TY - JOUR A1 - Wagner, Johanna C. A1 - Wetz, Anja A1 - Wiegering, Armin A1 - Lock, Johan F. A1 - Löb, Stefan A1 - Germer, Christoph-Thomas A1 - Klein, Ingo T1 - Successful surgical closure of infected abdominal wounds following preconditioning with negative pressure wound therapy JF - Langenbeck's Archives of Surgery N2 - Purpose Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. Methods Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). Results One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care. Conclusion Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs. KW - open wound treatment KW - surgical site infections KW - secondary skin closure KW - negative pressure wound therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267541 SN - 1435-2451 VL - 406 IS - 7 ER - TY - THES A1 - Eiring, Patrick T1 - Super-resolution microscopy of plasma membrane receptors T1 - Hochauflösende Mikroskopie von Plasmamembran Rezeptoren N2 - Plasma membrane receptors are the most crucial and most commonly studied components of cells, since they not only ensure communication between the extracellular space and cells, but are also responsible for the regulation of cell cycle and cell division. The composition of the surface receptors, the so-called "Receptome", differs and is characteristic for certain cell types. Due to their significance, receptors have been important target structures for diagnostic and therapy in cancer medicine and often show aberrant expression patterns in various cancers compared to healthy cells. However, these aberrations can also be exploited and targeted by different medical approaches, as in the case of personalized immunotherapy. In addition, advances in modern fluorescence microscopy by so-called single molecule techniques allow for unprecedented sensitive visualization and quantification of molecules with an attainable spatial resolution of 10-20 nm, allowing for the detection of both stoichiometric and expression density differences. In this work, the single molecule sensitive method dSTORM was applied to quantify the receptor composition of various cell lines as well as in primary samples obtained from patients with hematologic malignancies. The focus of this work lies on artefact free quantification, stoichiometric analyses of oligomerization states and co localization analyses of membrane receptors. Basic requirements for the quantification of receptors are dyes with good photoswitching properties and labels that specifically mark the target structure without generating background through non-specific binding. To ensure this, antibodies with a predefined DOL (degree of labeling) were used, which are also standard in flow cytometry. First background reduction protocols were established on cell lines prior analyses in primary patient samples. Quantitative analyses showed clear expression differences between the cell lines and the patient cells, but also between individual patients. An important component of this work is the ability to detect the oligomerization states of receptors, which enables a more accurate quantification of membrane receptor densities compared to standard flow cytometry. It also provides information about the activation of a certain receptor, for example of FLT3, a tyrosine kinase, dimerizing upon activation. For this purpose, different well-known monomers and dimers were compared to distinguish the typical localization statistics of single bound antibodies from two or more antibodies that are in proximity. Further experiments as well as co localization analyses proved that antibodies can bind to closely adjacent epitopes despite their size. These analytical methods were subsequently applied for quantification and visualization of receptors in two clinically relevant examples. Firstly, various therapeutically relevant receptors such as CD38, BCMA and SLAMF7 for multiple myeloma, a malignant disease of plasma cells, were analyzed and quantified on patient cells. Furthermore, the influence of TP53 and KRAS mutations on receptor expression levels was investigated using the multiple myeloma cell lines OPM2 and AMO1, showing clear differences in certain receptor quantities. Secondly, FLT3 which is a therapeutic target receptor for acute myeloid leukemia, was quantified and stoichiometrically analyzed on both cell lines and patient cells. In addition, cells that have developed resistance against midostaurin were compared with cells that still respond to this type I tyrosine-kinase-inhibitor for their FLT3 receptor expression and oligomerization state. N2 - Plasmamembranrezeptoren sind die wohl wichtigsten und meist untersuchten Komponenten einer Zelle, da sie nicht nur die Kommunikation zwischen dem extrazellulären Bereich und den Zellen gewährleisten, sondern auch für die Regulierung des Zellzyklus und der Zellteilung zuständig sind. Dabei unterscheidet sich die Zusammensetzung der Oberflächenrezeptoren, das sogenannte „Rezeptom“, und ist charakteristisch für bestimme Zelltypen. Aufgrund ihrer Bedeutsamkeit sind Rezeptoren wichtige Zielstrukturen für Diagnose und Therapie in der Krebsmedizin, welche häufig bei verschiedensten Krebserkrankungen im Vergleich zu gesunden Zellen aberrante Expressionsmuster aufweisen. Diese Abweichungen können sich allerdings auch zu Nutze gemacht werden und zum Ziel verschiedener medizinischer Behandlungsmethoden, wie es bei der personalisierten Immuntherapie der Fall ist, werden. Zusätzlich hat der Fortschritt in der modernen Fluoreszenzmikroskopie durch sogenannte Einzelmolekültechniken, es auch erlaubt, eine noch nie dagewesene empfindliche Visualisierung und Quantifizierung von Molekülen mit einer räumlichen Auflösung von 10-20 nm zu erreichen, wodurch sowohl stöchiometrische Unterschiede, als auch Unterschiede in der Expressionsdichte detektiert werden können. In dieser Arbeit wurde die einzelmolekülsensitive Methode dSTORM genutzt, um die Rezeptorkomposition von verschiedenen Zelllinien aber auch von primären Patientenzellen mit zugrundeliegenden hämatologischen Erkrankungen zu quantifizieren. Schwerpunkte dieser Arbeit sind dabei die artefaktfreie Quantifizierung, stöchiometrische Analysen von Oligomerisierungszuständen, sowie die Kolokalisationsanalyse von Membranrezeptoren. Grundvoraussetzung für die Quantifizierung von Rezeptoren sind dabei gut schaltbare Farbstoffe, sowie Label, welche die Zielstruktur spezifisch markieren ohne dabei Hintergrund durch unspezifische Bindung zu generieren. Um dies zu gewährleisten, kamen Antikörper mit einem vordefinierten DOL (degree of labeling; engl. für: Markierungsgrad) zum Einsatz, welche auch in der Durchflusszytometrie standardmäßig eingesetzt werden. Protokolle zur Hintergrundreduktion wurden dabei an Zelllinien etabliert, bevor Primärzellen von Krebspatienten analysiert wurden. Durch quantitative Analysen konnten dabei deutliche Expressionsunterschiede zwischen den Zelllinien und den Patientenzellen, aber auch zwischen den verschiedenen Patienten gezeigt werden. Ein wichtiger Bestandteil dieser Arbeit ist die Fähigkeit, den Oligomerisierungszustand von Rezeptoren zu erkennen, was eine genauere Quantifizierung der Membran-rezeptordichten im Vergleich zur Durchflusszytometrie ermöglicht. Allerdings können diese Oligomerisierungszustände auch Informationen über die Aktivierung eines Rezeptors beinhalten, wie zum Beispiel von FLT3, einer Tyrosinkinase, welche zur Aktivierung dimerisieren muss. Hierfür wurden verschiedene bekannte Monomere und Dimere verglichen, um die typische Lokalisationsstatistik von vereinzelten gebundenen Antikörpern mit der von zwei oder mehr Antikörpern, welche nah beieinanderliegen, zu vergleichen. Durch weitere Etablierungsexperimente sowie Kolokalisationsanalysen konnte außerdem bewiesen werden, dass Antikörper trotz ihrer Größe auch an nah benachbarte Epitope binden können. Diese Analyseverfahren wurden im weiteren Verlauf zur Quantifizierung und Visualisierung von Rezeptoren an zwei klinisch relevanten Beispielen angewendet. Zum einen wurden verschiedene therapeutisch relevante Rezeptoren wie z.B. CD38, BCMA und SLAMF7 für das Multiple Myelom, einer malignen Erkrankung von Plasmazellen, auf Patientenzellen analysiert und quantifiziert. Zusätzlich wurde der Einfluss von TP53 und KRAS Mutationen auf die Rezeptorexpressionen anhand der Multiplen Myelom Zelllinien OPM2 und AMO1 untersucht, bei denen eindeutige Unterschiede in der Rezeptorexpression detektiert wurden. Zum anderen wurde FLT3, welches ein therapeutischer Zielrezeptor für die akute myeloische Leukämie ist, sowohl auf Zelllinien als auch auf Patientenzellen quantifiziert und stöchiometrisch analysiert. Hierbei wurden auch Zellen welche eine Midostaurinresistenz entwickelt haben mit Zellen, welche auf diesen Typ I Tyrosinkinase Inhibitor ansprechen, auf ihre FLT3 Rezeptorexpression und ihren Oligomerisierungszustand verglichen. KW - Fluoreszenzmikroskopie KW - Membranrezeptor KW - Hochaufgelöste Fluoreszenzmikroskopie KW - Super-resolution microscopy KW - Membrane receptor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250048 ER - TY - THES A1 - Schlegel, Jan T1 - Super-Resolution Microscopy of Sphingolipids and Protein Nanodomains T1 - Hochaufgelöste Mikroskopie von Sphingolipiden und Protein Nanodomänen N2 - The development of cellular life on earth is coupled to the formation of lipid-based biological membranes. Although many tools to analyze their biophysical properties already exist, their variety and number is still relatively small compared to the field of protein studies. One reason for this, is their small size and complex assembly into an asymmetric tightly packed lipid bilayer showing characteristics of a two-dimensional heterogenous fluid. Since membranes are capable to form dynamic, nanoscopic domains, enriched in sphingolipids and cholesterol, their detailed investigation is limited to techniques which access information below the diffraction limit of light. In this work, I aimed to extend, optimize and compare three different labeling approaches for sphingolipids and their subsequent