,000 phosphorylation sites are believed to exist in the cellular proteome. Protein phosphorylation plays a crucial role in signaling many different cell processes, such as intercellular communication, cell growth, differentiation of proliferation and apoptosis. Whereas MS-based identification and relative quantification of singly phosphorylated peptides have been greatly improved during the last decade, and large-scale analysis of thousands of phosphopeptides can now be performed on a routine-base, the analysis of multi-phosphorylated peptides is still lagging vastly behind. The low pKa value of phosphate group and the associated negative charge are considered the major source of the problems with the analysis of multi-phosphorylated peptides. These problems include the formation of phosphopeptide-metal complexes during liquid chromatography (e.g. Fe 3+), which leads to a drastic deterioration of the chromatographic properties of these peptides (peak tailing), the decreased ionization efficiencies of phosphorylated peptides compared to their unphosphorylated counterparts, the labile nature of phosphate during CID/HCD fragmentation, and the unsuitability of low-charged phosphopeptides for ETD fragmentation are the most important factors that hinder phosphorylation analysis by LC-MS/MS. Here we aimed to develop a method for improving the identification of multi-phosphorylated peptides as well as the localization of phosphorylation sites by charge-reversal derivatization of the phosphate groups. This method employs a carbodiimide-mediated phosphoramidation to converted the phosphates to stable aromatic phosphoramidates. This chemical modification of phosphosite(s) reversed the negative charge of the phosphate group(s) and increased the number of the positive charges within the phosphopeptide. This modification prevented the formation of phosphopeptide-metal ion complexes that dramatically decreases or completely diminishes the signal intensity of protonated phosphopeptides, specifically multi-phosphorylated peptides. Furthermore, the increased net charge the (phospho-)peptides made them suitable for ETD fragmentation, which generated a high number of fragment ions with high intensities that led to a better phosphopeptide identification and localization of phosphosite(s) with high confidence.}, subject = {LC-MS}, language = {en} } @article{MorbachWagnerGuentneretal.2017, author = {Morbach, Caroline and Wagner, Martin and G{\"u}ntner, Stefan and Malsch, Carolin and Oezkur, Mehmet and Wood, David and Kotseva, Kornelia and Leyh, Rainer and Ertl, Georg and Karmann, Wolfgang and Heuschmann, Peter U and St{\"o}rk, Stefan}, title = {Heart failure in patients with coronary heart disease: Prevalence, characteristics and guideline implementation - Results from the German EuroAspire IV cohort}, series = {BMC Cardiovascular Disorders}, volume = {17}, journal = {BMC Cardiovascular Disorders}, number = {108}, doi = {10.1186/s12872-017-0543-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157738}, year = {2017}, abstract = {Background: Adherence to pharmacotherapeutic treatment guidelines in patients with heart failure (HF) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Our aim was to investigate prevalence and characteristics of HF in patients with coronary heart disease (CHD), and to assess the adherence to current HF guidelines in patients with HF stage C, thus identifying potential targets for the optimization of guideline implementation. Methods: Patients from the German sample of the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EuroAspire) IV survey with a hospitalization for CHD within the previous six to 36 months providing valid data on echocardiography as well as on signs and symptoms of HF were categorized into stages of HF: A, prevalence of risk factors for developing HF; B, asymptomatic but with structural heart disease; C, symptomatic HF. A Guideline Adherence Indicator (GAI-3) was calculated for patients with reduced (≤40\%) left ventricular ejection fraction (HFrEF) as number of drugs taken per number of drugs indicated; beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRA) were considered. Results: 509/536 patients entered analysis. HF stage A was prevalent in n = 20 (3.9\%), stage B in n = 264 (51.9\%), and stage C in n = 225 (44.2\%) patients; 94/225 patients were diagnosed with HFrEF (42\%). Stage C patients were older, had a longer duration of CHD, and a higher prevalence of arterial hypertension. Awareness of pre-diagnosed HF was low (19\%). Overall GAI-3 of HFrEF patients was 96.4\% with a trend towards lower GAI-3 in patients with lower LVEF due to less thorough MRA prescription. Conclusions: In our sample of CHD patients, prevalence of HF stage C was high and a sizable subgroup suffered from HFrEF. Overall, pharmacotherapy was fairly well implemented in HFrEF patients, although somewhat worse in patients with more reduced ejection fraction. Two major targets were identified possibly suited to further improve the implementation of HF guidelines: 1) increase patients´ awareness of diagnosis and importance of HF; and 2) disseminate knowledge about the importance of appropriately implementing the use of mineralocorticoid receptor antagonists. Trial registration: This is a cross-sectional analysis of a non-interventional study. Therefore, it was not registered as an interventional trial.}, language = {en} } @article{WegertVokuhZiegleretal.2017, author = {Wegert, Jenny and Vokuh, Christian and Ziegler, Barbara and Ernestus, Karen and Leuschner, Ivo and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Gessler, Manfred}, title = {TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia}, series = {The Journal of Pathology: Clinical Research}, volume = {3}, journal = {The Journal of Pathology: Clinical Research}, doi = {10.1002/cjp2.77}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158302}, pages = {234-248}, year = {2017}, abstract = {TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60\% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90\% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87\%), but this rate dropped to 26\% for stages II-IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26\% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.}, language = {en} } @phdthesis{Leubner2017, author = {Leubner, Philipp}, title = {Strain-engineering of the Topological Insulator HgTe}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152446}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The subject of this thesis is the control of strain in HgTe thin-film crystals. Such systems are members of the new class of topological insulator materials and therefore of special research interest. A major task was the experimental control of the strain in the HgTe films. This was achieved by a new epitaxial approach and confirmed by cristallographic analysis and magneto-transport measurements. In this work, strain was induced in thin films by means of coherent epitaxy on substrate crystals. This means that the film adopts the lattice constant of the substrate in the plane of the substrate-epilayer interface. The level of strain is determined by the difference between the strain-free lattice constants of the substrate and epilayer material (the so-called lattice mismatch). The film responds to an in-plane strain with a change of its lattice constant perpendicular to the interface. This relationship is crucial for both the correct interpretation of high resolution X-ray diffraction (HRXRD) measurements, and the precise determination of the band dispersion. The lattice constant of HgTe is smaller than the lattice constant of CdTe. Therefore, strain in HgTe is tensile if it is grown on a CdTe substrate. In principle, compressive strain can be achieved by using an appropriate \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) substrate. This concept was modified and applied in this work. Epilayers have been fabricated by molecular-beam epitaxy (MBE). The growth of thick buffer layers of CdTe on GaAs:Si was established as an alternative to commercial CdTe and \(text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The growth conditions have been optimized by an analysis of atomic force microscopy and HRXRD studies. HRXRD measurements reveal a power-law increase of the crystal quality with increasing thickness. Residual strain was found in the buffer layers, and was attributed to a combination of finite layer thickness and mismatch of the thermal expansion coefficients of CdTe and GaAs. In order to control the strain in HgTe epilayers, we have developed a new type of substrate with freely adjustable lattice constant. CdTe-\(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) strained-layer-superlattices have been grown by a combination of MBE and atomic-layer epitaxy (ALE), and have been analyzed by HRXRD. ALE of the \(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) layer is self-limiting to one monolayer, and the effective lattice constant can be controlled reproducibly and straightforward by adjusting the CdTe layer thickness. The crystal quality has been found to degrade with increasing Zn-fraction. However, the effect is less drastic compared to single layer \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) solid solutions. HgTe quantum wells (QWs) sandwiched in between CdHgTe barriers have been fabricated in a similar fashion on superlattices and conventional CdTe and \(\text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The lower critical thickness of the CdHgTe barrier material grown on superlattice substrates had to be considered regarding the sample design. The electronic properties of the QWs depend on the strain and thickness of the QW. We have determined the QW thickness with an accuracy of \(\pm\)0.5 nm by an analysis of the beating patterns in the thickness fringes of HRXRD measurements and X-ray reflectometry measurements. We have, for the first time, induced compressive strain in HgTe QWs by an epitaxial technique (i.e. the effective lattice constant of the superlattice is lower compared to the lattice constant of HgTe). The problem of the lattice mismatch between superlattice and barriers has been circumvented by using CdHgTe-ZnHgTe superlattices instead of CdHgTe as a barrier material. Furthermore, the growth of compressively strained HgTe bulk layers (with a thickness of at least 50 nm) was demonstrated as well. The control of the state of strain adds a new degree of freedom to the design of HgTe epilayers, which has a major influence on the band structure of QWs and bulk layers. Strain in bulk layers lifts the degeneracy of the \(\Gamma_8\) bands at \(\mathbf{k}=0\). Tensile strain opens an energy gap, compressive strain shifts the touching points of the valence- and conduction band to positions in the Brillouin zone with finite \(\mathbf{k}\). Such a situation has been realized for the first time in the course of this work. For QWs in the inverted regime, it is demonstrated that compressive strain can be used to significantly enhance the thermal energy gap of the two-dimensional electron gas (2DEG). In addition, semi-metallic and semiconducting behavior is expected in wide QWs, depending on the state of strain. An examination of the temperature dependence of the subband ordering in QWs revealed that the band gap is only temperature-stable for appropriate sample parameters and temperature regimes. The band inversion is always lifted for sufficiently high temperatures. A large number of models investigate the influence of the band gap on the stability of the quantum-spin-Hall (QSH) effect. An enhancement of the stability of QSH edge state conductance is expected for enlarged band gaps. Furthermore, experimental studies on the temperature dependence of the QSH conductance are in contradiction to theoretical predictions. Systematic studies of these aspects have become feasible based on the new flexibility of the sample design. Detailed low-temperature magnetotransport studies have been carried out on QWs and bulk layers. For this purpose, devices have been fabricated lithographically, which consist of two Hall-bar geometries with different dimensions. This allows to discriminate between conductance at the plane of the 2DEG and the edge of the sample. The Fermi energy in the 2DEG has been adjusted by means of a top gate electrode. The strain-induced transition from semi-metallic to semiconducting characteristics in wide QWs was shown. The magnitude of the semi-metallic overlap of valence- and conduction band was determined by an analysis of the two-carrier conductance and is in agreement with band structure calculations. The band gap of the semiconducting sample was determined by measurements of the temperature dependence of the conductance at the charge-neutrality point. Agreement with the value expected from theory has been achieved for the first time in this work. The influence of the band gap on the stability of QSH edge state conductance has been investigated on a set of six samples. The band gap of the set spans a range of 10 to 55 meV. The latter value has been achieved in a highly compressively strained QW, has been confirmed by temperature-dependent conductance measurements, and is the highest ever reported in the inverted regime. Studies of the carrier mobility reveal a degradation of the sample quality with increasing Zn-fraction in the superlattice, in agreement with HRXRD observations. The enhanced band gap does not suppress scattering mechanisms in QSH edge channels, but lowers the conductance in the plane of the 2DEG. Hence, edge state conductance is the dominant conducting process even at elevated temperatures. An increase in conductance with increasing temperature has been found, in agreement with reports from other groups. The increase follows a power-law dependency, the underlying physical mechanism remains open. A cause for the lack of an increase of the QSH edge state conductance with increasing energy gap has been discussed. Possibly, the sample remains insulating even at finite carrier densities, due to localization effects. The measurement does not probe the QSH edge state conductance at the situation where the Fermi energy is located in the center of the energy gap, but in the regime of maximized puddle-driven scattering. In a first set of measurements, it has been shown that the QSH edge state conductance can be influenced by hysteretic charging effects of trapped states in the insulating dielectric. A maximized conductance of \(1.6\ \text{e}^2/\text{h}\) was obtained in a \(58\ \mu\text{m}\) edge channel. Finally, measurements on three dimensional samples have been discussed. Recent theoretical works assign compressively strained HgTe bulk layers to the Weyl semi-metal class of materials. Such layers have been synthesized and studied in magnetotransport experiments for the first time. Pronounced quantum-Hall- and Shubnikov-de-Haas features in the Hall- and longitudinal resistance indicate two-dimensional conductance on the sample surface. However, this conductance cannot be assigned definitely to Weyl surface states, due to the inversion of \(\Gamma_6\) and \(\Gamma_8\) bands. If a magnetic field is aligned parallel to the current in the device, a decrease in the longitudinal resistance is observed with increasing magnetic field. This is a signature of the chiral anomaly, which is expected in Weyl semi-metals.}, subject = {Quecksilbertellurid}, language = {en} } @article{SchoeneggeGallionPicardetal.2017, author = {Sch{\"o}negge, Anne-Marie and Gallion, Jonathan and Picard, Louis-Philippe and Wilkins, Angela D. and Le Gouill, Christian and Audet, Martin and Stallaert, Wayne and Lohse, Martin J. and Kimmel, Marek and Lichtarge, Olivier and Bouvier, Michel}, title = {Evolutionary action and structural basis of the allosteric switch controlling β\(_2\)AR functional selectivity}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, doi = {10.1038/s41467-017-02257-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172268}, year = {2017}, abstract = {Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β\(_2\)-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity.}, language = {en} } @article{LapaHerrmannSchirbeletal.2017, author = {Lapa, Constantin and Herrmann, Ken and Schirbel, Andreas and H{\"a}nscheid, Heribert and L{\"u}ckerath, Katharina and Schottelius, Margret and Kircher, Malte and Werner, Rudolf A. and Schreder, Martin and Samnick, Samuel and Kropf, Saskia and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and Wester, Hans-Juergen and Kort{\"u}m, K. Martin}, title = {CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {6}, doi = {10.7150/thno.19050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172095}, pages = {1589-1597}, year = {2017}, abstract = {C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.}, language = {en} } @article{OPUS4-17238, title = {Measurements of top-quark pair differential cross-sections in the lepton+jets channel in pp collisions at \( \sqrt{s}=13 \) TeV using the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {2017}, journal = {Journal of High Energy Physics}, number = {191}, organization = {The ATLAS Collaboration}, doi = {10.1007/JHEP11(2017)191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172386}, year = {2017}, abstract = {Measurements of differential cross-sections of top-quark pair production in fiducial phase-spaces are presented as a function of top-quark and \(t\overline{t}\) system kinematic observables in proton-proton collisions at a centre-of-mass energy of \(\sqrt{s}\) = 13 TeV. The data set corresponds to an integrated luminosity of 3.2 fb\(^{-1}\), recorded in 2015 with the ATLAS detector at the CERN Large Hadron Collider. Events with exactly one electron or muon and at least two jets in the final state are used for the measurement. Two separate selections are applied that each focus on different top-quark momentum regions, referred to as resolved and boosted topologies of the \(t\overline{t}\) final state. The measured spectra are corrected for detector effects and are compared to several Monte Carlo simulations by means of calculated \(χ^2\) and \(p\)-values.}, language = {en} } @article{LapaSchrederSchirbeletal.2017, author = {Lapa, Constantin and Schreder, Martin and Schirbel, Andreas and Samnick, Samuel and Kort{\"u}m, Klaus Martin and Herrmann, Ken and Kropf, Saskia and Einsele, Herrmann and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Knop, Stefan and L{\"u}ckerath, Katharina}, title = {[\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {1}, doi = {10.7150/thno.16576}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172106}, pages = {205-212}, year = {2017}, abstract = {Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66\%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21\%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37\%). In the remaining 8/19 (42\%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018). [\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.}, language = {en} } @article{HarterHaukeHeitzetal.2017, author = {Harter, Philipp and Hauke, Jan and Heitz, Florian and Reuss, Alexander and Kommoss, Stefan and Marm{\´e}, Frederik and Heimbach, Andr{\´e} and Prieske, Katharina and Richters, Lisa and Burges, Alexander and Neidhardt, Guido and de Gregorio, Nikolaus and El-Balat, Ahmed and Hilpert, Felix and Meier, Werner and Kimmig, Rainer and Kast, Karin and Sehouli, Jalid and Baumann, Klaus and Jackisch, Christian and Park-Simon, Tjoung-Won and Hanker, Lars and Kr{\"o}ber, Sandra and Pfisterer, Jacobus and Gevensleben, Heidrun and Schnelzer, Andreas and Dietrich, Dimo and Neunh{\"o}ffer, Tanja and Krockenberger, Mathias and Brucker, Sara Y. and N{\"u}rnberg, Peter and Thiele, Holger and Altm{\"u}ller, Janine and Lamla, Josefin and Elser, Gabriele and du Bois, Andreas and Hahnen, Eric and Schmutzler, Rita}, title = {Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1)}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0186043}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173553}, year = {2017}, abstract = {Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6\%) had a high-grade serous ovarian cancer. In total, 27.9\% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4\% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5\%), \(BRCA2\) (5.5\%), \(RAD51C\) (2.5\%) and \(PALB2\) (1.1\%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2\% (33.2\%) versus 10.6\% (18.9\%) in patients \(\geq\)60 years. Family history was positive in 43\% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6\% (36.0\%) versus 11.4\% (17.6\%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2\% (29.1\%) and 10.2\% (14.8\%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5\% of the patients with a deleterious variant in established risk genes. Conclusions 26.4\% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10\% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be not sufficient.}, language = {en} } @article{WernerSheikhbahaeiJonesetal.2017, author = {Werner, Rudolf A. and Sheikhbahaei, Sara and Jones, Krystyna M. and Javadi, Mehrbod S. and Solnes, Lilja B. and Ross, Ashley E. and Allaf, Mohamad E. and Pienta, Kenneth J. and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro and Pomper, Martin G. and Gorin, Micheal A. and Rowe, Steven P.}, title = {Patterns of uptake of prostate-specific membrane antigen (PSMA)-targeted \(^{18}\)F-DCFPyL in peripheral ganglia}, series = {Annals of Nuclear Medicine}, volume = {31}, journal = {Annals of Nuclear Medicine}, number = {9}, issn = {0914-7187}, doi = {10.1007/s12149-017-1201-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166971}, pages = {696-702}, year = {2017}, abstract = {Objective: Radiotracers targeting prostate-specific membrane antigen (PSMA) have increasingly been recognized as showing uptake in a number of normal structures, anatomic variants, and non-prostate-cancer pathologies. We aimed to explore the frequency and degree of uptake in peripheral ganglia in patients undergoing PET with the PSMA-targeted agent \(^{18}\)F-DCFPyL. Methods: A total of 98 patients who underwent \(^{18}\)F-DCFPyL PET/CT imaging were retrospectively analyzed. This included 76 men with prostate cancer (PCa) and 22 patients with renal cell carcinoma (RCC; 13 men, 9 women). Scans were evaluated for uptake in the cervical, stellate, celiac, lumbar and sacral ganglia. Maximum standardized uptake value corrected to body weight (SUV\(_{max}\)), and maximum standardized uptake value corrected to lean body mass (SUL\(_{max}\)) were recorded for all ganglia with visible uptake above background. Ganglia-to-background ratios were calculated by dividing the SUV\(_{max}\) and SUL\(_{max}\) values by the mean uptake in the ascending aorta (Aortamean) and the right gluteus muscle (Gluteusmean). Results: Overall, 95 of 98 (96.9\%) patients demonstrated uptake in at least one of the evaluated peripheral ganglia. With regard to the PCa cohort, the most frequent sites of radiotracer accumulation were lumbar ganglia (55/76, 72.4\%), followed by the cervical ganglia (51/76, 67.1\%). Bilateral uptake was found in the majority of cases [lumbar 44/55 (80\%) and cervical 30/51 (58.8\%)]. Additionally, discernible radiotracer uptake was recorded in 50/76 (65.8\%) of the analyzed stellate ganglia and in 45/76 (59.2\%) of the celiac ganglia, whereas only 5/76 (6.6\%) of the sacral ganglia demonstrated \(^{18}\)F-DCFPyL accumulation. Similar findings were observed for patients with RCC, with the most frequent locations of radiotracer uptake in both the lumbar (20/22, 90.9\%) and cervical ganglia (19/ 22, 86.4\%). No laterality preference was found in mean PSMA-ligand uptake for either the PCa or RCC cohorts. Conclusion: As PSMA-targeted agents become more widely disseminated, the patterns of uptake in structures that are not directly relevant to patients' cancers must be understood. This is the first systematic evaluation of the uptake of \(^{18}\)F-DCFPyL in ganglia demonstrating a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. The underlying biology that leads to variability of PSMA-targeted radiotracers in peripheral ganglia is not currently understood, but may provide opportunities for future research.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @article{FaggionApazaArizaFritasetal.2017, author = {Faggion, Clovis Mariano, Jr. and Apaza, Karol and Ariza-Fritas, Tania and M{\´a}laga, Lilian and Giannakopoulos, Nikolaos Nikitas and Alarc{\´o}n, Marco Antonio}, title = {Methodological quality of consensus guidelines in implant dentistry}, series = {PLOS One}, volume = {12}, journal = {PLOS One}, number = {1}, doi = {10.1371/journal.pone.0170262}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180987}, pages = {13}, year = {2017}, abstract = {Background: Consensus guidelines are useful to improve clinical decision making. Therefore, the methodological evaluation of these guidelines is of paramount importance. Low quality information may guide to inadequate or harmful clinical decisions. Objective: To evaluate the methodological quality of consensus guidelines published in implant dentistry using a validated methodological instrument. Methods: The six implant dentistry journals with impact factors were scrutinised for consensus guidelines related to implant dentistry. Two assessors independently selected consensus guidelines, and four assessors independently evaluated their methodological quality using the Appraisal of Guidelines for Research \& Evaluation (AGREE) II instrument. Disagreements in the selection and evaluation of guidelines were resolved by consensus. First, the consensus guidelines were analysed alone. Then, systematic reviews conducted to support the guidelines were included in the analysis. Non-parametric statistics for dependent variables (Wilcoxon signed rank test) was used to compare both groups. Results: Of 258 initially retrieved articles, 27 consensus guidelines were selected. Median scores in four domains (applicability, rigour of development, stakeholder involvement, and editorial independence), expressed as percentages of maximum possible domain scores, were below 50\% (median, 26\%, 30.70\%, 41.70\%, and 41.70\%, respectively). The consensus guidelines and consensus guidelines + systematic reviews data sets could be compared for 19 guidelines, and the results showed significant improvements in all domain scores (p < 0.05). Conclusions: Methodological improvement of consensus guidelines published in major implant dentistry journals is needed. The findings of the present study may help researchers to better develop consensus guidelines in implant dentistry, which will improve the quality and trust of information needed to make proper clinical decisions.}, language = {en} } @phdthesis{Mann2017, author = {Mann, Daniel}, title = {"The smell of Ujamaa is still there" - Tanzania's Path of Development between Grassroots Socialism and Central State Control in Ruvuma}, edition = {1. Auflage}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-066-5 (print)}, issn = {0510-9833}, doi = {10.25972/WUP-978-3-95826-067-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154079}, school = {W{\"u}rzburg University Press}, pages = {332}, year = {2017}, abstract = {In the 1960s, when most African nations gained their independence after the age of colonialism, several theories and strategies emerged with the goal of "developing" these apparently "underdeveloped" territories. One of the most influential approaches for this task was represented in Julius K. Nyerere´s idea of Ujamaa, the Tanzanian version of African socialism. Even before the Arusha Declaration established Ujamaa as a national development strategy in 1967, several groups of politicized young farmers took to the empty countryside of Tanzania to implement their own version of cooperative development. From one of these attempts emerged the Ruvuma Development Association (RDA), which organized up to 18 villages in southwestern Tanzania. The RDA became the inspiration for Nyerere´s concretization of Ujamaa and its implementation on national level. Yet, the central state could not replicate the success of the peasants, which was based on voluntariness and intrinsic motivation. In 2015, this exploratory study has revisited the Region of Ruvuma. Through a case study approach, relying mostly on qualitative methods, new insights into the local history of Ujamaa and its perception have been gathered. In particular, narrative interviews with contemporary witnesses and group interviews with the present-day farmers' groups have been conducted. Furthermore, NGOs active within the region, as well as regional and local government institutions were among the key stakeholders identified to concretize the local narrative of Ujamaa development. All interviews were analyzed according to the principles of qualitative content analysis. Additionally, individual villager questionnaires were used to achieve a more holistic picture of the local perception of development, challenges and the Ujamaa era. None of the original Ujamaa groups of the times of the RDA was still operational at the time of research and no case of village-wide organization of collective agriculture could be observed. Nevertheless, in all of the three case study villages, several farmers' groups (vikundi) were active in organizing development activities for their members. Furthermore, the perception of the Ujamaa era was generally positive throughout all of the case study sites. Yet, there have been significant differences in this perception, based on the village, age, gender and field size of the recipients. Overall, the period of Ujamaa was seen as an inspiration for present-day group activities, and the idea of such activities as a remedy for the developmental challenges of these villages was common among all stakeholders. This thesis concludes that the positive perception of group activities as a vehicle for village development and the perception of Ujamaa history as a positive asset for the inception and organization of farmers' groups would be highly beneficial to further attempts to support such development activities. However, the limitations in market access and capital availability for these highly-motivated group members have to be addressed by public and private development institutions. Otherwise, "the smell of Ujamaa" will be of little use for the progress of these villages.}, subject = {Ujamaa-Sozialismus}, language = {en} } @article{TsonevaMinevFrentzenetal.2017, author = {Tsoneva, Desislava and Minev, Boris and Frentzen, Alexa and Zhang, Qian and Wege, Anja K. and Szalay, Aladar A.}, title = {Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis}, series = {Molecular Therapy Oncolytics}, volume = {5}, journal = {Molecular Therapy Oncolytics}, doi = {10.1016/j.omto.2017.03.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170786}, pages = {41-61}, year = {2017}, abstract = {Oncolytic vaccinia virus (VACV) therapy is an alternative cancer treatment modality that mediates targeted tumor destruction through a tumor-selective replication and an induction of anti-tumor immunity. We developed a humanized tumor mouse model with subcutaneous human tumors to analyze the interactions of VACV with the developing tumors and human immune system. A successful systemic reconstitution with human immune cells including functional T cells as well as development of tumors infiltrated with human T and natural killer (NK) cells was observed. We also demonstrated successful in vivo colonization of such tumors with systemically administered VACVs. Further, a new recombinant GLV-1h376 VACV encoding for a secreted human CTLA4-blocking single-chain antibody (CTLA4 scAb) was tested. Surprisingly, although proving CTLA4 scAb's in vitro binding ability and functionality in cell culture, beside the significant increase of CD56\(^{bright}\) NK cell subset, GLV-1h376 was not able to increase cytotoxic T or overall NK cell levels at the tumor site. Importantly, the virus-encoded β-glucuronidase as a measure of viral titer and CTLA4 scAb amount was demonstrated. Therefore, studies in our "patient-like" humanized tumor mouse model allow the exploration of newly designed therapy strategies considering the complex relationships between the developing tumor, the oncolytic virus, and the human immune system.}, language = {en} } @phdthesis{Hillner2017, author = {Hillner, Judith}, title = {Pr{\"a}valenz chronischer Hepatitis B und C - Infektionen bei Patienten mit hepatolienaler Schistosomiasis in Tansania}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155265}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Hintergrund: Die hepatolienale Schistosomiasis, verursacht durch Schistosoma mansoni, und die chronische Hepatitis B und C sind mit Prävalenzen von bis zu 50\%, 8,8\% bzw. 1,5\% Hauptursachen chronischer Lebererkrankungen in Tansania (Clements et al. 2006, Matee et al. 2006). Bisher liegen jedoch keine Daten {\"u}ber die Rate an Koinfektionen von Schistosoma mansoni und chronischer Hepatitis B/C und ihre Auswirkung auf die Schwere der Lebererkrankung aus Tansania vor. Die Region Mwanza am Viktoriasee gehört zu den Gebieten mit der höchsten Prävalenz an Schistosomiasis des Landes. Methoden: Am Bugando Medical Center (BMC) in Mwanza, Tansania, wurde im Zeitraum von Januar bis September 2010 eine prospektive Beobachtungsstudie durchgef{\"u}hrt. Insgesamt wurden 98 Patienten eingeschlossen, bei denen eine portale Hypertension durch den Nachweis von Ösophagusvarizen Grad I-IV mittels Ösophagogastroduodenoskopie (ÖGD) diagnostiziert worden war. In einem standardisierten Interview wurden Risikofaktoren f{\"u}r Hepatitis B / C sowie die Exposition gegen{\"u}ber der Schistosomiasis erfasst. Neben der Dokumentation klinischer Parameter wurde eine abdominelle Ultraschalluntersuchung mit Klassifizierung der sonomorphologischen Veränderungen der Leber nach den Empfehlungen der WHO (Richter 1996) durchgef{\"u}hrt. Serumproben wurden auf Schistosomen-Antikörper, Anti-HBc, HBsAg, Anti- HCV und HCV-RNA untersucht. Es erfolgte eine Bestimmung des Blutbildes, der ALT, AST, Cholinesterase und GGT. Stuhlproben wurden nach Anreicherung mikroskopisch auf Schistosomeneier und Urinproben mittels des Schistosoma - CCA (Circulating Cathodic Antigen) - Schnelltest (Rapid Medical Diagnostics, S{\"u}dafrika) untersucht. Ergebnisse: Von 98 Patienten wurden 62 (63,3\%) positiv auf Schistosomen-Antikörper getestet, bei 92 (93,9\%) konnte Anti-HBc, bei 31 (31,6\%) HBsAg, bei 3 (3,0\%) Anti-HCV und bei 2 (2,0\%) HCV-RNA nachgewiesen werden. Bei 22 (35,5\%) der 62 Patienten mit serologisch bestätigter Schistosomiasis bestand eine Koinfektion mit chronischer Hepatitis B. Zusätzlich bestand in der Gruppe der Schistosomiasis-Infizierten bei einem Teilnehmer eine chronische Hepatitis C. Die Cholinesterase als Parameter f{\"u}r die Lebersyntheseleistung war in der Gruppe der Koinfizierten signifikant erniedrigt (P <0.05). Sonographisch zeigte sich in dieser Gruppe eine höhere Rate an Leberzirrhose und Aszites (P <0.05) als in der Vergleichsgruppe. Schlussfolgerung: Die Schistosomiasis ist die häufigste Ursache einer portalen Hypertension in der Region Mwanza, gefolgt von der chronischen Hepatitis B. Bei mehr als einem Drittel der Schistosomiasis-Antikörper-positiven Patienten bestand eine chronische Hepatitis B - Koinfektion. Die Koinfektion beeinflusst entscheidend die Schwere der Lebererkrankung und erhöht das Risiko einer Ösophagusvarizenblutung in diesen Patienten.