analysis by the single-molecule localization microscopy (SMLM) technique direct stochastic optical reconstruction microscopy (dSTORM). First, I applied classical immunofluorescence by immunoglobulin G (IgG) antibody labeling to detect and quantify sphingolipid nanodomains in the plasma membrane of eukaryotic cells. I was able to identify and characterize ceramide-rich platforms (CRPs) with a size of ~ 75nm on the basal and apical membrane of different cell lines. Next, I used click-chemistry to characterize sphingolipid analogs in living and fixed cells. By using a combination of fluorescence microscopy and anisotropy experiments, I analyzed their accessibility and configuration in the plasma membrane, respectively. Azide-modified, short fatty acid side chains, were accessible to membrane impermeable dyes and localized outside the hydrophobic membrane core. In contrast, azide moieties at the end of longer fatty acid side chains were less accessible and conjugated dyes localized deeper within the plasma membrane. By introducing photo-crosslinkable diazirine groups or chemically addressable amine groups, I developed methods to improve their immobilization required for dSTORM. Finally, I harnessed the specific binding characteristics of non-toxic shiga toxin B subunits (STxBs) and cholera toxin B subunits (CTxBs) to label and quantify glycosphingolipid nanodomains in the context of Neisseria meningitidis infection. Under pyhsiological conditions, these glycosphingolipids were distributed homogenously in the plasma membrane but upon bacterial infection CTxB detectable gangliosides accumulated around invasive Neisseria meningitidis. I was able to highlight the importance of cell cycle dependent glycosphingolipid expression for the invasion process. Blocking membrane accessible sugar headgroups by pretreatment with CTxB significantly reduced the number of invasive bacteria which confirmed the importance of gangliosides for bacterial uptake into cells. Based on my results, it can be concluded that labeling of sphingolipids should be carefully optimized depending on the research question and applied microscopy technique. In particular, I was able to develop new tools and protocols which enable the characterization of sphingolipid nanodomains by dSTORM for all three labeling approaches. N2 - Die Entwicklung von zellulären Lebensformen auf der Erde basiert auf der Entstehung biologischer Lipid-Membranen. Obwohl viele Techniken zur Verfügung stehen, welche es erlauben deren biophysikalische Eigenschaften zu untersuchen, sind die Möglichkeiten, verglichen mit der Analyse von Proteinen, eher eingeschränkt. Ein Grund hierfür, ist die geringe Größe von Lipiden und deren komplexe Zusammenlagerung in eine asymmetrische dicht gepackte Lipiddoppelschicht, welche sich wie eine heterogene zweidimensionale Flüssigkeit verhält. Durch die lokale Anreicherung von Sphingolipiden und Cholesterol sind Membranen in der Lage dynamische, nanoskopische Domänen auszubilden, welche lediglich mit Techniken, welche die optische Auflösungsgrenze umgehen, detailliert untersucht werden können. Ein wesentliches Ziel meiner Arbeit war es, drei Färbeverfahren für Sphingolipide zu vergleichen, erweitern und optimieren, um eine anschliessende Untersuchung mit Hilfe der einzelmolekülsensitiven Technik dSTORM (direct stochastic optical reconstruction microscopy) zu ermöglichen. Zunächst verwendete ich das klassische Färbeverfahren der Immunfluoreszenz, um Sphingolipid-Nanodomänen auf eukaryotischen Zellen mit Hilfe von Farbstoff-gekoppelten Antikörpern zu detektieren und quantifizieren. Dieses Vorgehen ermöglichte es mir, Ceramid-angereicherte Plattformen mit einer Größe von ~ 75nm auf der basalen und apikalen Membran verschiedener Zell-Linien zu identifizieren und charakterisieren. Als nächstes Verfahren verwendete ich die Klick-Chemie, um Sphingolipid-Analoge in lebenden und fixierten Zellen zu untersuchen. Eine Kombination aus Fluoreszenz-Mikroskopie und Anisotropie-Messungen erlaubte es mir Rückschlüsse über deren Zugänglichkeit und Konfiguration innerhalb der Plasmamembran zu ziehen. Hierbei lokalisierten Azid-Gruppen am Ende kurzkettiger Fettsäurereste außerhalb des hydrophoben Membrankerns, wodurch sie mittels membran-undurchlässige Farbstoffe angeklickt werden konnten. Im Gegensatz dazu, waren Azide an längeren Fettsäureresten weniger zugänglich und konjugierte Farbstoffe tauchten tiefer in die Plasmamembran ein. Durch die Einführung photoreaktiver Diazirin-Gruppen oder chemisch modifzierbarer Amin-Gruppen wurden Wege geschaffen, welche eine Immobilisierung und anschließende Analyse mit Hilfe von dSTORM ermöglichen. Schließlich nutzte ich das spezifische Bindeverhalten der nicht toxischen B Untereinheiten von Shiga- (STxB) und Cholera-Toxin (CTxB) aus, um Glycosphingolipid Nanodomänen im Kontext einer Neisseria meningitidis Infektion zu untersuchen. Unter physiologischen Bedingungen waren diese homogen in der Plasmamembran verteilt, jedoch reicherten sich CTxB-detektierbare Ganglioside um eindringende Bakterien an. Darüber hinaus konnte ich einen Zusammenhang zwischen der zellzyklusabhängigen Expression von Glycosphingolipiden und dem Eindringen der Bakterien herstellen. Eine Absättigung der Zucker an der äußeren Membran durch CTxB-Vorbehandlung reduzierte die Anzahl von invasiven Bakterien signifikant und bestätigte die Schlüsselrolle von Gangliosiden bei der Aufnahme von Bakterien. Meine Ergebnisse legen Nahe, dass das Färbeverfahren für Sphingolipide an die jeweilige Fragestellung und Mikroskopietechnik angepasst werden sollte. Im Rahmen dieser Arbeit konnten neue Werkzeuge und Protokolle geschaffen werden, die die Charakterisierung von Sphingolipid-Nanodomänen mittels dSTORM für alle drei Färbeverfahren ermöglichen. KW - Sphingolipide KW - Lipide KW - Einzelmolekülmikroskopie KW - Click-Chemie KW - Lipid Raft KW - super-resolution microscopy KW - sphingolipids KW - labeling techniques KW - dSTORM KW - lipid rafts Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229596 ER - TY - JOUR A1 - Haack, Stephanie A1 - Baiker, Sarah A1 - Schlegel, Jan A1 - Sauer, Markus A1 - Sparwasser, Tim A1 - Langenhorst, Daniela A1 - Beyersdorf, Niklas T1 - Superagonistic CD28 stimulation induces IFN‐γ release from mouse T helper 1 cells in vitro and in vivo JF - European Journal of Immunology N2 - Like human Th1 cells, mouse Th1 cells also secrete IFN‐γ upon stimulation with a superagonistic anti‐CD28 monoclonal antibody (CD28‐SA). Crosslinking of the CD28‐SA via FcR and CD40‐CD40L interactions greatly increased IFN‐γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans. KW - CD28 KW - Th1 cells KW - cytokine release KW - interferon γ KW - Superagonistic antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239028 VL - 51 IS - 3 SP - 738 EP - 741 ER - TY - JOUR A1 - Sputh, Sebastian A1 - Panzer, Sabine A1 - Stigloher, Christian A1 - Terpitz, Ulrich T1 - Superaufgelöste Mikroskopie: Pilze unter Beobachtung JF - BIOspektrum N2 - The diffraction limit of light confines fluorescence imaging of subcellular structures in fungi. Different super-resolution methods are available for the analysis of fungi that we briefly discuss. We exploit the filamentous fungus Fusarium fujikuroi expressing a YFP-labeled membrane protein showing the benefit of correlative light- and electron microscopy (CLEM), that combines structured illumination microscopy (SIM) and scanning election microscopy (SEM). KW - Pilze KW - mikroskopische Untersuchung KW - Abbe-Limit Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270014 SN - 1868-6249 VL - 27 IS - 4 ER - TY - JOUR A1 - Radeloff, Katrin A1 - Ramos Tirado, Mario A1 - Haddad, Daniel A1 - Breuer, Kathrin A1 - Müller, Jana A1 - Hochmuth, Sabine A1 - Hackenberg, Stephan A1 - Scherzad, Agmal A1 - Kleinsasser, Norbert A1 - Radeloff, Andreas T1 - Superparamagnetic iron oxide particles (VSOPs) show genotoxic effects but no functional impact on human adipose tissue-derived stromal cells (ASCs) JF - Materials N2 - Adipose tissue-derived stromal cells (ASCs) represent a capable source for cell-based therapeutic approaches. For monitoring a cell-based application in vivo, magnetic resonance imaging (MRI) of cells labeled with iron oxide particles is a common method. It is the aim of the present study to analyze potential DNA damage, cytotoxicity and impairment of functional properties of human (h)ASCs after labeling with citrate-coated very small superparamagnetic iron oxide particles (VSOPs). Cytotoxic as well as genotoxic effects of the labeling procedure were measured in labeled and unlabeled hASCs using the MTT assay, comet assay and chromosomal aberration test. Trilineage differentiation was performed to evaluate an impairment of the differentiation potential due to the particles. Proliferation as well as migration capability were analyzed after the labeling procedure. Furthermore, the labeling of the hASCs was confirmed by Prussian blue staining, transmission electron microscopy (TEM) and high-resolution MRI. Below the concentration of 0.6 mM, which was used for the procedure, no evidence of genotoxic effects was found. At 0.6 mM, 1 mM as well as 1.5 mM, an increase in the number of chromosomal aberrations was determined. Cytotoxic effects were not observed at any concentration. Proliferation, migration capability and differentiation potential were also not affected by the procedure. Labeling with VSOPs is a useful labeling method for hASCs that does not affect their proliferation, migration and differentiation potential. Despite the absence of cytotoxicity, however, indications of genotoxic effects have been demonstrated. KW - ASCs KW - adipose tissue-derived stromal cells KW - VSOP KW - iron oxide nanoparticles KW - toxicity KW - MRI KW - cell labeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222970 SN - 1996-1944 VL - 14 IS - 2 ER - TY - THES A1 - Wehner, Marius T1 - Supramolecular Polymorphism in Homo- and Heterochiral Supramolecular Polymerizations T1 - Supramolekularer Polymorphismus in homo- und heterochiralen supramolekularen Polymerisationen