}, subject = {Bilharziose}, language = {de} } @article{LudwigsAmann2017, author = {Ludwigs, Markus and Amann, Hannah}, title = {Klausur im Kommunalrecht: Ausschluss aus dem Gemeinderat}, series = {JURA - Juristische Ausbildung}, volume = {39}, journal = {JURA - Juristische Ausbildung}, number = {9}, issn = {1612-7021}, doi = {10.1515/jura-2017-0205}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195589}, pages = {1106 -- 1115}, year = {2017}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @phdthesis{Pakkayil2017, author = {Pakkayil, Shijin Babu}, title = {Towards ferromagnet/superconductor junctions on graphene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153863}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {This thesis reports a successful fabrication and characterisation of ferromagnetic/superconductor junction (F/S) on graphene. The thesis preposes a fabrication method to produce F/S junctions on graphene which make use of ALD grown Al2O3 as the tunnel barrier for the ferromagnetic contacts. Measurements done on F/G/S/G/F suggests that by injecting spin polarised current into the superconductor, a spin imbalance is created in the quasiparticle density of states of the superconductor which then diffuses through the graphene channel. The observed characteristic curves are similar to the ones which are already reported on metallic ferromagnet/superconductor junctions where the spin imbalance is created using Zeeman splitting. Further measurements also show that the curves loose their characteristic shapes when the temperature is increased above the critical temperature (Tc) or when the external magnetic field is higher then the critical field (Hc) of the superconducting contact. But to prove conclusively and doubtlessly the existence of spin imbalance in ferromagnet/superconductor junctions on graphene, more devices have to be made and characterised preferably in a dilution refrigerator.}, subject = {Graphen}, language = {en} } @article{SperlichWallmannSperlichZinneretal.2017, author = {Sperlich, Billy and Wallmann-Sperlich, Birgit and Zinner, Christoph and Von Stauffenberg, Valerie and Losert, Helena and Holmberg, Hans-Christer}, title = {Functional High-intensity Circuit Training Improves Body Composition,Peak Oxygen Uptake, Strength, and Alters Certain Dimensions of Quality of Life in Overweight Women}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {172}, doi = {10.3389/fphys.2017.00172}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171015}, year = {2017}, abstract = {The effects of circuit-like functional high-intensity training (Circuit\(_{HIIT}\)) alone or in combination with high-volume low-intensity exercise (Circuit\(_{combined}\)) on selected cardio-respiratory and metabolic parameters, body composition, functional strength and the quality of life of overweight women were compared. In this single-center, two-armed randomized, controlled study, overweight women performed 9-weeks (3 sessions·wk\(^{-1}\)) of either Circuit\(_{HIIT}\) (n = 11), or Circuit\(_{combined}\) (n = 8). Peak oxygen uptake and perception of physical pain were increased to a greater extent (p < 0.05) by Circuit\(_{HIIT}\), whereas Circuit\(_{combined}\) improved perception of general health more (p < 0.05). Both interventions lowered body mass, body-mass-index, waist-to-hip ratio, fat mass, and enhanced fat-free mass; decreased ratings of perceived exertion during submaximal treadmill running; improved the numbers of push-ups, burpees, one-legged squats, and 30-s skipping performed, as well as the height of counter-movement jumps; and improved physical and social functioning, role of physical limitations, vitality, role of emotional limitations, and mental health to a similar extent (all p < 0.05). Either forms of these multi-stimulating, circuit-like, multiple-joint training can be employed to improve body composition, selected variables of functional strength, and certain dimensions of quality of life in overweight women. However, Circuit\(_{HIIT}\) improves peak oxygen uptake to a greater extent, but with more perception of pain, whereas Circuit\(_{Combined}\) results in better perception of general health.}, language = {en} } @article{OPUS4-17369, title = {A measurement of the calorimeter response to single hadrons and determination of the jet energy scale uncertainty using LHC Run-1 \(pp\)-collision data with the ATLAS detector}, series = {European Physical Journal C}, volume = {77}, journal = {European Physical Journal C}, number = {26}, organization = {The ATLAS Collaboration}, doi = {10.1140/epjc/s10052-016-4580-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173690}, year = {2017}, abstract = {A measurement of the calorimeter response to isolated charged hadrons in the ATLAS detector at the LHC is presented. This measurement is performed with 3.2 nb\(^{-1}\) of proton-proton collision data at \(\sqrt{s}\) = 7 TeV from 2010 and 0.1 nb\(^{-1}\) of data at \(\sqrt{s}\) = 8 TeV from 2012. A number of aspects of the calorimeter response to isolated hadrons are explored. After accounting for energy deposited by neutral particles, there is a 5\% discrepancy in the modelling, using various sets of GEANT4 hadronic physics models, of the calorimeter response to isolated charged hadrons in the central calorimeter region. The description of the response to anti-protons at low momenta is found to be improved with respect to previous analyses. The electromagnetic and hadronic calorimeters are also examined separately, and the detector simulation is found to describe the response in the hadronic calorimeter well. The jet energy scale uncertainty and correlations in scale between jets of different momenta and pseudorapidity are derived based on these studies. The uncertainty is 2-5\% for jets with transverse momenta above 2 TeV, where this method provides the jet energy scale uncertainty for ATLAS.}, language = {en} } @article{BistiRogalevKarolaketal.2017, author = {Bisti, F. and Rogalev, V. A. and Karolak, M. and Paul, S. and Gupta, A. and Schmitt, T. and G{\"u}ntherodt, G. and Eyert, V. and Sangiovanni, G. and Profeta, G. and Strocov, V. N.}, title = {Weakly-correlated nature of ferromagnetism in nonsymmorphic CrO\(_2\) revealed by bulk-sensitive soft-X-ray ARPES}, series = {Physical Review X}, volume = {7}, journal = {Physical Review X}, number = {4}, doi = {10.1103/PhysRevX.7.041067}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172251}, year = {2017}, abstract = {Chromium dioxide CrO\(_2\) belongs to a class of materials called ferromagnetic half-metals, whose peculiar aspect is that they act as a metal in one spin orientation and as a semiconductor or insulator in the opposite one. Despite numerous experimental and theoretical studies motivated by technologically important applications of this material in spintronics, its fundamental properties such as momentumresolved electron dispersions and the Fermi surface have so far remained experimentally inaccessible because of metastability of its surface, which instantly reduces to amorphous Cr\(_2\)O\(_3\). In this work, we demonstrate that direct access to the native electronic structure of CrO\(_2\) can be achieved with soft-x-ray angle-resolved photoemission spectroscopy whose large probing depth penetrates through the Cr\(_2\)O\(_3\) layer. For the first time, the electronic dispersions and Fermi surface of CrO\(_2\) are measured, which are fundamental prerequisites to solve the long debate on the nature of electronic correlations in this material. Since density functional theory augmented by a relatively weak local Coulomb repulsion gives an exhaustive description of our spectroscopic data, we rule out strong-coupling theories of CrO\(_2\). Crucial for the correct interpretation of our experimental data in terms of the valence-band dispersions is the understanding of a nontrivial spectral response of CrO\(_2\) caused by interference effects in the photoemission process originating from the nonsymmorphic space group of the rutile crystal structure of CrO\(_2\).}, language = {en} } @article{LeopoldZeilbeckWeberetal.2017, author = {Leopold, Stephanie A. and Zeilbeck, Ludwig F. and Weber, Gregor and Seitz, Roswitha and B{\"o}sl, Michael R. and J{\"a}gle, Herbert and Fuchshofer, Rudolf and Tamm, Ernst R. and Ohlmann, Andreas}, title = {Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-14423-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173494}, year = {2017}, abstract = {Norrin is a secreted signaling molecule activating the Wnt/β-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a β-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/β-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.}, language = {en} } @article{TsamadouFuerstVucinicetal.2017, author = {Tsamadou, Chrysanthi and F{\"u}rst, Daniel and Vucinic, Vladan and Bunjes, Donald and Neuchel, Christine and Mytilineos, Daphne and Gramatzki, Martin and Arnold, Renate and Wagner, Eva Maria and Einsele, Hermann and M{\"u}ller, Carlheinz and Schrezenmeier, Hubert and Mytilineos, Joannis}, title = {Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients}, series = {Haematologica}, volume = {102}, journal = {Haematologica}, number = {11}, doi = {10.3324/haematol.2017.169805}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173325}, pages = {1947-1955}, year = {2017}, abstract = {The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53\% vs. 38\%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95\%=0.48-0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50\% vs. 18\%, P=0.005; HR=0.40, CI 95\%=0.22-0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post-transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.}, language = {en} } @article{AeschlimannBrixnerCinchettietal.2017, author = {Aeschlimann, Martin and Brixner, Tobias and Cinchetti, Mirko and Frisch, Benjamin and Hecht, Bert and Hensen, Matthias and Huber, Bernhard and Kramer, Christian and Krauss, Enno and Loeber, Thomas H. and Pfeiffer, Walter and Piecuch, Martin and Thielen, Philip}, title = {Cavity-assisted ultrafast long-range periodic energy transfer between plasmonic nanoantennas}, series = {Light: Science \& Applications}, volume = {6}, journal = {Light: Science \& Applications}, doi = {10.1038/lsa.2017.111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173265}, year = {2017}, abstract = {Radiationless energy transfer is at the core of diverse phenomena, such as light harvesting in photosynthesis\(^1\), energy-transfer-based microspectroscopies\(^2\), nanoscale quantum entanglement\(^3\) and photonic-mode hybridization\(^4\). Typically, the transfer is efficient only for separations that are much shorter than the diffraction limit. This hampers its application in optical communication and quantum information processing, which require spatially selective addressing. Here, we demonstrate highly efficient radiationless coherent energy transfer over a distance of twice the excitation wavelength by combining localized and delocalized\(^5\) plasmonic modes. Analogous to the Tavis-Cummings model, two whispering-gallery-mode antennas\(^6\) placed in the foci of an elliptical plasmonic cavity\(^7\) fabricated from single-crystal gold plates act as a pair of oscillators coupled to a common cavity mode. Time-resolved two-photon photoemission electron microscopy (TR 2P-PEEM) reveals an ultrafast long-range periodic energy transfer in accordance with the simulations. Our observations open perspectives for the optimization and tailoring of mesoscopic energy transfer and long-range quantum emitter coupling.}, language = {en} } @article{JessbergerHoeggerGenestetal.2017, author = {Jessberger, Steffen and H{\"o}gger, Petra and Genest, Franca and Salter, Donald M. and Seefried, Lothar}, title = {Cellular pharmacodynamic effects of Pycnogenol\(^{®}\) in patients with severe osteoarthritis: a randomized controlled pilot study}, series = {BMC Complementary and Alternative Medicine}, volume = {17}, journal = {BMC Complementary and Alternative Medicine}, number = {537}, doi = {10.1186/s12906-017-2044-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159532}, year = {2017}, abstract = {Background: The standardized maritime pine bark extract (Pycnogenol\(^{®}\)) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol\(^{®}\) and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol\(^{®}\) twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol\(^{®}\) downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol\(^{®}\) on symptom scores of patients suffering from OA.}, language = {en} } @article{PolatKaiserWohllebenetal.2017, author = {Polat, B{\"u}lent and Kaiser, Philipp and Wohlleben, Gisela and Gehrke, Thomas and Scherzad, Agmal and Scheich, Matthias and Malzahn, Uwe and Fischer, Thomas and Vordermark, Dirk and Flentje, Michael}, title = {Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer}, series = {BMC Cancer}, volume = {17}, journal = {BMC Cancer}, number = {6}, doi = {10.1186/s12885-016-3024-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157529}, year = {2017}, abstract = {Background: In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery. Methods: Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2). Results: A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003). Conclusions: Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact.}, language = {en} } @article{KaltdorfSchulzeHelmprobstetal.2017, author = {Kaltdorf, Kristin Verena and Schulze, Katja and Helmprobst, Frederik and Kollmannsberger, Philip and Dandekar, Thomas and Stigloher, Christian}, title = {Fiji macro 3D ART VeSElecT: 3D automated reconstruction tool for vesicle structures of electron tomograms}, series = {PLoS Computational Biology}, volume = {13}, journal = {PLoS Computational Biology}, number = {1}, doi = {10.1371/journal.pcbi.1005317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172112}, year = {2017}, abstract = {Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial.}, language = {en} } @article{ChiesaGreinerSchoenherretal.2017, author = {Chiesa, Mauro and Greiner, Nicolas and Sch{\"o}nherr, Marek and Tramontano, Francesco}, title = {Electroweak corrections to diphoton plus jets}, series = {Journal of High Energy Physics}, journal = {Journal of High Energy Physics}, number = {10}, doi = {10.1007/JHEP10(2017)181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173512}, year = {2017}, abstract = {We calculate the next-to-leading order electroweak corrections to the production of a photon pair in association with zero, one and two jets at the LHC. We use GoSam and Sherpa to obtain the results in a fully automated way. For a typical set of fiducial cuts the electroweak corrections lead to a modification of the total cross section of up to 3\%, depending on the jet multiplicity. We find substantial contributions in differential distributions, leading to tens of per cent corrections for phase space regions within the reach of the LHC. Furthermore we investigate the importance of photon induced processes as well as subleading contributions. Photon induced processes are found to be negligible, subleading contributions can have a sizeable impact however they can be removed by appropriate phase space cuts.}, language = {en} } @phdthesis{Seufert2017, author = {Seufert, Michael Thomas}, title = {Quality of Experience and Access Network Traffic Management of HTTP Adaptive Video Streaming}, issn = {1432-8801}, doi = {10.25972/OPUS-15413}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154131}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The thesis focuses on Quality of Experience (QoE) of HTTP adaptive video streaming (HAS) and traffic management in access networks to improve the QoE of HAS. First, the QoE impact of adaptation parameters and time on layer was investigated with subjective crowdsourcing studies. The results were used to compute a QoE-optimal adaptation strategy for given video and network conditions. This allows video service providers to develop and benchmark improved adaptation logics for HAS. Furthermore, the thesis investigated concepts to monitor video QoE on application and network layer, which can be used by network providers in the QoE-aware traffic management cycle. Moreover, an analytic and simulative performance evaluation of QoE-aware traffic management on a bottleneck link was conducted. Finally, the thesis investigated socially-aware traffic management for HAS via Wi-Fi offloading of mobile HAS flows. A model for the distribution of public Wi-Fi hotspots and a platform for socially-aware traffic management on private home routers was presented. A simulative performance evaluation investigated the impact of Wi-Fi offloading on the QoE and energy consumption of mobile HAS.}, subject = {Quality of Experience}, language = {en} } @phdthesis{Sharan2017, author = {Sharan, Malvika}, title = {Bio-computational identification and characterization of RNA-binding proteins in bacteria}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153573}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {RNA-binding proteins (RBPs) have been extensively studied in eukaryotes, where they post-transcriptionally regulate many cellular events including RNA transport, translation, and stability. Experimental techniques, such as cross-linking and co-purification followed by either mass spectrometry or RNA sequencing has enabled the identification and characterization of RBPs, their conserved RNA-binding domains (RBDs), and the regulatory roles of these proteins on a genome-wide scale. These developments in quantitative, high-resolution, and high-throughput screening techniques have greatly expanded our understanding of RBPs in human and yeast cells. In contrast, our knowledge of number and potential diversity of RBPs in bacteria is comparatively poor, in part due to the technical challenges associated with existing global screening approaches developed in eukaryotes. Genome- and proteome-wide screening approaches performed in silico may circumvent these technical issues to obtain a broad picture of the RNA interactome of bacteria and identify strong RBP candidates for more detailed experimental study. Here, I report APRICOT ("Analyzing Protein RNA Interaction by Combined Output Technique"), a computational pipeline for the sequence-based identification and characterization of candidate RNA-binding proteins encoded in the genomes of all domains of life using RBDs known from experimental studies. The pipeline identifies functional motifs in protein sequences of an input proteome using position-specific scoring matrices and hidden Markov models of all conserved domains available in the databases and then statistically score them based on a series of sequence-based features. Subsequently, APRICOT identifies putative RBPs and characterizes them according to functionally relevant structural properties. APRICOT performed better than other existing tools for the sequence-based prediction on the known RBP data sets. The applications and adaptability of the software was demonstrated on several large bacterial RBP data sets including the complete proteome of Salmonella Typhimurium strain SL1344. APRICOT reported 1068 Salmonella proteins as RBP candidates, which were subsequently categorized using the RBDs that have been reported in both eukaryotic and bacterial proteins. A set of 131 strong RBP candidates was selected for experimental confirmation and characterization of RNA-binding activity using RNA co-immunoprecipitation followed by high-throughput sequencing (RIP-Seq) experiments. Based on the relative abundance of transcripts across the RIP-Seq libraries, a catalogue of enriched genes was established for each candidate, which shows the RNA-binding potential of 90\% of these proteins. Furthermore, the direct targets of few of these putative RBPs were validated by means of cross-linking and co-immunoprecipitation (CLIP) experiments. This thesis presents the computational pipeline APRICOT for the global screening of protein primary sequences for potential RBPs in bacteria using RBD information from all kingdoms of life. Furthermore, it provides the first bio-computational resource of putative RBPs in Salmonella, which could now be further studied for their biological and regulatory roles. The command line tool and its documentation are available at https://malvikasharan.github.io/APRICOT/.}, language = {en} } @article{VargasCasanovaRodriguezGuerraUmanaPerezetal.2017, author = {Vargas Casanova, Yerly and Rodr{\´i}guez Guerra, Jorge Antonio and Uma{\~n}a P{\´e}rez, Yadi Adriana and Leal Castro, Aura Luc{\´i}a and Almanzar Reina, Giovanni and Garc{\´i}a Casta{\~n}eda, Javier Eduardo and Rivera Monroy, Zuly Jenny}, title = {Antibacterial synthetic peptides derived from bovine lactoferricin exhibit cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines}, series = {Molecules}, volume = {22}, journal = {Molecules}, number = {10}, doi = {10.3390/molecules22101641}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173887}, year = {2017}, abstract = {Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B, containing the RRWQWR motif, were designed, synthesized, purified, and characterized using RP-HPLC chromatography and MALDI-TOF mass spectrometry. The antibacterial activity of the designed peptides against E. coli (ATCC 11775 and 25922) and their cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines were evaluated. Dimeric and tetrameric peptides showed higher antibacterial activity in both bacteria strains than linear peptides. The dimeric peptide (RRWQWR)\(_2\)K-Ahx exhibited the highest antibacterial activity against the tested bacterial strains. Furthermore, the peptides with high antibacterial activity exhibited significant cytotoxic effect against the tested breast cancer cell lines. This cytotoxic effect was fast and dependent on the peptide concentration. The tetrameric molecule containing RRWQWR motif has an optimal cytotoxic effect at a concentration of 22 µM. The evaluated dimeric and tetrameric peptides could be considered as candidates for developing new therapeutic agents against breast cancer. Polyvalence of linear sequences could be considered as a novel and versatile strategy for obtaining molecules with high anticancer activity.}, language = {en} } @article{OPUS4-17371, title = {Search for triboson \({W^\pm}{W^\pm}{W^\mp}\) production in \(pp\) collisions at \(\sqrt{s}\) = 8 TeV with the ATLAS detector}, series = {European Physical Journal C}, volume = {77}, journal = {European Physical Journal C}, number = {141}, organization = {The ATLAS Collaboration}, doi = {10.1140/epjc/s10052-017-4692-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173710}, year = {2017}, abstract = {This paper reports a search for triboson \({W^\pm}{W^\pm}{W^\mp}\) production in two decay channels (\({W^\pm}{W^\pm}{W^\mp}\) → \({ℓ^\pm}{νℓ^\pm}{νℓ^\mp}{ν}\) and \({W^\pm}{W^\pm}{W^\mp}\) → \({ℓ^\pm}{νℓ^\pm}{νjj}\) with \(ℓ=e,μ\)) in proton-proton collision data corresponding to an integrated luminosity of 20.3 fb\(^{-1}\) at a centre-of-mass energy of 8 TeV with the ATLAS detector at the Large Hadron Collider. Events with exactly three charged leptons, or two leptons with the same electric charge in association with two jets, are selected. The total number of events observed in data is consistent with the Standard Model (SM) predictions. The observed 95\% confidence level upper limit on the SM \({W^\pm}{W^\pm}{W^\mp}\) production cross section is found to be 730 fb with an expected limit of 560 fb in the absence of SM \({W^\pm}{W^\pm}{W^\mp}\) production. Limits are also set on \(WWWW\) anomalous quartic gauge couplings.}, language = {en} } @phdthesis{Burger2017, author = {Burger, Valentin}, title = {Performance Evalution and Optimization of Content Delivery Networks}, issn = {1432-8801}, doi = {10.25972/OPUS-15276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152769}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Content Delivery Networks (CDNs) are networks that distribute content in the Internet. CDNs are increasingly responsible for the largest share of traffic in the Internet. CDNs distribute popular content to caches in many geographical areas to save bandwidth by avoiding unnecessary multihop retransmission. By bringing the content geographically closer to the user, CDNs also reduce the latency of the services. Besides end users and content providers, which require high availability of high quality content, CDN providers and Internet Service Providers (ISPs) are interested in an efficient operation of CDNs. In order to ensure an efficient replication of the content, CDN providers have a network of (globally) distributed interconnected datacenters at different points of presence (PoPs). ISPs aim to provide reliable and high speed Internet access. They try to keep the load on the network low and to reduce cost for connectivity with other ISPs. The increasing number of mobile devices such as smart phones and tablets, high definition video content and high resolution displays result in a continuous growth in mobile traffic. This growth in mobile traffic is further accelerated by newly emerging services, such as mobile live streaming and broadcasting services. The steep increase in mobile traffic is expected to reach by 2018 roughly 60\% of total network traffic, the majority of which will be video. To handle the growth in mobile networks, the next generation of 5G mobile networks is designed to have higher access rates and an increased densification of the network infrastructure. With the explosion of access rates and number of base stations the backhaul of wireless networks will become congested. To reduce the load on the backhaul, the research community suggests installing local caches in gateway routers between the wireless network and the Internet, in base stations of different sizes, and in end-user devices. The local deployment of caches allows keeping the traffic within the ISPs network. The caches are organized in a hierarchy, where caches in the lowest tier are requested first. The request is forwarded to the next tier, if the requested object is not found. Appropriate evaluation methods are required to optimally dimension the caches dependent on the traffic characteristics and the available resources. Additionally methods are necessary that allow performance evaluation of backhaul bandwidth aggregation systems, which further reduce the load on the backhaul. This thesis analyses CDNs utilizing locally available resources and develops the following evaluations and optimization approaches: Characterization of CDNs and distribution of resources in the Internet, analysis and optimization of hierarchical caching systems with bandwidth constraints and performance evaluation of bandwidth aggregation systems.}, subject = {CDN-Netzwerk}, language = {en} } @article{HalderAbdelfatahJoetal.2017, author = {Halder, Luke D. and Abdelfatah, Mahmoud A. and Jo, Emeraldo A. H. and Jacobsen, Ilse D. and Westermann, Martin and Beyersdorf, Niklas and Lorkowski, Stefan and Zipfel, Peter F. and Skerka, Christine}, title = {Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans}, series = {Frontiers in Immunology}, volume = {7}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2016.00671}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181127}, year = {2017}, abstract = {Upon systemic infection with human pathogenic yeast Candida albicans (C. albicans), human monocytes and polymorph nuclear neutrophilic granulocytes are the first immune cells to respond and come into contact with C. albicans. Monocytes exert immediate candidacidal activity and inhibit germination, mediate phagocytosis, and kill fungal cells. Here, we show that human monocytes spontaneously respond to C. albicans cells via phagocytosis, decondensation of nuclear DNA, and release of this decondensed DNA in the form of extracellular traps (called monocytic extracellular traps: MoETs). Both subtypes of monocytes (CD14\(^{++}\)CD16\(^-\)/CD14\(^+\)CD16\(^+\)) formed MoETs within the first hours upon contact with C. albicans. MoETs were characterized by the presence of citrullinated histone, myeloperoxidase, lactoferrin, and elastase. MoETs were also formed in response to Staphylococcus aureus and Escherichia coli, indicating a general reaction of monocytes to infectious microbes. MoET induction differs from extracellular trap formation in macrophages as MoETs are not triggered by simvastatin, an inhibitor of cholesterol synthesis and inducer of extracellular traps in macrophages. Extracellular traps from both monocytes and neutrophils activate complement and C3b is deposited. However, factor H (FH) binds via C3b to the extracellular DNA, mediates cofactor activity, and inhibits the induction of the inflammatory cytokine interleukin-1 beta in monocytes. Altogether, the results show that human monocytes release extracellular DNA traps in response to C. albicans and that these traps finally bind FH via C3b to presumably support clearance without further inflammation.}, language = {en} } @article{HankirPattPattetal.2017, author = {Hankir, Mohammed K. and Patt, Marianne and Patt, J{\"o}rg T. W. and Becker, Georg A. and Rullmann, Michael and Kranz, Mathias and Deuther-Conrad, Winnie and Schischke, Kristin and Seyfried, Florian and Brust, Peter and Hesse, Swen and Sabri, Osama and Kr{\"u}gel, Ute and Fenske, Wiebke}, title = {Suppressed fat appetite after Roux-en-Y gastric bypass surgery associates with reduced brain mu-opioid receptor availability in diet-induced obese male rats}, series = {Frontiers in Neuroscience}, volume = {10}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2016.00620}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181130}, year = {2017}, abstract = {Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.}, language = {en} } @book{Knoll2017, author = {Knoll, Leonhard}, title = {De exemplis deterrentibus : Bemerkenswerte Befunde aus der Praxis der rechtsgepr{\"a}gten Unternehmensbewertung in Aufgabenform}, edition = {1. Auflage}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-060-3 (print)}, doi = {10.25972/WUP-978-3-95826-061-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147587}, publisher = {W{\"u}rzburg University Press}, pages = {124}, year = {2017}, abstract = {Das vorliegende Buch besch{\"a}ftigt sich anhand einer Sammlung von realen F{\"a}llen, die in Aufgabenform formuliert sind, mit dem leider oft gest{\"o}rten Verh{\"a}ltnis von Theorie und Praxis in der rechtsgepr{\"a}gten Unternehmensbewertung. Es weist {\"a}hnlich wie „normale" Fallsammlungen die jeweiligen Aufgabenstellungen und die zugeh{\"o}rigen L{\"o}sungen aus. Die eigentlichen Fragestellungen in den Aufgabentexten sind durch kurze Erl{\"a}uterungen eingerahmt, damit jeder Fall als solcher von einem mit Bewertungsfragen halbwegs Vertrauten relativ leicht verstanden und in seiner Bedeutung eingeordnet werden kann. Dieses Vorgehen {\"a}hnelt wiederum Lehrb{\"u}chern, die Inhalte {\"u}ber F{\"a}lle vermitteln, nur dass hier nicht hypothetische F{\"a}lle das jeweils idealtypisch richtige Vorgehen zeigen, sondern Praxisf{\"a}lle plakative Verst{\"o}ße contra legem artis.}, subject = {Unternehmensbewertung}, language = {de} } @article{BenderRothJob2017, author = {Bender, Oliver and Roth, Charlotte E. and Job, Hubert}, title = {Protected areas and population development in the alps}, series = {eco.mont : Journal on Protected Mountain Areas Research and Management}, volume = {9}, journal = {eco.mont : Journal on Protected Mountain Areas Research and Management}, number = {Special issue}, doi = {10.1553/eco.mont-9-sis5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181901}, year = {2017}, abstract = {Nearly a quarter of the Alpine area is covered by a dense network of large protected areas (LPAs) of the four categories national park(NP), biosphere reserve (BR), nature park and world natural heritage site (WNHS). From the time of early industrialization, the Alpine area has undergone a mixed and increasingly polarized demographic development between the poles of immigration and emigration. This article investigates the possible mutual impact of population development and the existence of LPAs. The research design includes a quantitative survey of all Alpine LPAs in terms of their population development and the structure of immigration in the first decade of the 21st century. This will be linked with qualitative expert interviews in four selected NPs. The overall results allow an interpretation of the statistical correlations between type of LPA and migration.