N2 - The aim of the first part of this thesis was to investigate (R,R)-PBI as a model system for polymorphism at its origin by a supramolecular approach. The pathway complexity of (R,R)-PBI was fine-tuned by experimental parameters such as solvent, temperature and concentration to make several supramolecular polymorphs accessible. Mechanistic and quantum chemical studies on the kinetics and thermodynamics of the supramolecular polymerization of (R,R)-PBI were conducted to shed light on the initial stages of polymorphism. The second part of this work deals with mechanistic investigations on the supramolecular polymerization of the racemic mixture of (R,R)- and (S,S)-PBI with regard to homochiral and heterochiral aggregation leading to conglomerates and a racemic supramolecular polymer, respectively. N2 - Das Ziel des ersten Teils der Dissertation war es, anhand des Modellsystems (R,R)-PBI Polymorphismus mit Hilfe eines supramolekularen Ansatzes an dessen Ursprung zu untersuchen. Durch die Wahl geeigneter experimenteller Parameter wie Lösungsmittel, Temperatur und Konzentration wurden die komplexen Polymerisationspfade von (R,R)-PBI gezielt beeinflusst und verschiedene supramolekulare Polymorphe zugänglich gemacht. Mechanistische und quantenchemische Untersuchungen der Kinetik und Thermodynamik der supramolekularen Polymerisation von (R,R)-PBI wurden durchgeführt, um die Anfangsphase des Polymorphismus zu beleuchten. Der zweite Teil der vorliegenden Arbeit befasst sich mit mechanistischen Untersuchungen der supramolekularen Polymerisation der racemischen Mischung aus (R,R)- und (S,S)-PBI im Hinblick auf homo- und heterochirale Aggregation, welche zu Konglomeraten beziehungsweise einem racemischen supramolekularen Polymer führte. KW - Supramolekulare Chemie KW - Polymorphismus KW - Konglomerat KW - Aggregat KW - Organische Chemie KW - Aggregation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211519 ER - TY - JOUR A1 - Kriegel, Peter A1 - Fritze, Michael‐Andreas A1 - Thorn, Simon T1 - Surface temperature and shrub cover drive ground beetle (Coleoptera: Carabidae) assemblages in short‐rotation coppices JF - Agricultural and Forest Entomology N2 - Increasing demand for biomass has led to an on‐going intensification of fuel wood plantations with possible negative effects on open land biodiversity. Hence, ecologists increasingly call for measures that reduce those negative effects on associated biodiversity. However, our knowledge about the efficiency of such measures remains scarce. We investigated the effects of gap implementation in short rotation coppices (SRCs) on carabid diversity and assemblage composition over 3 years, with pitfall traps in gaps, edges and interiors. In parallel, we quantified soil surface temperature, shrub‐ and herb cover. Edges had the highest number of species and abundances per trap, whereas rarefied species richness was significantly lower in short rotation coppice interiors than in other habitat types. Carabid community composition differed significantly between habitat types. The main environmental drivers were temperature for number of species and abundance and shrub cover for rarefied species richness. We found significantly higher rarefied species richness in gaps compared with interiors. Hence, we argue that gap implementation benefits overall diversity in short rotation coppices. Furthermore, the differences in species community composition between habitat types through increased species turnover support carabid diversity in short rotation coppices. These positive effects were largely attributed to microclimate conditions. However, to maintain positive effects, continuous management of herb layer might be necessary. KW - Carabidae KW - fuel wood KW - short‐rotation coppice KW - shrub‐cover KW - temperature Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239873 VL - 23 IS - 4 SP - 400 EP - 410 ER - TY - JOUR A1 - Gil-Sepulcre, Marcos A1 - Lindner, Joachim O. A1 - Schindler, Dorothee A1 - Velasco, Lucía A1 - Moonshiram, Dooshaye A1 - Rüdiger, Olaf A1 - DeBeer, Serena A1 - Stepanenko, Vladimir A1 - Solano, Eduardo A1 - Würthner, Frank A1 - Llobet, Antoni T1 - Surface-promoted evolution of Ru-bda coordination oligomers boosts the efficiency of water oxidation molecular anodes JF - Journal of the American Chemical Society N2 - A new Ru oligomer of formula {[Ru-\(^{II}\)(bda-\(\kappa\)-N\(^2\)O\(^2\))(4,4'-bpy)]\(_{10}\)(4,4'-bpy)}, 10 (bda is [2,2'-bipyridine]-6,6'-dicarbox-ylate and 4,4'-bpy is 4,4'-bipyridine), was synthesized and thoroughly characterized with spectroscopic, X-ray, and electrochemical techniques. This oligomer exhibits strong affinity for graphitic materials through CH-\(\pi\) interactions and thus easily anchors on multiwalled carbon nanotubes (CNT), generating the molecular hybrid material 10@CNT. The latter acts as a water oxidation catalyst and converts to a new species, 10'(H\(_2\)O)\(_2\)@CNT, during the electrochemical oxygen evolution process involving solvation and ligand reorganization facilitated by the interactions of molecular Ru catalyst and the surface. This heterogeneous system has been shown to be a powerful and robust molecular hybrid anode for electrocatalytic water oxidation into molecular oxygen, achieving current densities in the range of 200 mA/cm\(^2\) at pH 7 under an applied potential of 1.45 V vs NHE. The remarkable long-term stability of this hybrid material during turnover is rationalized based on the supramolecular interaction of the catalyst with the graphitic surface. KW - electrodes KW - ligands KW - oligomers KW - surface interactions KW - water oxidation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-351514 VL - 143 IS - 30 ER - TY - JOUR A1 - Sivarajan, Rinu A1 - Kessie, David Komla A1 - Oberwinkler, Heike A1 - Pallmann, Niklas A1 - Walles, Thorsten A1 - Scherzad, Agmal A1 - Hackenberg, Stephan A1 - Steinke, Maria T1 - Susceptibility of Human Airway Tissue Models Derived From Different Anatomical Sites to Bordetella pertussis and Its Virulence Factor Adenylate Cyclase Toxin JF - Frontiers in Cellular and Infection Microbiology N2 - To study the interaction of human pathogens with their host target structures, human tissue models based on primary cells are considered suitable. Complex tissue models of the human airways have been used as infection models for various viral and bacterial pathogens. The Gram-negative bacterium Bordetella pertussis is of relevant clinical interest since whooping cough has developed into a resurgent infectious disease. In the present study, we created three-dimensional tissue models of the human ciliated nasal and tracheo-bronchial mucosa. We compared the innate immune response of these models towards the B. pertussis virulence factor adenylate cyclase toxin (CyaA) and its enzymatically inactive but fully pore-forming toxoid CyaA-AC\(^-\). Applying molecular biological, histological, and microbiological assays, we found that 1 µg/ml CyaA elevated the intracellular cAMP level but did not disturb the epithelial barrier integrity of nasal and tracheo-bronchial airway mucosa tissue models. Interestingly, CyaA significantly increased interleukin 6, interleukin 8, and human beta defensin 2 secretion in nasal tissue models, whereas tracheo-bronchial tissue models were not significantly affected compared to the controls. Subsequently, we investigated the interaction of B. pertussis with both differentiated primary nasal and tracheo-bronchial tissue models and demonstrated bacterial adherence and invasion without observing host cell type-specific significant differences. Even though the nasal and the tracheo-bronchial mucosa appear similar from a histological perspective, they are differentially susceptible to B. pertussis CyaA in vitro. Our finding that nasal tissue models showed an increased innate immune response towards the B. pertussis virulence factor CyaA compared to tracheo-bronchial tissue models may reflect the key role of the nasal airway mucosa as the first line of defense against airborne pathogens. KW - human nasal epithelial cells KW - human tracheo-bronchial epithelial cells KW - human airway mucosa tissue models KW - adenylate cyclase toxin KW - Bordetella pertussis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-253302 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Bianchi, Maria A1 - Sivarajan, Rinu A1 - Walles, Thorsten A1 - Hackenberg, Stephan A1 - Steinke, Maria T1 - Susceptibility of primary human airway epithelial cells to Bordetella pertussis adenylate cyclase toxin in two- and three-dimensional culture conditions JF - Innate Immunity N2 - The human pathogen Bordetella pertussis targets the respiratory epithelium and causes whooping cough. Its virulence factor adenylate cyclase toxin (CyaA) plays an important role in the course of infection. Previous studies on the impact of CyaA on human epithelial cells have been carried out using cell lines derived from the airways or the intestinal tract. Here, we investigated the interaction of CyaA and its enzymatically inactive but fully pore-forming toxoid CyaA-AC– with primary human airway epithelial cells (hAEC) derived from different anatomical sites (nose and tracheo-bronchial region) in two-dimensional culture conditions. To assess possible differences between the response of primary hAEC and respiratory cell lines directly, we included HBEC3-KT in our studies. In comparative analyses, we studied the impact of both the toxin and the toxoid on cell viability, intracellular cAMP concentration and IL-6 secretion. We found that the selected hAEC, which lack CD11b, were differentially susceptible to both CyaA and CyaA-AC–. HBEC3-KT appeared not to be suitable for subsequent analyses. Since the nasal epithelium first gets in contact with airborne pathogens, we further studied the effect of CyaA and its toxoid on the innate immunity of three-dimensional tissue models of the human nasal mucosa. The present study reveals first insights in toxin–cell interaction using primary hAEC. KW - Adenylate cyclase toxin KW - cyclic adenosine