}, language = {en} } @article{SayedSchimmerShadeetal.2017, author = {Sayed, Sameh and Schimmer, Christoph and Shade, Ina and Leyh, Rainer and Aleksic, Ivan}, title = {Combined pulmonary and left ventricular support with veno-pulmonary ECMO and impella 5.0 for cardiogenic shock after coronary surgery}, series = {Journal of Cardiothoracic Surgery}, volume = {12}, journal = {Journal of Cardiothoracic Surgery}, number = {38}, doi = {10.1186/s13019-017-0594-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157598}, year = {2017}, abstract = {Background: Mechanical circulatory support is a common practice nowadays in the management of patients after cardiogenic shock due to myocardial infarction. The single or combined use of one or more devices for mechanical support depends not only on the advantage or disadvantage of these devices but also on the timing of use of these devices before the development of multi organ failure. In our case we used more than one tool for mechanical circulatory support during the prolonged and complicated course of our patient with postcardiotomy cardiogenic shock after coronary artery bypass surgery. Case Presentation: We describe the combined use of Impella 5.0 and veno- pulmonary extra corporeal membrane oxygenation (VP-ECMO) for biventricular failure in a 52 years—old man. He presented with cardiogenic shock after inferior wall ST-elevation myocardial infarction. After emergency coronary artery bypass surgery and failure to wean from extracorporeal circulation we employed V-P ECMO and consecutively Impella 5.0 to manage the primarily failing right and secondarily failing left ventricles. He remained hemodynamically stable on both Impella 5.0 and VP-ECMO until Heart Mate II left ventricular assist device implantation on the 14th postoperative day. Right sided support was weaned on 66th postoperative day. The patient remained in the intensive care unit for 77 days. During his prolonged stay, he underwent renal replacement therapy and tracheostomy with complete recovery. Six months later, he was successfully heart transplanted and has completed three and half years of unremarkable follow up. Conclusions: The combined use of VP ECMO and Impella 5.0 is effective in the management of postcardiotomy biventricular failure as a bridge for further mechanical support or heart transplantation.}, language = {en} } @article{StrasserSchrauthDembskietal.2017, author = {Straßer, Marion and Schrauth, Joachim H. X. and Dembski, Sofia and Haddad, Daniel and Ahrens, Bernd and Schweizer, Stefan and Christ, Bastian and Cubukova, Alevtina and Metzger, Marco and Walles, Heike and Jakob, Peter M. and Sextl, Gerhard}, title = {Calcium fluoride based multifunctional nanoparticles for multimodal imaging}, series = {Beilstein Journal of Nanotechnology}, volume = {8}, journal = {Beilstein Journal of Nanotechnology}, doi = {10.3762/bjnano.8.148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170657}, pages = {1484-1493}, year = {2017}, abstract = {New multifunctional nanoparticles (NPs) that can be used as contrast agents (CA) in different imaging techniques, such as photoluminescence (PL) microscopy and magnetic resonance imaging (MRI), open new possibilities for medical imaging, e.g., in the fields of diagnostics or tissue characterization in regenerative medicine. The focus of this study is on the synthesis and characterization of CaF\(_{2}\):(Tb\(^{3+}\),Gd\(^{3+}\)) NPs. Fabricated in a wet-chemical procedure, the spherical NPs with a diameter of 5-10 nm show a crystalline structure. Simultaneous doping of the NPs with different lanthanide ions, leading to paramagnetism and fluorescence, makes them suitable for MR and PL imaging. Owing to the Gd\(^{3+}\) ions on the surface, the NPs reduce the MR T\(_{1}\) relaxation time constant as a function of their concentration. Thus, the NPs can be used as a MRI CA with a mean relaxivity of about r = 0.471 mL·mg\(^{-1}\)·s\(^{-1}\). Repeated MRI examinations of four different batches prove the reproducibility of the NP synthesis and determine the long-term stability of the CAs. No cytotoxicity of NP concentrations between 0.5 and 1 mg·mL\(^{-1}\) was observed after exposure to human dermal fibroblasts over 24 h. Overall this study shows, that the CaF\(_{2}\):(Tb\(^{3+}\),Gd\(^{3+}\)) NPs are suitable for medical imaging.}, language = {en} } @article{MeiningerBlumSchameletal.2017, author = {Meininger, Susanne and Blum, Carina and Schamel, Martha and Barralet, Jake E. and Ignatius, Anita and Gbureck, Uwe}, title = {Phytic acid as alternative setting retarder enhanced biological performance of dicalcium phosphate cement in vitro}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {558}, doi = {10.1038/s41598-017-00731-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171047}, year = {2017}, abstract = {Dicalcium phosphate cement preparation requires the addition of setting retarders to meet clinical requirements regarding handling time and processability. Previous studies have focused on the influence of different setting modifiers on material properties such as mechanical performance or injectability, while ignoring their influence on biological cement properties as they are used in low concentrations in the cement pastes and the occurrence of most compounds in human tissues. Here, analyses of both material and biological behavior were carried out on samples with common setting retardants (citric acid, sodium pyrophosphate, sulfuric acid) and novel (phytic acid). Cytocompatibility was evaluated by in vitro tests with osteoblastic (hFOB 1.19) and osteoclastic (RAW 264.7) cells. We found cytocompatibility was better for sodium pyrophosphate and phytic acid with a three-fold cell metabolic activity by WST-1 test, whereas samples set with citric acid showed reduced cell number as well as cell activity. The compressive strength (CS) of cements formed with phytic acid (CS = 13 MPa) were nearly equal to those formed with citric acid (CS = 15 MPa) and approximately threefold higher than for other setting retardants. Due to a proven cytocompatibility and high mechanical strength, phytic acid seems to be a candidate replacement setting retardant for dicalcium phosphate cements.}, language = {en} } @article{DoehlerSchneiderEckertetal.2017, author = {D{\"o}hler, Anja and Schneider, Theresa and Eckert, Ina and Ribechini, Eliana and Andreas, Nico and Riemann, Marc and Reizis, Boris and Weih, Falk and Lutz, Manfred B.}, title = {RelB\(^{+}\) Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3\(^{+}\) Regulatory T Cells}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {726}, doi = {10.3389/fimmu.2017.00726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158121}, year = {2017}, abstract = {Thymus-derived natural Foxp3\(^{+}\) CD4\(^{+}\) regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelB\(^{fl/fl}\) mice (RelB\(^{DCko}\)), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103\(^{-}\) Langerin\(^{-}\) dermal DCs (dDCs) and Langerhans cells but not CD103\(^{+}\) Langerin\(^{+}\) dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4\(^{+}\) CD44\(^{high}\) CD25\(^{low}\) memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelB\(^{DCko}\) mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelB\(^{DCko}\) mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2\(^{+}\) Tml frequencies during homeostasis.}, language = {en} } @article{MaierhoferFlunkertDittrichetal.2017, author = {Maierhofer, Anna and Flunkert, Julia and Dittrich, Marcus and M{\"u}ller, Tobias and Schindler, Detlev and Nanda, Indrajit and Haaf, Thomas}, title = {Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0177442}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170895}, pages = {e0177442}, year = {2017}, abstract = {Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.}, language = {en} } @article{BornZinnerSperlich2017, author = {Born, Dennis-Peter and Zinner, Christoph and Sperlich, Billy}, title = {The mucosal immune function is not compromised during a period of high-intensity interval training. Is it time to reconsider an old assumption?}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {485}, doi = {10.3389/fphys.2017.00485}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158025}, year = {2017}, abstract = {Purpose: The aim of the study was to evaluate the mucosal immune function and circadian variation of salivary cortisol, Immunoglobin-A (sIgA) secretion rate and mood during a period of high-intensity interval training (HIIT) compared to long-slow distance training (LSD). Methods: Recreational male runners (n = 28) completed nine sessions of either HIIT or LSD within 3 weeks. The HIIT involved 4 × 4 min of running at 90-95\% of maximum heart rate interspersed with 3 min of active recovery while the LSD comprised of continuous running at 70-75\% of maximum heart rate for 60-80 min. The psycho-immunological stress-response was investigated with a full daily profile of salivary cortisol and immunoglobin-A (sIgA) secretion rate along with the mood state on a baseline day, the first and last day of training and at follow-up 4 days after the last day of training. Before and after the training period, each athlete's running performance and peak oxygen uptake (V·O\(_{2peak}\)) was determined with an incremental exercise test. Results: The HIIT resulted in a longer time-to-exhaustion (P = 0.02) and increased V·O\(_{2peak}\) compared to LSD (P = 0.01). The circadian variation of sIgA secretion rate showed highest values in the morning immediately after waking up followed by a decrease throughout the day in both groups (P < 0.05). With HIIT, the wake-up response of sIgA secretion rate was higher on the last day of training (P < 0.01) as well as the area under the curve (AUC\(_{G}\)) higher on the first and last day of training and follow-up compared to the LSD (P = 0.01). Also the AUC\(_{G}\) for the sIgA secretion rate correlated with the increase in V·O\(_{2peak}\) and running performance. The AUC\(_{G}\) for cortisol remained unaffected on the first and last day of training but increased on the follow-up day with both, HIIT and LSD (P < 0.01). Conclusion: The increased sIgA secretion rate with the HIIT indicates no compromised mucosal immune function compared to LSD and shows the functional adaptation of the mucosal immune system in response to the increased stress and training load of nine sessions of HIIT.}, language = {en} } @article{ZinnerBornSperlich2017, author = {Zinner, Christoph and Born, Dennis-Peter and Sperlich, Billy}, title = {Ischemic preconditioning does not alter performance in multidirectional high-intensity intermittent exercise}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2017.01029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159348}, pages = {1029}, year = {2017}, abstract = {Purpose: Research dealing with ischemic preconditioning (IPC) has primarily focused on variables associated to endurance performance with little research about the acute responses of IPC on repeated multidirectional running sprint performance. Here we aimed to investigate the effects of IPC of the arms and the legs on repeated running sprint performance with changes-of-direction (COD) movements. Methods: Thirteen moderately-to-well-trained team-sport athletes (7 males; 6 females; age: 24 ± 2 years, size: 175 ± 8 cm, body mass: 67.9 ± 8.1 kg) performed 16 × 30 m all-out sprints (15 s rest) with multidirectional COD movements on a Speedcourt\(^{©}\) with IPC (3 × 5 min) of the legs (IPC\(_{leg}\); 240 mm Hg) or of the arms (remote IPC: IPC\(_{remote}\); 180-190 mm Hg) 45 min before the sprints and a control trial (CON; 20 mm Hg). Results: The mean (±SD) time for the 16 × 30 m multidirectional COD sprints was similar between IPC\(_{leg}\) (Mean t: 16.0 ± 1.8 s), IPC\(_{remote}\) (16.2 ± 1.7 s), and CON (16.0 ± 1.6 s; p = 0.50). No statistical differences in oxygen uptake (mean difference: 0\%), heart rate (1.1\%) nor muscle oxygen saturation of the vastus lateralis (4.7\%) and biceps brachii (7.8\%) between the three conditions were evident (all p > 0.05). Conclusions: IPC (3 × 5 min) of the legs (220 mm Hg) or arms (180-190 mm Hg; remote IPC) applied 45 min before 16 × 30 m repeated multidirectional running sprint exercise does not improve sprint performance, oxygen uptake, heart rate nor muscle oxygen saturation of the vastus lateralis muscle when compared to a control trial.}, language = {en} } @article{RoeschBiesterBogenriederetal.2017, author = {R{\"o}sch, Manfred and Biester, Harald and Bogenrieder, Arno and Eckmeier, Eileen and Ehrmann, Otto and Gerlach, Renate and Hall, Mathias and Hartkopf-Fr{\"o}der, Christoph and Herrmann, Ludger and Kury, Birgit and Lechterbeck, Jutta and Schier, Wolfram and Schulz, Erhard}, title = {Late neolithic agriculture in temperate Europe—a long-term experimental approach}, series = {Land}, volume = {6}, journal = {Land}, number = {1}, issn = {2073-445X}, doi = {10.3390/land6010011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198103}, pages = {11}, year = {2017}, abstract = {Long-term slash-and-burn experiments, when compared with intensive tillage without manuring, resulted in a huge data set relating to potential crop yields, depending on soil quality, crop type, and agricultural measures. Cultivation without manuring or fallow phases did not produce satisfying yields, and mono-season cropping on freshly cleared and burned plots resulted in rather high yields, comparable to those produced during modern industrial agriculture - at least ten-fold the ones estimated for the medieval period. Continuous cultivation on the same plot, using imported wood from adjacent areas as fuel, causes decreasing yields over several years. The high yield of the first harvest of a slash-and-burn agriculture is caused by nutrient input through the ash produced and mobilization from the organic matter of the topsoil, due to high soil temperatures during the burning process and higher topsoil temperatures due to the soil's black surface. The harvested crops are pure, without contamination of any weeds. Considering the amount of work required to fight weeds without burning, the slash-and-burn technique yields much better results than any other tested agricultural approach. Therefore, in dense woodland, without optimal soils and climate, slash-and-burn agriculture seems to be the best, if not the only, feasible method to start agriculture, for example, during the Late Neolithic, when agriculture expanded from the loess belt into landscapes less suitable for agriculture. Extensive and cultivation with manuring is more practical in an already-open landscape and with a denser population, but its efficiency in terms of the ratio of the manpower input to food output, is worse. Slash-and-burn agriculture is not only a phenomenon of temperate European agriculture during the Neolithic, but played a major role in land-use in forested regions worldwide, creating anthromes on a huge spatial scale.}, language = {en} } @article{SchuhmannFluri2017, author = {Schuhmann, Michael K. and Fluri, Felix}, title = {Effects of fullerenols on mouse brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms18081783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072}, year = {2017}, abstract = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.}, language = {en} } @article{DaineseSchneiderKraussetal.2017, author = {Dainese, Matteo and Schneider, Gudrun and Krauss, Jochen and Steffan-Dewenter, Ingolf}, title = {Complementarity among natural enemies enhances pest suppression}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-08316-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158621}, pages = {8172}, year = {2017}, abstract = {Natural enemies have been shown to be effective agents for controlling insect pests in crops. However, it remains unclear how different natural enemy guilds contribute to the regulation of pests and how this might be modulated by landscape context. In a field exclusion experiment in oilseed rape (OSR), we found that parasitoids and ground-dwelling predators acted in a complementary way to suppress pollen beetles, suggesting that pest control by multiple enemies attacking a pest during different periods of its occurrence in the field improves biological control efficacy. The density of pollen beetle significantly decreased with an increased proportion of non-crop habitats in the landscape. Parasitism had a strong effect on pollen beetle numbers in landscapes with a low or intermediate proportion of non-crop habitats, but not in complex landscapes. Our results underline the importance of different natural enemy guilds to pest regulation in crops, and demonstrate how biological control can be strengthened by complementarity among natural enemies. The optimization of natural pest control by adoption of specific management practices at local and landscape scales, such as establishing non-crop areas, low-impact tillage, and temporal crop rotation, could significantly reduce dependence on pesticides and foster yield stability through ecological intensification in agriculture.