monophosphate KW - human respiratory epithelial cells KW - IL-6 KW - Bordetella pertussis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219849 SN - 1753-4259 SN - 1753-4267 VL - 27 IS - 1 SP - 89-98 ER - TY - JOUR A1 - Redlich, Sarah A1 - Martin, Emily A. A1 - Steffan‐Dewenter, Ingolf T1 - Sustainable landscape, soil and crop management practices enhance biodiversity and yield in conventional cereal systems JF - Journal of Applied Ecology N2 - Input‐driven, modern agriculture is commonly associated with large‐scale threats to biodiversity, the disruption of ecosystem services and long‐term risks to food security and human health. A switch to more sustainable yet highly productive farming practices seems unavoidable. However, an integrative evaluation of targeted management schemes at field and landscape scales is currently lacking. Furthermore, the often‐disproportionate influence of soil conditions and agrochemicals on yields may mask the benefits of biodiversity‐driven ecosystem services. Here, we used a real‐world ecosystem approach to identify sustainable management practices for enhanced functional biodiversity and yield on 28 temperate wheat fields. Using path analysis, we assessed direct and indirect links between soil, crop and landscape management with natural enemies and pests, as well as follow‐on effects on yield quantity and quality. A paired‐field design with a crossed insecticide‐fertilizer experiment allowed us to control for the relative influence of soil characteristics and agrochemical inputs. We demonstrate that biodiversity‐enhancing management options such as reduced tillage, crop rotation diversity and small field size can enhance natural enemies without relying on agrochemical inputs. Similarly, we show that in this system controlling pests and weeds by agrochemical means is less relevant than expected for final crop productivity. Synthesis and applications. Our study highlights soil, crop and landscape management practices that can enhance beneficial biodiversity while reducing agrochemical usage and negative environmental impacts of conventional agriculture. The diversification of cropping systems and conservation tillage are practical measures most farmers can implement without productivity losses. Combining local measures with improved landscape management may also strengthen the sustainability and resilience of cropping systems in light of future global change. KW - crop management KW - ecological intensification KW - landscape heterogeneity KW - natural enemies KW - pests KW - soil characteristics KW - sustainable intensification KW - wheat yield Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228345 VL - 58 IS - 3 SP - 507 EP - 517 ER - TY - THES A1 - Georgiev, Kostadin T1 - Sustainable management of naturally disturbed forests T1 - Nachhaltiges Management von natürlichen Störungen in Wäldern N2 - Owing to climate change, natural forest disturbances and consecutive salvage logging are drastically increasing worldwide, consequently increasing the importance of understanding how these disturbances would affect biodiversity conservation and provision of ecosystem services. In chapter II, I used long-term water monitoring data and mid-term data on α-diversity of twelve species groups to quantify the effects of natural disturbances (windthrow and bark beetle) and salvage logging on concentrations of nitrate and dissolved organic carbon (DOC) in streamwater and α-diversity. I found that natural disturbances led to a temporal increase of nitrate concentrations in streamwater, but these concentrations remained within the health limits recommended by the World Health Organization for drinking water. Salvage logging did not exert any additional impact on nitrate and DOC concentrations, and hence did not affect streamwater quality. Thus, neither natural forest disturbances in watersheds nor associated salvage logging have a harmful effect on the quality of the streamwater used for drinking water. Natural disturbances increased the α-diversity in eight out of twelve species groups. Salvage logging additionally increased the α-diversity of five species groups related to open habitats, but decreased the biodiversity of three deadwood-dependent species groups. In chapter III, I investigated whether salvage logging following natural disturbances (wildfire and windthrow) altered the natural successional trajectories of bird communities. I compiled data on breeding bird assemblages from nine study areas in North America, Europe and Asia, over a period of 17 years and tested whether bird community dissimilarities changed over time for taxonomic, functional and phylogenetic diversity when rare, common and dominant species were weighted differently. I found that salvage logging led to significantly larger dissimilarities than expected by chance and that these dissimilarities persisted over time for rare, common and dominant species, evolutionary lineages, and for rare functional groups. Dissimilarities were highest for rare, followed by common and dominant species. In chapter IV, I investigated how β-diversity of 13 taxonomic groups would differ in intact, undisturbed forests, disturbed, unlogged forests and salvage-logged forests 11 years after a windthrow and salvage logging. The study suggests that both windthrow and salvage logging drive changes in between-treatment β-diversity, whereas windthrow alone seems to drive changes in within-treatment β-diversity. Over a decade after the windthrow at the studied site, the effect of subsequent salvage logging on within-treatment β-diversity was no longer detectable but the effect on between-treatment β-diversity persisted, with more prominent changes in saproxylic groups and rare species than in non-saproxylic groups or common and dominant species. Based on these results, I suggest that salvage logging needs to be carefully weighed against its long-lasting impact on communities of rare species. Also, setting aside patches of naturally disturbed areas is a valuable management alternative as these patches would enable post-disturbance succession of bird communities in unmanaged patches and would promote the conservation of deadwood-dependent species, without posing health risks to drinking water sources. N2 - In Folge des Klimawandels treten in Wäldern vermehrt natürliche Störungen auf, wodurch wiederum die Zahl an nachfolgenden Sanitärhieben (Räumungen) drastisch gestiegen ist. Wie sich natürliche Störungen und Sanitärhiebe auf die biologische Vielfalt und die Bereitstellung von Ökosystemleistungen auswirken können, ist bisher jedoch nur unzureichend bekannt. In Kapitel II nutzte ich langfristige Wassermonitoringdaten und mittelfristige Biodiversitätsdaten über zwölf Artengruppen, um die Effekte von natürlichen Störungen (Windwurf und Borkenkäfer) und Sanitärhieben auf die Konzentrationen von Nitraten und gelöster organischer Kohlenstoffe (GOK) in Bächen und Artenzahl zu quantifizieren. Die Ergebnisse zeigen, heraus, dass natürliche Störungen zu einer temporären Erhöhung der Nitratwerte führen, welche dennoch laut Angaben der Weltgesundheitsorganisation immer noch als unbedenklich eingestuft werden können. Die Sanitärhiebe hatten keinen zusätzlichen Einfluss auf die Nitrat- und GOK-Konzentrationen und daher keinen Einfluss auf die Wasserqualität. Daraus lässt sich schließen, dass sich weder natürliche Waldstörungen in Wassereinzugsgebieten noch die damit verbundenen Sanitärhiebe auf die Trinkwasserqualität aus auswirken. Natürliche Störungen erhöhten die Artenzahlen in acht von zwölf Artengruppen. Zusätzlich erhöhten die Sanitärhiebe die Artenzahlen von fünf Artengruppen, welche auf offene Lebensräume angewiesen sind, verringerte jedoch die Artenzahlen von drei xylobionte Artengruppen. In Kapitel III habe ich untersucht, ob Sanitärhiebe nach natürlichen Waldstörungen zu sukzessiven Veränderungen der Vogelgemeinschaften führen. Hierzu habe ich die taxonomische, funktionelle und phylogenetische Diversität von Brutvogelgemeinschaften aus neun Untersuchungsregionen in Nordamerika, Europa und Asien über die Zeit von 17 Jahren verglichen und analysiert, ob sich das jeweilige Diversitätsmaß verändert, wenn seltene, häufige und dominante Arten unterschiedlich gewichtet werden. Ich konnte zeigen, dass Sanitärhiebe zu signifikant größeren Unterschieden geführt haben als zufällig zu erwarten gewesen sind und dass diese Unterschiede über die Zeit sowohl für seltene, häufige und dominante Arten, als auch für evolutionäre Linien, und funktionelle Gruppen fortdauern. Diese Unterschiede waren am größten für seltene, gefolgt von häufigen und dominanten Arten. In Kapitel IV untersuchte ich wie sich die β-Diversität von 13 taxonomischen Gruppen zwischen ungestörten Wäldern, gestörten und ungeräumten Wäldern sowie gestörten und geräumten Wäldern 11 Jahre nach Windwurf und anschließender Räumung unterscheidet. Die Ergebnisse deuten darauf hin, dass sowohl Windwurf als auch Räumung Änderungen in der β-Diversität bewirken. Windwurf allein jedoch scheint diese Änderungen in der β-Diversität innerhalb der Behandlung bewirken zu können. Über ein Jahrzehnt nach dem Windwurf war der Effekt des Sanitärhiebes auf die β-Diversität innerhalb der Behandlung nicht mehr nachweisbar. Der Effekt auf die β-Diversität zwischen den Behandlungen blieb jedoch bestehen, wobei sich die xylobionten Gruppen und seltenen Arten stärker veränderten als die nicht-xylobionten Gruppen oder häufigen und dominanten Arten. Basierend auf diesen Ergebnissen schlage ich vor, dass der Einsatz von Sanitärhieben sorgfältig gegen ihre langfristigen Auswirkungen auf Gemeinschaften seltener Arten abgewogen werden muss. Zusätzlich, besteht mit dem Belassen von natürlich gestörten Waldgebieten eine wertvolle Managementalternative, da diese Flächen eine natürliche Entwicklung von Vogelgemeinschaften ermöglichen und xylobionte Arten fördern, ohne dass die Trinkwasserqualität negativ beeinträchtigt wird. KW - species richness KW - water quality KW - beta diversity KW - Hill numbers KW - post-disturbance logging KW - biodiversity response KW - ecosystem services Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242854 ER - TY - THES A1 - Kreß, Theresa T1 - Symptommanagement bei konservativ behandelten Tumorpatienten T1 - Symptom management of conservatively treated cancer patients N2 - Schmerz ist ein häufiges Problem bei Tumorpatienten und nach wie vor nicht ausreichend erkannt oder behandelt. Hierfür werden zunehmend standardisierte Fragebögen basierend auf patient-reported outcomes eingesetzt. QUIPS ist als solcher Fragebogen im perioperativen Bereich etabliert. Analog dazu wurde QUIKS als Fragebogen für das konservative Schmerzmanagement entwickelt. In dieser Studie konnte erstmals die Einsetzbarkeit des QUIKS-Bogens an Tumorpatienten getestet werden. Die Patienten wurden einmalig während ihres stationären Aufenthaltes befragt, ergänzt um den IPOS Fragebogen um ein umfassendes Bild auch des palliativmedizinischen Unterstützungsbedarfs zu erhalten. Die Ergebnisse zeigen, dass Schmerz bei konservativ behandelten Tumorpatienten insgesamt gut kontrolliert ist. Die bestehenden Strukturen sind geeignet, um Schmerzen zu erfassen und zu lindern. Dennoch sollte die Information über Schmerz und Schmerztherapie noch verbessert werden. Aufgrund der umfassenden Erfassung verschiedener Aspekte wie Schmerzintensität, -entwicklung sowie schmerzbedingter Einschränkungen und der Zufriedenheit mit der Schmerztherapie scheint QUIKS ein geeignetes Instrument zur Erfassung der Schmerzsituation bei Tumorpatienten zu sein. Die aufgedeckten Schwächen des Bogens könnten nur durch deutlich höheren Zeit- und Personalaufwand behoben werden. In Kombination mit den Ergebnissen des IPOS Fragebogens konnte die Verlässlichkeit des QUIKS Bogens indirekt bestätigt werden. N2 - Pain in a common problem in cancer patients and still not necessarily identified or treated. In this regard, standardized questionnaires based upon patient-reported outcomes are increasingly used. QUIPS as such a questionnaire is commonly used in perioperative settings. According to this QUIKS as tool for conservative pain management has been developed. During this study QUIKS could be used for the first time to test the usability in cancer patients. Patients were questioned once during their stay in hospital. They also answered the IPOS questionnaire to broadly identify the palliative care needs. The results show that pain in conservatively treated cancer patients is generally well controlled. The existing structures are suitable to register and lessen pain. Still, the information about pain and pain therapy should be improved. Due to the broad registration of many aspects of pain such as pain intensity, development, pain related disabilities and satisfaction with the pain therapy QUIKS seems to be a usable tool to capture the pain situation in cancer patients. The discovered limitations of the questionnaire could only be solved by investing much more time and staff. In combination with the results of the IPOS questionnaire the reliability of the QUIKS questionnaire could be confirmed. KW - Palliativtherapie KW - Schmerz KW - konservative Tumortherapie KW - Schmerzerfassung KW - Symptommanagement Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232879 ER - TY - JOUR A1 - Höhn, Stefan A1 - Frimmel, Hartwig E. A1 - Prince, Westley T1 - Syn-metamorphic sulfidation of the Gamsberg zinc deposit, South Africa JF - Mineralogy and Petrology N2 - The Mesoproterozoic Aggeneys-Gamsberg ore district, South Africa, is one of the world´s largest sulfidic base metal concentrations and well-known as a prime example of Broken Hill-type base metal deposits, traditionally interpreted as metamorphosed SEDEX deposits. Within this district, the Gamsberg deposit stands out for its huge size and strongly Zn-dominated ore ( >14 Mt contained Zn). New electron microprobe analyses and element abundance maps of sulfides and silicates point to fluid-driven sulfidation during retrograde metamorphism. Differences in the chemistry of sulfide inclusions within zoned garnet grains reflect different degrees of interaction of sulfides with high metal/sulfur-ratio with a sulfur-rich metamorphic fluid. Independent evidence of sulfidation during retrograde metamorphism comes from graphic-textured sulfide aggregates that previously have been interpreted as quenched sulfidic melts, replacement of pyrrhotite by pyrite along micro-fractures, and sulfides in phyllic alteration zones. Limited availability of fluid under retrograde conditions caused locally different degrees of segregation of Fe-rich sphalerite into Zn-rich sphalerite and pyrite, and thus considerable heterogeneity in sphalerite chemistry. The invoked sulfur-rich metamorphic fluids would have been able to sulfidize base metal-rich zones in the whole deposit and thus camouflage a potential pre-metamorphic oxidation. These findings support the recently established hypothesis of a pre-Klondikean weathering-induced oxidation event and challenge the traditional explanation of Broken Hill-type deposits as merely metamorphosed SEDEX deposits. Instead, we suggest that the massive sulfide deposits experienced a complex history, starting with initial SEDEX-type mineralization, followed by near-surface oxidation with spatial metal separation, and then sulfidation of this oxidized ore during medium- to high-grade metamorphism. KW - Gamsberg KW - metamorphic sulfidation KW - sulfide inclusions KW - base metal deposit KW - Aggeneys Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268574 SN - 1438-1168 VL - 115 IS - 6 ER - TY - THES A1 - Ciba, Manuel T1 - Synchrony Measurement and Connectivity Estimation of Parallel Spike Trains from in vitro Neuronal Networks T1 - Messung der Synchronität und Abschätzung der Konnektivität von in-vitro Spike-Trains N2 - The goal of this doctoral thesis is to identify appropriate methods for the estimation of connectivity and for measuring synchrony between spike trains from in vitro neuronal networks. Special focus is set on the parameter optimization, the suitability for massively parallel spike trains, and the consideration of the characteristics of real recordings. Two new methods were developed in the course of the optimization which outperformed other methods from the literature. The first method “Total spiking probability edges” (TSPE) estimates the effective connectivity of two spike trains, based on the cross-correlation and a subsequent analysis of the cross-correlogram. In addition to the estimation of the synaptic weight, a distinction between excitatory and inhibitory connections is possible. Compared to other methods, simulated neuronal networks could be estimated with higher accuracy, while being suitable for the analysis of massively parallel spike trains. The second method “Spike-contrast” measures the synchrony of parallel spike trains with the advantage of automatically optimizing its time scale to the data. In contrast to other methods, which also adapt to the characteristics of the data, Spike-contrast is more robust to erroneous spike trains and significantly faster for large amounts of parallel spike trains. Moreover, a synchrony curve as a function of the time scale is generated by Spike-contrast. This optimization curve is a novel feature for the analysis of parallel spike trains. N2 - Ziel dieser Dissertation ist die Identifizierung geeigneter Methoden zur Schätzung der Konnektivität und zur Messung der Synchronität von in-vitro Spike-Trains. Besonderes Augenmerk wird dabei auf die Parameteroptimierung, die Eignung für große Mengen paralleler Spike-Trains und die Berücksichtigung der Charakteristik von realen Aufnahmen gelegt. Im Zuge der Optimierung wurden zwei neue Methoden entwickelt, die anderen Methoden aus der Literatur überlegen waren. Die erste Methode “Total spiking probability edges” (TSPE) schätzt die effektive Konnektivität zwischen zwei Spike-Trains basierend auf der Berechnung einer Kreuzkorrelation und einer anschließenden Analyse des Kreuzkorrelograms. Neben der Schätzung der synaptischen Ge- wichtung ist eine Unterscheidung zwischen exzitatorischen und inhibitorischen Verbindungen möglich. Im Vergleich zu anderen Methoden, konnten simulierte neuronale Netzwerke mit einer höheren Genauigkeit geschätzt werden. Zudem ist TSPE aufgrund der hohen Rechengeschwindigkeit für große Datenmengen geeignet. Die zweite Methode “Spike-contrast” misst die Synchronität paralleler Spike-Trains mit dem Vorteil, dass die Zeitskala automatisch an die Daten angepasst wird. Im Gegensatz zu anderen Methoden, welche sich ebenfalls an die Daten anpassen, ist Spike-contrast robuster gegenüber fehlerhaften Spike-Trains und schneller für große Datenmengen. Darüber hinaus berechnet Spike-Contrast eine Synchronitätskurve als Funktion der Zeitskala. Diese Kurve ist ein neuartiges Feature zur Analyse paralleler Spike-Trains. KW - Synchronitätsmessung KW - Konnektivitätsschätzung KW - microelectrode array KW - bicuculline KW - similarity KW - distance KW - correlation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223646 ER - TY - THES A1 - Grebinyk, Anna T1 - Synergistic Chemo- and Photodynamic Treatment of Cancer Cells with C\(_{60}\) Fullerene Nanocomplexes T1 - Synergistische chemo- und photodynamische Behandlung von Krebszellen mit C\(_{60}\)-Fulleren-Nanokomplexen N2 - Recent progress in nanotechnology has attracted interest to a biomedical application of the carbon nanoparticle C60 fullerene (C60) due to its unique structure and versatile biological activity. In the current study the dual functionality of C60 as a photosensitizer and a drug nanocarrier was exploited to improve the efficiency of chemotherapeutic drugs towards human leukemic cells. Pristine C60 demonstrated time-dependent accumulation with predominant mitochondrial localization in leukemic cells. C60’s effects on leukemic cells irradiated with high power single chip LEDs of different wavelengths were assessed to find out the most effective photoexcitation conditions. A C60-based noncovalent nanosized system as a carrier for an optimized drug delivery to the cells