}, language = {en} } @article{Middelhoff2017, author = {Middelhoff, Frederike}, title = {Literary autozoographies: contextualizing species life in german animal autobiography}, series = {Humanities}, volume = {6}, journal = {Humanities}, number = {2}, publisher = {MDPI}, issn = {2076-0787}, doi = {10.3390/h6020023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198052}, pages = {23}, year = {2017}, abstract = {What does it mean to take animal autobiography seriously and how can we account for the representation of life-narrating animals? The article investigates animal autobiographies as 'literary autozoographies', drawing attention to both the generic contexts and the epistemological premises of these texts. Adopting a double-bind approach stemming from autobiographical research as well as cultural animal studies, the article focuses on early nineteenth-century equine autozoographies from the German-speaking tradition. These texts are discussed exemplarily in relation to the parameters of fictional autobiographies, before they are contextualized with historical discourses regarding horses in natural history and so-called 'horse-science'. Due to the fact that the poetics and aesthetics of the genre are modeled on the templates of factual autobiographies, the article argues that literary autozoographies can be read as fictional autobiographies as well as meta-auto/biographical discourse undermining autobiographical conventions. Furthermore, it shows that literary autozoography and zoology share a common historical and ideological epistemology accounting for the representation of animals in both fields. Literary autozoographies thus participate in the negotiation and production of species-specific knowledge. Reading Life of the Mecklenburg Mare Amante (1804), Life of a Job Horse (1807) and Life of a Worn-Out Hack (1819) alongside equine-centric discourses around 1800, the article demonstrates in what ways these texts can be regarded as part of a regime of knowledge attributing emotions and cognitive capacities to horses, while simultaneously arguing for humane treatment on the basis of interspecies homologies.}, language = {en} } @article{Duerner2017, author = {D{\"u}rner, Benedikt}, title = {Der lyrische Triebt{\"a}ter Andr{\´e} Pieyre de Mandiargues Gewalt und Erotik im Gedichtband L'{\^A}ge de craie}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {3}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2510-2613}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172876}, pages = {83-105}, year = {2017}, abstract = {The surrealists are not the only influence on the literary efforts of Andr{\´e} Pieyre de Mandiargues - but it's this influence that makes his oeuvre capable for an analysis based on Freudian theories. This way of an analysis is even more appropriate knowing that two of Mandiargues' main and favourite themes - the eroticism and the violence - coincide with the Freudian life and destruction drive. Analysing the two poems Les filles des gobes and Les ruines de l'amour from the volume of poems L'{\^A}ge de craie, it's these two paradigms that are clearly recognizable: Mandiargues' symbolism reveals the duality of the domination by desires.}, language = {de} } @article{WaiderPoppLangeetal.2017, author = {Waider, J and Popp, S and Lange, MD and Kern, R and Kolter, JF and Kobler, J and Donner, NC and Lowe, KR and Malzbender, JH and Brazell, CJ and Arnold, MR and Aboagye, B and Schmitt-B{\"o}hrer, A and Lowry, CA and Pape, HC and Lesch, KP}, title = {Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice}, series = {Translational Psychiatry}, volume = {7}, journal = {Translational Psychiatry}, number = {e1246}, doi = {10.1038/tp.2017.209}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170239}, year = {2017}, abstract = {Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.}, language = {en} } @article{HampeFriedmanEdgertonetal.2017, author = {Hampe, Irene A. I. and Friedman, Justin and Edgerton, Mira and Morschh{\"a}user, Joachim}, title = {An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses}, series = {PLoS Pathogens}, volume = {13}, journal = {PLoS Pathogens}, number = {9}, doi = {10.1371/journal.ppat.1006655}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158883}, pages = {e1006655}, year = {2017}, abstract = {The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C. albicans also can develop resistance to the antimicrobial peptide histatin 5, which is secreted in the saliva of humans to protect the oral mucosa from pathogenic microbes. As histatin 5 has been shown to be transported out of C. albicans cells by the Flu1 efflux pump, we screened a library of C. albicans strains that contain artificially activated forms of all zinc cluster transcription factors of this fungus for increased FLU1 expression. We found that a hyperactive Mrr1, which confers fluconazole resistance by upregulating the multidrug efflux pump MDR1 and other genes, also causes FLU1 overexpression. Similarly to the artificially activated Mrr1, naturally occurring gain-of-function mutations in this transcription factor also caused FLU1 upregulation and increased histatin 5 resistance. Surprisingly, however, Mrr1-mediated histatin 5 resistance was mainly caused by the upregulation of MDR1 instead of FLU1, revealing a previously unrecognized function of the Mdr1 efflux pump. Fluconazole-resistant clinical C. albicans isolates with different Mrr1 gain-of-function mutations were less efficiently killed by histatin 5, and this phenotype was reverted when MRR1 was deleted. Therefore, antimycotic therapy can promote the evolution of strains that, as a consequence of drug resistance mutations, simultaneously have acquired increased resistance against an innate host defense mechanism and are thereby better adapted to certain host niches.}, language = {en} } @article{SharanFoerstnerEulalioetal.2017, author = {Sharan, Malvika and F{\"o}rstner, Konrad U. and Eulalio, Ana and Vogel, J{\"o}rg}, title = {APRICOT: an integrated computational pipeline for the sequence-based identification and characterization of RNA-binding proteins}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {11}, doi = {10.1093/nar/gkx137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157963}, pages = {e96}, year = {2017}, abstract = {RNA-binding proteins (RBPs) have been established as core components of several post-transcriptional gene regulation mechanisms. Experimental techniques such as cross-linking and co-immunoprecipitation have enabled the identification of RBPs, RNA-binding domains (RBDs) and their regulatory roles in the eukaryotic species such as human and yeast in large-scale. In contrast, our knowledge of the number and potential diversity of RBPs in bacteria is poorer due to the technical challenges associated with the existing global screening approaches. We introduce APRICOT, a computational pipeline for the sequence-based identification and characterization of proteins using RBDs known from experimental studies. The pipeline identifies functional motifs in protein sequences using position-specific scoring matrices and Hidden Markov Models of the functional domains and statistically scores them based on a series of sequence-based features. Subsequently, APRICOT identifies putative RBPs and characterizes them by several biological properties. Here we demonstrate the application and adaptability of the pipeline on large-scale protein sets, including the bacterial proteome of Escherichia coli. APRICOT showed better performance on various datasets compared to other existing tools for the sequence-based prediction of RBPs by achieving an average sensitivity and specificity of 0.90 and 0.91 respectively. The command-line tool and its documentation are available at https://pypi.python.org/pypi/bio-apricot.}, language = {en} } @article{SilvaVilchesPletinckxLohnertetal.2017, author = {Silva-Vilches, Cinthia and Pletinckx, Katrien and Lohnert, Miriam and Pavlovic, Vladimir and Ashour, Diyaaeldin and John, Vini and Vendelova, Emilia and Kneitz, Susanne and Zhou, Jie and Chen, Rena and Reinheckel, Thomas and Mueller, Thomas D. and Bodem, Jochen and Lutz, Manfred B.}, title = {Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0178114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158244}, pages = {e0178114}, year = {2017}, abstract = {Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3\(^{+}\) induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT\(^{hi}\), CT\(^{lo}\)) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT\(^{hi}\) conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT\(^{lo}\)- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3\(^{+}\) iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT\(^{lo}\)- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3\(^{+}\) Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.}, language = {en} } @article{HergovitsMaisHaanetal.2017, author = {Hergovits, Sabine and Mais, Christine and Haan, Claude and Costa-Pereira, Ana P. and Hermanns, Heike M.}, title = {Oncostatin M induces RIG-I and MDA5 expression and enhances the double-stranded RNA response in fibroblasts}, series = {Journal of Cellular and Molecular Medicine}, volume = {21}, journal = {Journal of Cellular and Molecular Medicine}, number = {11}, doi = {10.1111/jcmm.13221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159558}, pages = {3087-3099}, year = {2017}, abstract = {Interleukin (IL)-6-type cytokines have no direct antiviral activity; nevertheless, they display immune-modulatory functions. Oncostatin M (OSM), a member of the IL-6 family, has recently been shown to induce a distinct number of classical interferon stimulated genes (ISG). Most of them are involved in antigen processing and presentation. However, induction of retinoic acid-inducible gene (RIG)-I-like receptors (RLR) has not been investigated. Here we report that OSM has the capability to induce the expression of the DExD/H-Box RNA helicases RIG-I and melanoma differentiation antigen 5 (MDA5) as well as of the transcription factors interferon regulatory factor (IRF)1, IRF7 and IRF9 in primary fibroblasts. Induction of the helicases depends on tyrosine as well as serine phosphorylation of STAT1. Moreover, we could show that the OSM-induced STAT1 phosphorylation is predominantly counter-regulated by a strong STAT3-dependent SOCS3 induction, as Stat3 as well as Socs3 knock-down results in an enhanced and prolonged helicase and IRF expression. Other factors involved in regulation of STAT1 or IRF1 activity, like protein tyrosine phosphatase, non-receptor type 2 (PTPN2), promyelocytic leukaemia protein (PML) or small ubiquitin-related modifier 1 (SUMO1), play a minor role in OSM-mediated induction of RLR. Remarkably, OSM and interferon-γ (IFN-γ) synergize to mediate transcription of RLR and pre-treatment of fibroblasts with OSM fosters the type I interferon production in response to a subsequent encounter with double-stranded RNA. Together, these findings suggest that the OSM-induced JAK/STAT1 signalling is implicated in virus protection of non-professional immune cells and may cooperate with interferons to enhance RLR expression in these cells.}, language = {en} } @article{ZellerHeidemeierGrigoleitetal.2017, author = {Zeller, Daniel and Heidemeier, Anke and Grigoleit, G{\"o}tz Ulrich and M{\"u}llges, Wolfgang}, title = {Case report: subacute tetraplegia in an immunocompromised patient}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {31}, doi = {10.1186/s12883-017-0814-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157576}, year = {2017}, abstract = {Background: Clinical reasoning in Neurology is based on general associations which help to deduce the site of the lesion. However, even "golden principles" may occasionally be deceptive. Here, we describe the case of subacute flaccid tetraparesis due to motor cortical lesions. To our knowledge, this is the first report to include an impressive illustration of nearly symmetric motor cortical involvement of encephalitis on brain MRI. Case presentation: A 51 year old immunocompromized man developed a high-grade pure motor flaccid tetraparesis over few days. Based on clinical presentation, critical illness polyneuromyopathy was suspected. However, brain MRI revealed symmetrical hyperintensities strictly limited to the subcortical precentral gyrus. An encephalitis, possibly due to CMV infection, turned out to be the most likely cause. Conclusion: While recognition of basic clinical patterns is indispensable in neurological reasoning, awareness of central conditions mimicking peripheral nervous disease may be crucial to detect unsuspected, potentially treatable conditions.}, language = {en} } @article{CollenburgBeyersdorfWieseetal.2017, author = {Collenburg, Lena and Beyersdorf, Niklas and Wiese, Teresa and Arenz, Christoph and Saied, Essa M. and Becker-Flegler, Katrin Anne and Schneider-Schaulies, Sibylle and Avota, Elita}, title = {The activity of the neutral sphingomyelinase is important in T cell recruitment and directional migration}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {1007}, doi = {10.3389/fimmu.2017.01007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158944}, year = {2017}, abstract = {Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton.}, language = {en} } @article{AwadOthmanStopper2017, author = {Awad, Eman and Othman, Eman M. and Stopper, Helga}, title = {Effects of resveratrol, lovastatin and the mTOR-inhibitor RAD-001 on insulin-induced genomic damage in vitro}, series = {Molecules}, volume = {22}, journal = {Molecules}, number = {12}, doi = {10.3390/molecules22122207}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159260}, pages = {2207}, year = {2017}, abstract = {Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy.}, language = {en} } @article{LohseBockMaiellaroetal.2017, author = {Lohse, Christian and Bock, Andreas and Maiellaro, Isabella and Hannawacker, Annette and Schad, Lothar R. and Lohse, Martin J. and Bauer, Wolfgang R.}, title = {Experimental and mathematical analysis of cAMP nanodomains}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0174856}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170972}, pages = {e0174856}, year = {2017}, abstract = {In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.}, language = {en} } @article{BenhalevyGuptaDananetal.2017, author = {Benhalevy, Daniel and Gupta, Sanjay K. and Danan, Charles H. and Ghosal, Suman and Sun, Hong-Wei and Kazemeier, Hinke G. and Paeschke, Katrin and Hafner, Markus and Juranek, Stefan A.}, title = {The Human CCHC-type Zinc Finger Nucleic Acid-Binding Protein Binds G-Rich Elements in Target mRNA Coding Sequences and Promotes Translation}, series = {Cell Reports}, volume = {18}, journal = {Cell Reports}, number = {12}, doi = {10.1016/j.celrep.2017.02.080}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171122}, pages = {2979-2990}, year = {2017}, abstract = {The CCHC-type zinc finger nucleic acid-binding protein (CNBP/ZNF9) is conserved in eukaryotes and is essential for embryonic development in mammals. It has been implicated in transcriptional, as well as post-transcriptional, gene regulation; however, its nucleic acid ligands and molecular function remain elusive. Here, we use multiple systems-wide approaches to identify CNBP targets and function. We used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to identify 8,420 CNBP binding sites on 4,178 mRNAs. CNBP preferentially bound G-rich elements in the target mRNA coding sequences, most of which were previously found to form G-quadruplex and other stable structures in vitro. Functional analyses, including RNA sequencing, ribosome profiling, and quantitative mass spectrometry, revealed that CNBP binding did not influence target mRNA abundance but rather increased their translational efficiency. Considering that CNBP binding prevented G-quadruplex structure formation in vitro, we hypothesize that CNBP is supporting translation by resolving stable structures on mRNAs.}, language = {en} } @article{ArmbrusterKriegWeissenbergeretal.2017, author = {Armbruster, Nicole and Krieg, Jennifer and Weißenberger, Manuel and Scheller, Carsten and Steinert, Andre F.