was evaluated in accordance to its physicochemical properties and toxic effects. Finally, nanomolar amounts of C60-drug nanocomplexes in 1:1 and 2:1 molar ratios were explored to improve the efficiency of cell treatment, complementing it with photodynamic approach. A proposed treatment strategy was developed for C60 nanocomplexes with the common chemotherapeutic drug Doxorubicin, whose intracellular accumulation and localization, cytotoxicity and mechanism of action were investigated. The developed strategy was revealed to be transferable to an alternative potent anticancer drug – the herbal alkaloid Berberine. Hereafter, a strong synergy of treatments arising from the combination of C60-mediated drug delivery and C60 photoexcitation was revealed. Presented data indicate that a combination of chemo- and photodynamic treatments with C60-drug nanoformulations could provide a promising synergetic approach for cancer treatment. N2 - Kürzliche Fortschritte in der Nanotechnologie haben Interesse an einer biomedizinischen Anwendung des Kohlenstoffnanopartikels C60 Fulleren (C60) aufgrund seiner einzigartigen Struktur und breiten biologischen Aktivität geweckt. In der aktuellen Studie wurde die doppelte Funktionalität von C60 als Photosensibilisator und als Wirkstoff-Nanoträger genutzt, um die Wirkung von Chemotherapeutika auf menschliche Leukämiezellen zu verbessern. C60 alleine zeigte in den Zellen eine zeitabhängige Akkumulation mit vorherrschender mitochondrialer Lokalisation. Die Wirkung von C60 auf Leukämiezellen, die mit unterschiedlicher Wellenlänge bestrahlt wurden, wurde bewertet, um die effektivsten Photoanregungsbedingungen zu finden. Die physikochemischen Eigenschaften und toxischen Wirkungen von C60 auf die Leukämiezellen wurden nach nicht kovalenter Bindung von Arzneistoffen bewertet. Schließlich wurden nanomolare Mengen von C60-Wirkstoff-Nanokomplexen in Molverhältnissen von 1:1 und 2:1 untersucht, um die Effizienz der Behandlung von Zellen zu verbessern und sie durch photodynamischen Ansatz zu ergänzen. Mit dem gängigen Chemotherapeutikum Doxorubicin wurde eine Behandlungsstrategie entwickelt und dessen intrazelluläre Akkumulation und Lokalisation, Zytotoxizität und Wirkmechanismus untersucht wurden. Es wurde gezeigt, dass die entwickelte Strategie auch auf ein alternatives Krebsmedikament übertragbar ist – das pflanzliche Alkaloid Berberin. Die erhaltenen Daten deuten darauf hin, dass eine Kombination von chemo- und photodynamischen Behandlungen mit C60-Nanokomplexen einen vielversprechenden synergetischen Ansatz für die Krebsbehandlung bieten könnte. KW - cancer KW - drug delivery KW - photodynamic therapy KW - fullerene Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222075 ER - TY - THES A1 - Lang, Katharina T1 - Synthese leitfähiger elastischer Materialkomposite durch Verwendung metallischer Nanodrähte T1 - Synthesis of conductive elastic material composites by using metallic nanowires N2 - Silbernanodrähte (AgNW) wurden in verschiedene Hybridpolymere und in eine als Referenz dienende Silikonzusammensetzung eingebaut. Durch Spincoating konnten transparente leitfähige Filme erhalten werden. Deren jeweilige Nanodrahtverteilung, thermische Aktivierung und visuelle Transparenz wurden charakterisiert. Die Perkolationsschwelle der Filme hängt dabei von der individuellen durchschnittlichen AgNW-Länge ab. Eine beträchtliche Leitfähigkeit wurde während des mechanischen Streckens bis zu 30 % aufrechterhalten. Mikrostrukturierte Hybridpolymer-Verbundfilme wurden durch UV-Lithographie erhalten. ... N2 - In the context of the present work, silver nanowires were successfully synthesized using a modified polyol process according to Sun et al.[43-45]. The reproducibility of the synthesis was increased by adjusting the reaction parameters. Silver nanowires with an average length of the of ~ 12 µm and diameters of around 50 nm were obtained. The investigations of the silver nanowires were carried out on an optical level, using LSM and SEM (Section 5.1 / Section 9). In this work silver nanowire batches of different lengths were used in the manufacture of composite systems with regard to compatibility. Correspondingly, the selected resin systems from chapter 5.2 with different polarities were introduced. ... KW - Verbundwerkstoff KW - Nanodraht KW - Polymere KW - Elastizität KW - Elastizität KW - Hybridpolymere KW - Komposit Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248253 ER - TY - THES A1 - Wolf, Natalia T1 - Synthese multifunktionaler Farbstoffe und Linker zur Visualisierung biologischer Strukturen T1 - Synthesis of multifunctional dyes and linkers for visualization of biological structures N2 - Durch stetige Entwicklung der Mikroskopiemethoden in den letzten Jahrzehnten ist es nun möglich Strukturen und Abläufe in biologischen Systemen detaillierter darzustellen als mit der von Abbe entdeckten maximalen Auflösungsgrenze. Oft werden dabei Fluoreszenzmarker benutzt, welche die unsichtbare Welt der Mikrobiologie und deren biochemische Prozesse illuminieren. Diese werden entweder durch Expression, wie z.B. das grün fluoreszierende Protein (GFP), in das zu untersuchende Objekt eingebracht oder durch klassische Markierungsmethoden mithilfe von fluoreszierenden Immunkonjugaten installiert. Jedoch gewinnt eine alternative Strategie, die von der interdisziplinären Zusammenarbeit zwischen Chemikern, Physikern und Biologen profitiert, immer mehr an Bedeutung – die bioorthogonale Click-Chemie. Sie ermöglicht eine effiziente Fluoreszenzmarkierung der biologischen Strukturen unter minimalem Eingriff in die Abläufe der Zelle. Dazu müssen allerdings sowohl Farbstoffe als auch die biologisch aktiven Substanzen chemisch modifiziert werden, da nur dadurch die Bioorthogonalität gewährleistet werden kann. Mittlerweile existiert eine breite Palette an fluoreszierenden Farbstoffen, die das komplette sichtbare Spektrum abdecken und sich für diverse Mikroskopiemethoden eignen. Allerdings gibt es zwei Farbstoffklassen, die sich aus der gesamten Fülle abheben und sich für hochauflösende bildgebende Experimente auf Einzelmolekülebene eignen. Zum einen ist es die Farbstofffamilie der Cyanine und insbesondere der wasserlöslichen Pentamethincyanine, die reversibel und kontrolliert zum Photoschalten animiert werden können und in der stochastisch optischen Rekonstruktionsmikroskopie Anwendung finden. Zum anderen ist es die Gruppe, der Rhodamine und Fluoresceine, die zu Xanthenfarbstoffen gehören und sich durch gute photophysikalische Eigenschaften auszeichnen. Trotz der Beliebtheit stellt ihre Darstellung immer noch eine Herausforderung dar und limitiert deren Einsatz. Deshalb war es notwendig im Rahmen der vorliegenden Arbeit Möglichkeiten zur Syntheseoptimierung beider Farbstoffklassen zu finden, damit diese im Folgenden weiterentwickelt und an die biologische Fragestellung angepasst werden können. Die Arbeit unterteilt sich deshalb in Relation an die oben genannten Farbstoffklassen in zwei Bereiche. Im ersten Teil wurden Projekte basierend auf den wasserlöslichen Pentamethincyaninen behandelt. Im zweiten Teil beschäftigte sich die Arbeit mit Projekten, die auf Xanthen-Farbstoffen aufbauen. N2 - Due to steady development in microscopy methods during the last decades its now possible to visualize biological structures in more detail than Abbes low would allow. Frequently fluorescence labeling is used to illuminate the world of microbiology and its processes. There are two classical methods to introduce fluorescent markers to the target of interest. The first way is to use the expression of fluorescent proteins like GFP (green fluorescent protein). The second one is the application of fluorescent immunoconjugates. However, an alternative strategy that benefits from the interdisciplinary cooperation between chemists, physicists and biologists is becoming increasingly important – bioorthogonal click chemistry. It enables efficient fluorescent labelling of biological structures with minimal influence in cell processes. But this requires chemical modification of both dyes and the biologically active substances, as this is the only way to guarantee bioorthogonal click reactions. In the meantime, a wide range of fluorescent dyes is available that cover the entire visible spectrum and are suitable for various microscopy methods. However, there are two classes of dyes that stand out from the rest and are suitable for high-resolution imaging experiments at the single molecule level. On the one hand, there is the dye family of cyanines and in particular the water-soluble pentamethine cyanines, which can be reversibly and in a controlled manner animated to photoswitch. Therefore, they are used in stochastic optical reconstruction microscopy like dStorm. On the other hand, there is the group of rhodamines and fluoresceins, which belong to xanthene dyes and are characterized by good photophysical properties. Despite their popularity, their synthesis still poses a challenge and limits their use. Therefore, it was necessary to find ways to optimize the synthesis of both dye classes within the scope of the present work, so that they can be further developed and adapted to the biological question. This thesis is therefore divided into two parts in relation to the two above mentioned dye classes. In the first part three projects based on the water-soluble pentamethine cyanines were addressed. In the second part the work dealt with projects based on the HMSiR-dyes. KW - Farbstoff KW - Cyanin KW - Rhodaminderivate KW - Click-Chemie KW - Farbstoffsynthese KW - Pentamethincyanine KW - Siliziumrhodaminderivate KW - bioorthogonale Click-Chemie KW - Synthese Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205312 ER - TY - THES A1 - Thiess, Torsten T1 - Synthese und Reaktivität von 1,4-Diaza-2,3-diborininen T1 - Synthesis and reactivity of 1,4-diaza-2,3-diborinines N2 - In der vorliegenden Arbeit wurde die Synthese, Funktionalisierung und Reaktivität von 1,4,2,3-Diazadiborininen untersucht. Zu Beginn sollten Bis(dimethylamino)-substituierte Diazadiborinine mit unterschiedlichen Resten an den Stickstoffatomen dargestellt werden, deren weitere Funktionalisierung später im Fokus stand. Die Synthese erfolgte durch Reduktion von 1,4-Diazabutadienen mit elementarem Lithium und anschließender Salzeliminierungsreaktion mit B2(NMe2)2Cl2. Dadurch ließen sich die monocyclischen vier N,N’-Diaryl-substituierten Diazadiborinine sowie ein Alkyl-substituiertes Diazadiborinin darstellen. Durch etablierte Methoden der Diboran(4)-Chemie wurden diese in ihre Halogenderivate (Cl, Br, I) überführt. Aus diesen konnten drei 2,3-Diazido-1,4,2,3-diazadiborinine durch Umsetzung mit TMSN3 aus den Dihalogenderivaten dargestellt werden. Diese stellen hierbei die ersten isolierten Diboran(4)azidverbindugen dar. Ebenso gelang die Synthese eines bicyclischen Naphthalinisosters, welches erneut erfolgreich in seine Halogenderivate sowie das Diazdidoderivat überführt werden konnte. Einen Einblick in den Mechanismus der 1,4,2,3-Diazadiborininbildung ermöglichte die Isolierung eines Diazadiboretidinintermediats, welches durch doppelte Salzeliminierung entsteht. Dieses erwies sich jedoch als metastabil und lagerte zum Sechsring Diazadiborinin um. Quantenchemische Berechnungen unterstutzten die experimentellen Befunde. Über Kommutierungsreaktionen konnte eine Vielzahl an B,B‘-unsymmetrisch substituierten Diazadiborininen dargestellt und isoliert werden, wobei je nach verwendeten Startmaterialien entweder Gleichgewichtsreaktionen oder quantitative Umsetzungen beobachtet wurden. Ebenso wurde die Reaktivität der neuartigen Diazidodiborane(4) gegenüber Lewis-Basen untersucht. Sowohl das monocyclische Diazadiborinin, als auch das Benzodiazadiborinin konnten mit NHC-Basen zu den fünf verschiedenen Addukten umgesetzt werden. Unter thermischer Belastung wurde bei den monocyclischen Addukten eine Staudinger-artige Reaktion beobachtet, die unter Freisetzung von N2 zur Bildung von Guanadin-substituierten Diborane(4) führte. Die Benzodiazadiborininaddukte zeigten jedoch eine gänzlich andere Reaktivität. Hier fand eine Ringverkleinerungsreaktion unter Bildung von Diazaborolen statt, welche unter Wanderung einer Azidfunktion auf das NHC-stabilisierte Boratom gebildet wurden. Auf diese Weise konnten drei 1,1-Diamino-2,2-diazidodiborane(5) isoliert werden. Während bei der Umsetzung des Naphtalenderivats mit cAAC keine selektive Reaktion beobachtet wurde, reagierte das monocyclische Diazadiborinin mit zwei Äquivalenten cAAC. Hier bedingte das erste Carbon eine Staudinger-artige Reaktion, die unter Distickstofffreisetzung zu einem Formamidin führte. Die zweite Azidgruppe wurde am $\gamma$-Stickstoffatom von einem weiteren Äquivalent cAAC koordiniert. In weiteren Reaktivitätsstudien wurde die Generierung von transienten Iminoboranen aus Diazidodiazadiborininen untersucht. Die Diazide zeigten bei Temperaturen von über 150 °C ein sehr selektives Reaktionsverhalten und gingen unter Freisetzung von Distickstoff zu 1,3,2,4-Diazadiboretidin über, wobei dies über die Dimerisierung eines intermediär gebildeten siebengliedrigen, endocyclischen Iminoborans verlief. Der Mechanismus zur Bildung der transienten Iminoborane wurde anhand zweier möglicher Bildungswege mit quantenchemischen Methoden untersucht. Im letzten Kapitel wurde die Reaktivität des Dihydrodiazadiborinins gegenüber NHC- und cAAC-Lewis-Basen untersucht. Die Umsetzung mit cAAC führte zu einer B–H-Bindungsaktivierung durch das Carbenkohlenstoffatom, die vermutlich über eine Adduktspezies verläuft. Mit dem gesättigten NHC SIMes wurde ebenfalls keine Adduktbildung beobachtet, auch wenn ein derartiges Intermediat vermutlich durchlaufen wird. Als Produkt der Umsetzung wurde indes ein bicyclisches Molekül identifiziert, welches durch doppelte Ringerweiterung gebildet wurde. Mit ungesättigten NHCs wurden drei Addukte isoliert, welche jedoch nur metastabil waren und beim Erwärmen in bicyclische Verbindungen umlagerten. Die Umlagerungsprodukte konnten weiterhin durch Koordination eines weiteren Äquivalents IMe an die B–H-Funktionalität erneut zu Addukten umgesetzt werden. Die Bildung der zweier bicyclischer Verbindungen wurde ebenfalls mit quantenchemischen Methoden untersucht, wobei ein vierstufiger Prozess durchlaufen wird. Nach der Bildung des NHC-Addukts erfolgt die Übertragung eines Hydrids auf das Carbenkohlenstoffatom. Durch Insertion eines Boratoms in die NC-Bindung des Carbenrings wird eine Spiroverbindung gebildet und im letzten Schritt folgt die Spaltung der BB-Bindung durch Insertion des ehemaligen Carbenkohlenstoffatoms, was zur Bildung der Bicyclen führt. N2 - In the present work the synthesis, functionalization and reactivity of 1,4,2,3-diazadiborinines was investigated. Initially, bis(dimethylamino)-substituted diazadiborinines with different residues on the nitrogen atoms were to be synthesized, whose further functionalization was later in focus. The synthesis was performed by reduction of 1,4-diazabutadienes with elemental lithium and subsequent salt elimination reaction with B2(NMe2)2Cl2. Thus, the monocyclic four N,N'-diaryl-substituted diazadiborinines and one alkyl-substituted diazadiborinine could be prepared. By established methods of diborane(4) chemistry, these were converted into their halogen derivatives (Cl, Br, I). From these, three 2,3-diazido-1,4,2,3-diazadiborinines could be prepared by reaction with TMSN3 from the dihalogen derivatives. These represent the first isolated diborane(4)azide compounds. The synthesis of a bicyclic naphthalene isoster was also successful, which could again be successfully converted into its halogen derivatives as well as the diazdido derivative. An insight into the mechanism of 1,4,2,3-diazadiborinine formation was gained by isolating a diazadiboretidine intermediate, which is formed by double salt elimination. However, this proved to be metastable and rearranged to the six-membered ring of diazadiborinine. Quantum chemical calculations supported the experimental findings. Via commutation reactions, a large number of B,B'-unsymmetrically substituted diazadiborinines could be represented and isolated. Depending on the starting materials used, either equilibrium reactions or quantitative conversions were observed. The reactivity of the novel diazidodiboranes(4) to Lewis bases was also investigated. Both the monocyclic diazadiborinine and the benzodiazadiborinine could be converted with NHC bases to the five different adducts. Under thermal stress a Staudinger-like reaction was observed in the monocyclic adducts, which led to the formation of guanadine-substituted diboranes(4) with the release of N2. However, the benzodiazadiborinine adducts showed a completely different reactivity. Here, a ring reduction reaction took place with formation of diazaborols, which were formed by migration of an azide function to the NHC-stabilized boron atom. In this way, three 1,1-diamino-2,2-diazidodiboranes(5) could be isolated. While no selective reaction was observed during the reaction of the naphthalene derivative with cAAC, the monocyclic diazadiborinine reacted with two equivalents of cAAC. In this case, the first carbon caused a Staudinger-like reaction, which led to the release of dinitrogen to formamidine. The second azide group was coordinated at the $\gamma$ nitrogen atom by another equivalent cAAC. In further reactivity studies the generation of transient iminoboranes from diazidodiazadiborinines was investigated. The diazides showed a highly selective reaction behavior at temperatures above 150 °C and converted to 1,3,2,4-diazadiboretidine with the release of dinitrogen. This was achieved by dimerization of an intermediately formed seven-membered endocyclic iminoborane. The mechanism for the formation of the transient iminoboranes was investigated by quantum chemical methods on the basis of two possible formation pathways. In the last chapter the reactivity of dihydrodiazadiborinine towards NHC and cAAC Lewis bases were investigated. The reaction with cAAC resulted in B-H bond activation by the carbene carbon atom, which is thought to be via an adduct species. No adduct formation was observed with the saturated NHC SIMes either, although such an intermediate is likely to be passed through. However, a bicyclic molecule formed by double ring extension was identified as the product of the reaction. Three adducts were isolated with unsaturated NHCs, but they were only metastable and rearranged into bicyclic compounds upon heating. The rearrangement products were further converted back to adducts by coordinating another equivalent IMe to the B-H functionality. The formation of the two bicyclic compounds was also investigated by quantum chemical methods, whereby a four-step process is used. After formation of the NHC adduct, a hydride is transferred to the carbene carbon atom. By insertion of a boron atom into the NC bond of the carbene ring a spiro compound is formed and in the last step the BB bond is cleaved by insertion of the former carbene carbon atom, which leads to the formation of the bicycles. KW - Heterocyclische Verbindungen KW - Chemie KW - Elementorganik KW - Diazadiborinin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214598 ER - TY - THES A1 - Duda, Katharina T1 - Synthesen und Eigenschaften von Dicarba-closo-dodecaboran-Derivaten und ersten gemischten Fluorohydridoborat-Anionen T1 - Syntheses and properties of dicarba-closo-dodecaborane derivatives and first mixed fluorohydridoborate anions N2 - Ein wesentliches Ziel dieser Arbeit war die Durchführung von regioselektiven Deborierungsreaktionen von 1,7-Dicarba-closo-dodecaboranen sowie die Herstellung von polyfunktionalisierten meta-Carboran-Derivaten. Die synthetisierten {nido-7,9-C2B9}- und {closo-1,7-C2B10}-Derivate und ausgewählte ortho-Carboran-Derivate wurden nach erfolgter Kumada-artiger Kreuzkupplungsreaktion bzgl. ihrer Koordinationschemie untersucht. Die ethinylfunktionalisierten Borcluster wurden als Edukte für die Herstellung von Gold(I)-Komplexen genutzt. Weitere Ziele dieser Arbeit waren außerdem die Synthese und umfassende Charakterisierung des gemischten