}, title = {Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer}, series = {Frontiers in Pharmacology}, volume = {8}, journal = {Frontiers in Pharmacology}, number = {255}, doi = {10.3389/fphar.2017.00255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170919}, year = {2017}, abstract = {Background: Mesenchymal stem cells (MSCs) and their chondrogenic differentiation have been extensively investigated in vitro as MSCs provide an attractive source besides chondrocytes for cartilage repair therapies. Here we established prototype foamyviral vectors (FVV) that are derived from apathogenic parent viruses and are characterized by a broad host range and a favorable integration pattern into the cellular genome. As the inflammatory cytokine interleukin 1 beta (IL1β) is frequently present in diseased joints, the protective effects of FVV expressing the human interleukin 1 receptor antagonist protein (IL1RA) were studied in an established in vitro model (aggregate culture system) of chondrogenesis in the presence of IL1β. Materials and Methods: We generated different recombinant FVVs encoding enhanced green fluorescent protein (EGFP) or IL1RA and examined their transduction efficiencies and transgene expression profiles using different cell lines and human primary MSCs derived from bone marrow-aspirates. Transgene expression was evaluated by fluorescence microscopy (EGFP), flow cytometry (EGFP), and ELISA (IL1RA). For evaluation of the functionality of the IL1RA transgene to block the inhibitory effects of IL1β on chondrogenesis of primary MSCs and an immortalized MSC cell line (TERT4 cells), the cells were maintained following transduction as aggregate cultures in standard chondrogenic media in the presence or absence of IL1β. After 3 weeks of culture, pellets were harvested and analyzed by histology and immunohistochemistry for chondrogenic phenotypes. Results: The different FVV efficiently transduced cell lines as well as primary MSCs, thereby reaching high transgene expression levels in 6-well plates with levels of around 100 ng/ml IL1RA. MSC aggregate cultures which were maintained in chondrogenic media without IL1β supplementation revealed a chondrogenic phenotype by means of strong positive staining for collagen type II and matrix proteoglycan (Alcian blue). Addition of IL1β was inhibitory to chondrogenesis in untreated control pellets. In contrast, foamyviral mediated IL1RA expression rescued the chondrogenesis in pellets cultured in the presence of IL1β. Transduced MSC pellets reached thereby very high IL1RA transgene expression levels with a peak of 1087 ng/ml after day 7, followed by a decrease to 194 ng/ml after day 21, while IL1RA concentrations of controls were permanently below 200 pg/ml. Conclusion: Our results indicate that FVV are capable of efficient gene transfer to MSCs, while reaching IL1RA transgene expression levels, that were able to efficiently block the impacts of IL1β in vitro. FVV merit further investigation as a means to study the potential as a gene transfer tool for MSC based therapies for cartilage repair.}, language = {en} } @article{Kramer2017, author = {Kramer, Susanne}, title = {The ApaH-like phosphatase TbALPH1 is the major mRNA decapping enzyme of trypanosomes}, series = {PLoS Pathogens}, volume = {13}, journal = {PLoS Pathogens}, number = {6}, doi = {10.1371/journal.ppat.1006456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158482}, pages = {e1006456}, year = {2017}, abstract = {5'-3' decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5'-3' exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5'-3' degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5'-3' exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5'-3' decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5' polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA's 5' end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap.}, language = {en} } @article{KunzGoettlichWallesetal.2017, author = {Kunz, Meik and G{\"o}ttlich, Claudia and Walles, Thorsten and Nietzer, Sarah and Dandekar, Gudrun and Dandekar, Thomas}, title = {MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact}, series = {Tumor Biology}, volume = {39}, journal = {Tumor Biology}, number = {7}, doi = {10.1177/1010428317706430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158399}, year = {2017}, abstract = {MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.}, language = {en} } @article{MuellerDeubertSeefriedKrugetal.2017, author = {M{\"u}ller-Deubert, Sigrid and Seefried, Lothar and Krug, Melanie and Jakob, Franz and Ebert, Regina}, title = {Epidermal growth factor as a mechanosensitizer in human bone marrow stromal cells}, series = {Stem Cell Research}, volume = {24}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2017.08.012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170247}, pages = {69-76}, year = {2017}, abstract = {Epidermal growth factors (EGFs) e.g. EGF, heparin-binding EGF and transforming growth factor alpha and their receptors e.g. EGFR and ErbB2 control proinflammatory signaling and modulate proliferation in bone marrow stromal cells (BMSC). Interleukin-6 and interleukin-8 are EGF targets and participate in the inflammatory phase of bone regeneration via non-canonical wnt signaling. BMSC differentiation is also influenced by mechanical strain-related activation of ERK1/2 and AP-1, but the role of EGFR signaling in mechanotransduction is unclear. We investigated the effects of EGFR signaling in telomerase-immortalized BMSC, transfected with a luciferase reporter, comprising a mechanoresponsive AP1 element, using ligands, neutralizing antibodies and EGFR inhibitors on mechanotransduction and we found that EGF via EGFR increased the response to mechanical strain. Results were confirmed by qPCR analysis of mechanoresponsive genes. EGF-responsive interleukin-6 and interleukin-8 were synergistically enhanced by EGF stimulation and mechanical strain. We show here in immortalized and primary BMSC that EGFR signaling enhances mechanotransduction, indicating that the EGF system is a mechanosensitizer in BMSC. Alterations in mechanosensitivity and -adaptation are contributors to age-related diseases like osteoporosis and the identification of a suitable mechanosensitizer could be beneficial. The role of the synergism of these signaling cascades in physiology and disease remains to be unraveled.}, language = {en} } @article{MumcuogluSiverinoTabiszetal.2017, author = {Mumcuoglu, Didem and Siverino, Claudia and Tabisz, Barbara and Kluijtmans, Bas and Nickel, Joachim}, title = {How to use BMP-2 for clinical applications? A review on pros and cons of existing delivery strategies}, series = {Journal of Translational Science}, volume = {3}, journal = {Journal of Translational Science}, number = {5}, doi = {10.15761/JTS.1000195}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158678}, year = {2017}, abstract = {No abstract available.}, language = {en} } @article{SchusterKruegerSubotaetal.2017, author = {Schuster, Sarah and Kr{\"u}ger, Timothy and Subota, Ines and Thusek, Sina and Rotureau, Brice and Beilhack, Andreas and Engstler, Markus}, title = {Developmental adaptations of trypanosome motility to the tsetse fly host environments unravel a multifaceted in vivo microswimmer system}, series = {eLife}, volume = {6}, journal = {eLife}, doi = {10.7554/eLife.27656}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158662}, pages = {e27656}, year = {2017}, abstract = {The highly motile and versatile protozoan pathogen Trypanosoma brucei undergoes a complex life cycle in the tsetse fly. Here we introduce the host insect as an expedient model environment for microswimmer research, as it allows examination of microbial motion within a diversified, secluded and yet microscopically tractable space. During their week-long journey through the different microenvironments of the fly´s interior organs, the incessantly swimming trypanosomes cross various barriers and confined surroundings, with concurrently occurring major changes of parasite cell architecture. Multicolour light sheet fluorescence microscopy provided information about tsetse tissue topology with unprecedented resolution and allowed the first 3D analysis of the infection process. High-speed fluorescence microscopy illuminated the versatile behaviour of trypanosome developmental stages, ranging from solitary motion and near-wall swimming to collective motility in synchronised swarms and in confinement. We correlate the microenvironments and trypanosome morphologies to high-speed motility data, which paves the way for cross-disciplinary microswimmer research in a naturally evolved environment.}, language = {en} } @article{DrescherKleinNeumannetal.2017, author = {Drescher, Nora and Klein, Alexandra-Maria and Neumann, Peter and Ya{\~n}ez, Orlando and Leonhardt, Sara D.}, title = {Inside Honeybee Hives: Impact of Natural Propolis on the Ectoparasitic Mite Varroa destructor and Viruses}, series = {Insects}, volume = {8}, journal = {Insects}, number = {1}, doi = {10.3390/insects8010015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171164}, pages = {15}, year = {2017}, abstract = {Social immunity is a key factor for honeybee health, including behavioral defense strategies such as the collective use of antimicrobial plant resins (propolis). While laboratory data repeatedly show significant propolis effects, field data are scarce, especially at the colony level. Here, we investigated whether propolis, as naturally deposited in the nests, can protect honeybees against ectoparasitic mites Varroa destructor and associated viruses, which are currently considered the most serious biological threat to European honeybee subspecies, Apis mellifera, globally. Propolis intake of 10 field colonies was manipulated by either reducing or adding freshly collected propolis. Mite infestations, titers of deformed wing virus (DWV) and sacbrood virus (SBV), resin intake, as well as colony strength were recorded monthly from July to September 2013. We additionally examined the effect of raw propolis volatiles on mite survival in laboratory assays. Our results showed no significant effects of adding or removing propolis on mite survival and infestation levels. However, in relation to V. destructor, DWV titers increased significantly less in colonies with added propolis than in propolis-removed colonies, whereas SBV titers were similar. Colonies with added propolis were also significantly stronger than propolis-removed colonies. These findings indicate that propolis may interfere with the dynamics of V. destructor-transmitted viruses, thereby further emphasizing the importance of propolis for honeybee health.}, language = {en} } @article{GrobFleischmannGruebeletal.2017, author = {Grob, Robin and Fleischmann, Pauline N. and Gr{\"u}bel, Kornelia and Wehner, R{\"u}diger and R{\"o}ssler, Wolfgang}, title = {The role of celestial compass information in Cataglyphis ants during learning walks and for neuroplasticity in the central complex and mushroom bodies}, series = {Frontiers in Behavioral Neuroscience}, volume = {11}, journal = {Frontiers in Behavioral Neuroscience}, number = {226}, doi = {10.3389/fnbeh.2017.00226}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159235}, year = {2017}, abstract = {Central place foragers are faced with the challenge to learn the position of their nest entrance in its surroundings, in order to find their way back home every time they go out to search for food. To acquire navigational information at the beginning of their foraging career, Cataglyphis noda performs learning walks during the transition from interior worker to forager. These small loops around the nest entrance are repeatedly interrupted by strikingly accurate back turns during which the ants stop and precisely gaze back to the nest entrance—presumably to learn the landmark panorama of the nest surroundings. However, as at this point the complete navigational toolkit is not yet available, the ants are in need of a reference system for the compass component of the path integrator to align their nest entrance-directed gazes. In order to find this directional reference system, we systematically manipulated the skylight information received by ants during learning walks in their natural habitat, as it has been previously suggested that the celestial compass, as part of the path integrator, might provide such a reference system. High-speed video analyses of distinct learning walk elements revealed that even exclusion from the skylight polarization pattern, UV-light spectrum and the position of the sun did not alter the accuracy of the look back to the nest behavior. We therefore conclude that C. noda uses a different reference system to initially align their gaze directions. However, a comparison of neuroanatomical changes in the central complex and the mushroom bodies before and after learning walks revealed that exposure to UV light together with a naturally changing polarization pattern was essential to induce neuroplasticity in these high-order sensory integration centers of the ant brain. This suggests a crucial role of celestial information, in particular a changing polarization pattern, in initially calibrating the celestial compass system.}, language = {en} } @article{RoemerBollazziRoces2017, author = {R{\"o}mer, Daniela and Bollazzi, Martin and Roces, Flavio}, title = {Carbon dioxide sensing in an obligate insect-fungus symbiosis: CO\(_{2}\) preferences of leaf-cutting ants to rear their mutualistic fungus}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0174597}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159561}, pages = {e0174597}, year = {2017}, abstract = {Defense against biotic or abiotic stresses is one of the benefits of living in symbiosis. Leaf-cutting ants, which live in an obligate mutualism with a fungus, attenuate thermal and desiccation stress of their partner through behavioral responses, by choosing suitable places for fungus-rearing across the soil profile. The underground environment also presents hypoxic (low oxygen) and hypercapnic (high carbon dioxide) conditions, which can negatively influence the symbiont. Here, we investigated whether workers of the leaf-cutting ant Acromyrmex lundii use the CO\(_{2}\) concentration as an orientation cue when selecting a place to locate their fungus garden, and whether they show preferences for specific CO\(_{2}\) concentrations. We also evaluated whether levels preferred by workers for fungus-rearing differ from those selected for themselves. In the laboratory, CO\(_{2}\) preferences were assessed in binary choices between chambers with different CO\(_{2}\) concentrations, by quantifying number of workers in each chamber and amount of relocated fungus. Leaf-cutting ants used the CO\(_{2}\) concentration as a spatial cue when selecting places for fungus-rearing. A. lundii preferred intermediate CO\(_{2}\) levels, between 1 and 3\%, as they would encounter at soil depths where their nest chambers are located. In addition, workers avoided both atmospheric and high CO\(_{2}\) levels as they would occur outside the nest and at deeper soil layers, respectively. In order to prevent fungus desiccation, however, workers relocated fungus to high CO\(_{2}\) levels, which were otherwise avoided. Workers' CO\(_{2}\) preferences for themselves showed no clear-cut pattern. We suggest that workers avoid both atmospheric and high CO\(_{2}\) concentrations not because they are detrimental for themselves, but because of their consequences for the symbiotic partner. Whether the preferred CO\(_{2}\) concentrations are beneficial for symbiont growth remains to be investigated, as well as whether the observed preferences for fungus-rearing influences the ants' decisions where to excavate new chambers across the soil profile.}, language = {en} } @article{HalbothRoces2017, author = {Halboth, Florian and Roces, Flavio}, title = {The construction of ventilation turrets in Atta vollenweideri leaf-cutting ants: Carbon dioxide levels in the nest tunnels, but not airflow or air humidity, influence turret structure}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0188162}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159133}, pages = {e0188162}, year = {2017}, abstract = {Nest ventilation in the leaf-cutting ant Atta vollenweideri is driven via a wind-induced mechanism. On their nests, workers construct small turrets that are expected to facilitate nest ventilation. We hypothesized that the construction and structural features of the turrets would depend on the colony's current demands for ventilation and thus might be influenced by the prevailing environmental conditions inside the nest. Therefore, we tested whether climate-related parameters, namely airflow, air humidity and CO\(_{2}\) levels in the outflowing nest air influenced turret construction in Atta vollenweideri. In the laboratory, we simulated a semi-natural nest arrangement with fungus chambers, a central ventilation tunnel providing outflow of air and an aboveground building arena for turret construction. In independent series, different climatic conditions inside the ventilation tunnel were experimentally generated, and after 24 hours, several features of the built turret were quantified, i.e., mass, height, number and surface area (aperture) of turret openings. Turret mass and height were similar in all experiments even when no airflow was provided in the ventilation tunnel. However, elevated CO\(_{2}\) levels led to the construction of a turret with several minor openings and a larger total aperture. This effect was statistically significant at higher CO\(_{2}\) levels of 5\% and 10\% but not at 1\% CO\(_{2}\). The construction of a turret with several minor openings did not depend on the strong differences in CO\(_{2}\) levels between the outflowing and the outside air, since workers also built permeated turrets even when the CO\(_{2}\) levels inside and outside were both similarly high. We propose that the construction of turrets with several openings and larger opening surface area might facilitate the removal of CO\(_{2}\) from the underground nest structure and could therefore be involved in the control of nest climate in leaf-cutting ants.}, language = {en} } @article{NuernbergerSteffanDewenterHaertel2017, author = {N{\"u}rnberger, Fabian and Steffan-Dewenter, Ingolf and H{\"a}rtel, Stephan}, title = {Combined effects of waggle dance communication and landscape heterogeneity on nectar and pollen uptake in honey bee colonies}, series = {PeerJ}, volume = {5}, journal = {PeerJ}, number = {e3441}, doi = {10.7717/peerj.3441}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170813}, year = {2017}, abstract = {The instructive component of waggle dance communication has been shown to increase resource uptake of Apis mellifera colonies in highly heterogeneous resource environments, but an assessment of its relevance in temperate landscapes with different levels of resource heterogeneity is currently lacking. We hypothesized that the advertisement of resource locations via dance communication would be most relevant in highly heterogeneous landscapes with large spatial variation of floral resources. To test our hypothesis, we placed 24 Apis mellifera colonies with either disrupted or unimpaired instructive component of dance communication in eight Central European agricultural landscapes that differed in heterogeneity and resource availability. We monitored colony weight change and pollen harvest as measure of foraging success. Dance disruption did not significantly alter colony weight change, but decreased pollen harvest compared to the communicating colonies by 40\%. There was no general effect of resource availability on nectar or pollen foraging success, but the effect of landscape heterogeneity on nectar uptake was stronger when resource availability was high. In contrast to our hypothesis, the effects of disrupted bee communication on nectar and pollen foraging success were not stronger in landscapes with heterogeneous compared to homogenous resource environments. Our results indicate that in temperate regions intra-colonial communication of resource locations benefits pollen foraging more than nectar foraging, irrespective of landscape heterogeneity. We conclude that the so far largely unexplored role of dance communication in pollen foraging requires further consideration as pollen is a crucial resource for colony development and health.}, language = {en} } @article{FrankSchmittHovestadtetal.2017, author = {Frank, Erik Thomas and Schmitt, Thomas and Hovestadt, Thomas and Mitesser, Oliver and Stiegler, Jonas and Linsenmair, Karl Eduard}, title = {Saving the injured: Rescue behavior in the termite-hunting ant Megaponera analis}, series = {Science Advances}, volume = {3}, journal = {Science Advances}, number = {4}, doi = {10.1126/sciadv.1602187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157933}, pages = {e1602187}, year = {2017}, abstract = {Predators of highly defensive prey likely develop cost-reducing adaptations. The ant Megaponera analis is a specialized termite predator, solely raiding termites of the subfamily Macrotermitinae (in this study, mostly colonies of Pseudocanthotermes sp.) at their foraging sites. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites (for example, a caste specialized in fighting predators). Because M. analis incurs high injury/mortality risks when preying on termites, some risk-mitigating adaptations seem likely to have evolved. We show that a unique rescue behavior in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. After a fight, injured ants are carried back by their nestmates; these ants have usually lost an extremity or have termites clinging to them and are able to recover within the nest. Injured ants that are forced experimentally to return without help, die in 32\% of the cases. Behavioral experiments show that two compounds, dimethyl disulfide and dimethyl trisulfide, present in the mandibular gland reservoirs, trigger the rescue behavior. A model accounting for this rescue behavior identifies the drivers favoring its evolution and estimates that rescuing enables maintenance of a 28.7\% larger colony size. Our results are the first to explore experimentally the adaptive value of this form of rescue behavior focused on injured nestmates in social insects and help us to identify evolutionary drivers responsible for this type of behavior to evolve in animals.}, language = {en} } @article{HeibyRajabRatetal.2017, author = {Heiby, Julia C. and Rajab, Suhaila and Rat, Charlotte and Johnson, Christopher M. and Neuweiler, Hannes}, title = {Conservation of folding and association within a family of spidroin N-terminal domains}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-16881-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159272}, pages = {16789}, year = {2017}, abstract = {Web spiders synthesize silk fibres, nature's toughest biomaterial, through the controlled assembly of fibroin proteins, so-called spidroins. The highly conserved spidroin N-terminal domain (NTD) is a pH-driven self-assembly device that connects spidroins to super-molecules in fibres. The degree to which forces of self-assembly is conserved across spider glands and species is currently unknown because quantitative measures are missing. Here, we report the comparative investigation of spidroin NTDs originating from the major ampullate glands of the spider species Euprosthenops australis, Nephila clavipes, Latrodectus hesperus, and Latrodectus geometricus. We characterized equilibrium thermodynamics and kinetics of folding and self-association using dynamic light scattering, stopped-flow fluorescence and circular dichroism spectroscopy in combination with thermal and chemical denaturation experiments. We found cooperative two-state folding on a sub-millisecond time scale through a late transition state of all four domains. Stability was compromised by repulsive electrostatic forces originating from clustering of point charges on the NTD surface required for function. pH-driven dimerization proceeded with characteristic fast kinetics yielding high affinities. Results showed that energetics and kinetics of NTD self-assembly are highly conserved across spider species despite the different silk mechanical properties and web geometries they produce.}, language = {en} } @article{SperlichHolmberg2017, author = {Sperlich, Billy and Holmberg, Hans-Christer}, title = {The responses of elite athletes to exercise: an all-day, 24-h integrative view is required!}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {564}, doi = {10.3389/fphys.2017.00564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158655}, year = {2017}, abstract = {No abstract available.}, language = {en} } @article{SperlichDuekingHolmberg2017, author = {Sperlich, Billy and D{\"u}king, Peter and Holmberg, Hans-Christer}, title = {A SWOT analysis of the use and potential misuse of implantable monitoring devices by athletes}, series = {Frontiers in Physiology}, volume = {8}, journal = {Frontiers in Physiology}, number = {629}, doi = {10.3389/fphys.2017.00629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158742}, year = {2017}, abstract = {Kein Abstract vorhanden.}, language = {en} } @article{BecamWalterBurgertetal.2017, author = {Becam, J{\´e}r{\^o}me and Walter, Tim and Burgert, Anne and Schlegel, Jan and Sauer, Markus and Seibel, J{\"u}rgen and Schubert-Unkmeir, Alexandra}, title = {Antibacterial activity of ceramide and ceramide analogs against pathogenic Neisseria}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-18071-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159367}, pages = {17627}, year = {2017}, abstract = {Certain fatty acids and sphingoid bases found at mucosal surfaces are known to have antibacterial activity and are thought to play a more direct role in innate immunity against bacterial infections. Herein, we analysed the antibacterial activity of sphingolipids, including the sphingoid base sphingosine as well as short-chain C\(_{6}\) and long-chain C\(_{16}\)-ceramides and azido-functionalized ceramide analogs against pathogenic Neisseriae. Determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) demonstrated that short-chain ceramides and a ω-azido-functionalized C\(_{6}\)-ceramide were active against Neisseria meningitidis and N. gonorrhoeae, whereas they were inactive against Escherichia coli and Staphylococcus aureus. Kinetic assays showed that killing of N. meningitidis occurred within 2 h with ω-azido-C\(_{6}\)-ceramide at 1 X the MIC. Of note, at a bactericidal concentration, ω-azido-C\(_{6}\)-ceramide had no significant toxic effect on host cells. Moreover, lipid uptake and localization was studied by flow cytometry and confocal laser scanning microscopy (CLSM) and revealed a rapid uptake by bacteria within 5 min. CLSM and super-resolution fluorescence imaging by direct stochastic optical reconstruction microscopy demonstrated homogeneous distribution of ceramide analogs in the bacterial membrane. Taken together, these data demonstrate the potent bactericidal activity of sphingosine and synthetic short-chain ceramide analogs against pathogenic Neisseriae.}, language = {en} } @article{GoosDejungJanzenetal.2017, author = {Goos, Carina and Dejung, Mario and Janzen, Christian J. and Butter, Falk and Kramer, Susanne}, title = {The nuclear proteome of Trypanosoma brucei}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0181884}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158572}, pages = {e0181884}, year = {2017}, abstract = {Trypanosoma brucei is a protozoan flagellate that is transmitted by tsetse flies into the mammalian bloodstream. The parasite has a huge impact on human health both directly by causing African sleeping sickness and indirectly, by infecting domestic cattle. The biology of trypanosomes involves some highly unusual, nuclear-localised processes. These include polycistronic transcription without classical promoters initiated from regions defined by histone variants, trans-splicing of all transcripts to the exon of a spliced leader RNA, transcription of some very abundant proteins by RNA polymerase I and antigenic variation, a switch in expression of the cell surface protein variants that allows the parasite to resist the immune system of its mammalian host. Here, we provide the nuclear proteome of procyclic Trypanosoma brucei, the stage that resides within the tsetse fly midgut. We have performed quantitative label-free mass spectrometry to score 764 significantly nuclear enriched proteins in comparison to whole cell lysates. A comparison with proteomes of several experimentally characterised nuclear and non-nuclear structures and pathways confirmed the high quality of the dataset: the proteome contains about 80\% of all nuclear proteins and less than 2\% false positives. Using motif enrichment, we found the amino acid sequence KRxR present in a large number of nuclear proteins. KRxR is a sub-motif of a classical eukaryotic monopartite nuclear localisation signal and could be responsible for nuclear localization of proteins in Kinetoplastida species. As a proof of principle, we have confirmed the nuclear localisation of six proteins with previously unknown localisation by expressing eYFP fusion proteins. While proteome data of several T. brucei organelles have been published, our nuclear proteome closes an important gap in knowledge to study trypanosome biology, in particular nuclear-related processes.}, language = {en} } @article{WagenerLoiko2017, author = {Wagener, Johannes and Loiko, Veronika}, title = {Recent insights into the paradoxical effect of echinocandins}, series = {Journal of Fungi}, volume = {4}, journal = {Journal of Fungi}, number = {1}, issn = {2309-608X}, doi = {10.3390/jof4010005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197960}, pages = {5}, year = {2017}, abstract = {Echinocandin antifungals represent one of the most important drug classes for the treatment of invasive fungal infections. The mode of action of the echinocandins relies on inhibition of the β-1,3-glucan synthase, an enzyme essentially required for the synthesis of the major fungal cell wall carbohydrate β-1,3-glucan. Depending on the species, echinocandins may exert fungicidal or fungistatic activity. Apparently independent of this differential activity, a surprising in vitro phenomenon called the "paradoxical effect" can be observed. The paradoxical effect is characterized by the ability of certain fungal isolates to reconstitute growth in the presence of higher echinocandin concentrations, while being fully susceptible at lower concentrations. The nature of the paradoxical effect is not fully understood and has been the focus of multiple studies in the last two decades. Here we concisely review the current literature and propose an updated model for the paradoxical effect, taking into account recent advances in the field.}, language = {en} } @article{SbirkovKwokBhamraetal.2017, author = {Sbirkov, Yordan and Kwok, Colin and Bhamra, Amandeep and Thompson, Andrew J. and Gil, Veronica and Zelent, Arthur and Petrie, Kevin}, title = {Semi-quantitative mass spectrometry in AML cells identifies new non-genomic targets of the EZH2 methyltransferase}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms18071440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285541}, year = {2017}, abstract = {Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all-trans retinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML.}, language = {en} } @article{ErlbeckMochtyKuebleretal.2017, author = {Erlbeck, Helena and Mochty, Ursula and K{\"u}bler, Andrea and Real, Ruben G. L.}, title = {Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI)}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {3}, doi = {10.1186/s12883-016-0782-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157423}, year = {2017}, abstract = {Background: Accidents or neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) can lead to progressing, extensive, and complete paralysis leaving patients aware but unable to communicate (locked-in state). Brain-computer interfaces (BCI) based on electroencephalography represent an important approach to establish communication with these patients. The most common BCI for communication rely on the P300, a positive deflection arising in response to rare events. To foster broader application of BCIs for restoring lost function, also for end-users with impaired vision, we explored whether there were specific time windows during the day in which a P300 driven BCI should be preferably applied. Methods: The present study investigated the influence of time of the day and modality (visual vs. auditory) on P300 amplitude and latency. A sample of 14 patients (end-users) with ALS and 14 healthy age matched volunteers participated in the study and P300 event-related potentials (ERP) were recorded at four different times (10, 12 am, 2, \& 4 pm) during the day. Results: Results indicated no differences in P300 amplitudes or latencies between groups (ALS patients v. healthy participants) or time of measurement. In the auditory condition, latencies were shorter and amplitudes smaller as compared to the visual condition. Conclusion: Our findings suggest applicability of EEG/BCI sessions in patients with ALS throughout normal waking hours. Future studies using actual BCI systems are needed to generalize these findings with regard to BCI effectiveness/efficiency and other times of day.}, language = {en} } @article{GulveFrankKlepschetal.2017, author = {Gulve, Nitish and Frank, Celina and Klepsch, Maximilian and Prusty, Bhupesh K.}, title = {Chromosomal integration of HHV-6A during non-productive viral infection}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {512}, doi = {10.1038/s41598-017-00658-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158117}, year = {2017}, abstract = {Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two different species of betaherpesviruses that integrate into sub-telomeric ends of human chromosomes, for which different prevalence rates of integration have been reported. It has been demonstrated that integrated viral genome is stable and is fully retained. However, study of chromosomally integrated viral genome in individuals carrying inherited HHV-6 (iciHHV-6) showed unexpected number of viral DR copies. Hence, we created an in vitro infection model and studied retention of full or partial viral genome over a period of time. We observed an exceptional event where cells retained viral direct repeats (DRs) alone in the absence of the full viral genome. Finally, we found evidence for non-telomeric integration of HHV-6A DR in both cultured cells and in an iciHHV-6 individual. Our results shed light on several novel features of HHV-6A chromosomal integration and provide valuable information for future screening techniques.}, language = {en} }