Fluorohydridoborat-Anions [BHF3]− und der carboranylsubstituierten Borat-Anionen [1-HF2B-closo-1,2-C2B10H11]− und [1-HF2B-9,12-I2-closo-1,2-C2B10H9]− sowie die Untersuchung hinsichtlich ihrer Folgechemie. N2 - An essential aim of the presented work was the investigation of regioselective deboronation reactions of 1,7-dicarba-closo-dodecaboranes as well as the preparation of poly-functionalized meta-carboranes. After the {nido-7,9-C2B9}-, {closo-1,7-C2B10}- and selected ortho-carborane derivates were prepared by a Kumada-type cross coupling reaction, the behaviour of these compounds in coordination chemistry was examined. The ethynyl-functionalised boron clusters were used as educts for the preparation of gold(I) complexes. Further objectives of this work were the synthesis and complete characterisation of the mixed fluorohydridoborate anion [BHF3]− and of the carboranyl substituted anions [1-HF2B-closo-1,2-C2B10H11]− and [1-HF2B-9,12-I2-closo-1,2-C2B10H9]− and in further applications in syntheses. KW - Carborane KW - Fluoroborate KW - regioselektive Deborierungsreaktionen KW - Gold(I)-Komplexe KW - gemischte Fluorohydridoborat-Anionen KW - Cluster-Aufbau Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181038 ER - TY - JOUR A1 - Gentzsch, Christian A1 - Chen, Xinyu A1 - Spatz, Philipp A1 - Košak, Urban A1 - Knez, Damijan A1 - Nose, Naoko A1 - Gobec, Stanislav A1 - Higuchi, Takahiro A1 - Decker, Michael T1 - Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase JF - Molecular Imaging and Biology N2 - Purpose A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM). Conclusions The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield. KW - Alzheimer’s disease KW - amyloid-β (Aβ) KW - butyrylcholinesterase Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269870 SN - 1860-2002 VL - 23 IS - 4 ER - TY - JOUR A1 - Gentzsch, Christian A1 - Hoffmann, Matthias A1 - Ohshima, Yasuhiro A1 - Nose, Naoko A1 - Chen, Xinyu A1 - Higuchi, Takahiro A1 - Decker, Michael T1 - Synthesis and Initial Characterization of a Selective, Pseudo‐irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer JF - ChemMedChem N2 - The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution. KW - carbamate KW - enzyme kinetics KW - fluorine-18 KW - positron emission tomography KW - radiotracers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239904 VL - 16 IS - 9 SP - 1427 EP - 1437 ER - TY - JOUR A1 - Krebs, Johannes A1 - Haehnel, Martin A1 - Krummenacher, Ivo A1 - Friedrich, Alexandra A1 - Braunschweig, Holger A1 - Finze, Maik A1 - Ji, Lei A1 - Marder, Todd B. T1 - Synthesis and Structure of an o-Carboranyl-Substituted Three-Coordinate Borane Radical Anion JF - Chemistry—A European Journal N2 - Bis(1-(4-tolyl)-carboran-2-yl)-(4-tolyl)-borane [(1-(4-MeC\(_{6}\)H\(_{4}\))-closo-1,2-C\(_{2}\)B\(_{10}\)H\(_{10}\)-2-)\(_{2}\)(4-MeC\(_{6}\)H\(_{4}\))B] (1), a new bis(o-carboranyl)-(R)-borane was synthesised by lithiation of the o-carboranyl precursor and subsequent salt metathesis reaction with (4-tolyl)BBr\(_{2}\). Cyclic voltammetry experiments on 1 show multiple distinct reduction events with a one-electron first reduction. In a selective reduction experiment the corresponding paramagnetic radical anion 1\(^{.−}\) was isolated and characterized. Single-crystal structure analyses allow an in-depth comparison of 1, 1\(^{.−}\), their calculated geometries, and the S\(_{1}\) excited state of 1. Photophysical studies of 1 show a charge transfer (CT) emission with low quantum yield in solution but a strong increase in the solid state. TD-DFT calculations were used to identify transition-relevant orbitals. KW - Wade’s rules KW - carborane KW - charge transfer KW - radical KW - threecoordinate boron Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256841 VL - 27 IS - 31 ER - TY - JOUR A1 - Brückner, Tobias A1 - Heß, Merlin A1 - Stennett, Tom E. A1 - Rempel, Anna A1 - Braunschweig, Holger T1 - Synthesis of Boron Analogues of Enamines via Hydroamination of a Boron-Boron Triple Bond BT - Dedicated to Professor Wolfgang Kaim on the occasion of his 70th birthday JF - Angewandte Chemie, International Edition N2 - An N-heterocyclic-carbene-stabilized diboryne undergoes rapid, high-yielding and catalyst-free hydroamina- tion reactions with primary amines, yielding 1-amino-2-hydro- diborenes, which can be considered boron analogues of enamines. The electronics of the organic substituent at nitrogen influence the structure and further reactivity of the diborene product. With electron-rich anilines, a second hydroamination can occur at the diborene to generate 1,1-diamino-2,2-dihy- drodiboranes. With isopropylamine, the electronic influence of the alkyl substituent upon the diborene leads to an unprece- dented boron-mediated intramolecular N-dearylation reaction of an N-heterocyclic carbene unit. KW - boron KW - diborynes KW - diborenes KW - DFT KW - enamines KW - hydroamination KW - multiple bonds Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240669 VL - 60 IS - 2 ER - TY - JOUR A1 - Ferger, Matthias A1 - Berger, Sarina M. A1 - Rauch, Florian A1 - Schönitz, Markus A1 - Rühe, Jessica A1 - Krebs, Johannes A1 - Friedrich, Alexandra A1 - Marder, Todd B. T1 - Synthesis of Highly Functionalizable Symmetrically and Unsymmetrically Substituted Triarylboranes from Bench-Stable Boron Precursors JF - Chemistry—A European Journal N2 - A novel and convenient methodology for the one-pot synthesis of sterically congested triarylboranes by using bench-stable aryltrifluoroborates as the boron source is reported. This procedure gives systematic access to symmetrically and unsymmetrically substituted triarylboranes of the types BAr\(_{2}\)Ar’ and BArAr'Ar’’, respectively. Three unsymmetrically substituted triarylboranes as well as their iridium-catalyzed C−H borylation products are reported. These borylated triarylboranes contain one to three positions that can subsequently be orthogonally functionalized in follow-up reactions, such as Suzuki-Miyaura cross-couplings or Sonogashira couplings. KW - synthetic methods KW - boranes KW - borylation KW - chromophore KW - functionalization Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256827 VL - 27 IS - 35 ER - TY - THES A1 - Ming, Wenbo T1 - Synthesis of α‑Aminoboronates and PBP Pincer Palladium Boryl Complexes T1 - Synthese von α-Aminoboronaten und PBP-Pincer-Palladium-Boryl-Komplexen N2 - The first Borono-Strecker reaction has been developed to synthesize α-aminoboronates via a multicomponent reaction of readily available carbonyl compounds (aldehydes and ketones), amines and B2pin2. The preparation of α-amino cyclic boronates can be achieved via multicomponent coupling of salicylaldehydes, amines, and B2(OH)4. In addition, the diazaborole-based PBP pincer palladium chloride and the diazaborole-based PBP pincer palladium trifluoromethanesulfonate complexes were synthesized and fully characterized for the first time, and used as catalysts for Suzuki-Miyaura cross-coupling reactions. N2 - Wurde die erste Borono-Strecker Reaktion zur Synthese von α-Aminoboronaten, mittels einer Multikomponenten-Reaktion aus leicht zugänglichen Carbonylverbindungen (Aldehyde und Ketone), Aminen und B2pin2, entwickelt. Außerdem gelang die Darstellung von zyklischen α-Aminoboronaten durch Multikomponenten-Kupplung von leicht zugänglichen Salicylaldehyden, Aminen und B2(OH)4. Des Weiteren wurde der Diazaborol-basierte PBP Pincer Palladium Chlorid Komplex und der Diazaborol-basierte PBP Pincer Palladium Trifluoromethylsulfonat Komplex erstmalig synthetisiert, vollständig charakterisiert und als Katalysator für Suzuki-Miyaura Kreuzkupplungen eingesetzt. KW - borylation KW - α-aminoboronates KW - PBP pincer palladium complexes KW - cross-coupling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198323 ER - TY - THES A1 - Roos, Markus T1 - Synthesis, Photophysics and Photocatalysis of [FeFe] Complex Containing Dyads and Bimolecular Systems T1 - Synthese, Photophysik und Photokatalyse von [FeFe]-Komplex enthaltenden Dyaden und bimolekularen Systemen N2 - In the course of this work, a total of three photocatalytically active dyads for proton reduction could be synthesized together with the associated individual components. Two of them, D1 and D2, comprised a [Ru(bpy)3]2+ photosensitizer and D3 an [Ir(ppy)2bpy]+ photosensitizer. A Ppyr3-substituted propyldithiolate [FeFe] complex was used as catalyst in all systems. The absorption spectroscopic and electrochemical investigations showed that an inner-dyadic electronic coupling is effectively prevented in the dyads due to conjugation blockers within the bridging units used. The photocatalytic investigations exhibited that all dyad containing two-component systems (2CS) showed a significantly worse performance than the corresponding bimolecular three-component systems (3CS). Transient absorption spectroscopy showed that the 2CS behave very similarly to the associated multicomponent systems during photocatalysis. The electron that was intended for the intramolecular transfer from the photosensitizer unit to the catalyst unit within the dyads remains at the photosensitizer for a relatively long time, analogous to the 3CS and despite the covalently bound catalyst. It is therefore assumed that this intramolecular electron transfer is likely to be hindered as a result of the weak electronic coupling caused by the bridge units used. Instead, the system bypasses this through an intermolecular transfer to other dyad molecules in the immediate vicinity. In addition, with the help of emission quenching experiments and electrochemical investigations, it could be clearly concluded that all investigated systems proceed via the reductive quenching mechanism during photocatalysis. N2 - Im Rahmen dieser Arbeit konnten insgesamt drei photokatalytisch aktive Dyaden zur Protonenreduktion zusammen mit den zugehörigen Einzelkomponenten synthetisiert werden. Zwei von ihnen, D1 und D2, umfassten einen [Ru(bpy)3]2+-Photosensibilisator und D3 einen [Ir(ppy)2bpy]+-Photosensibilisator. Als Katalysator wurde in allen Systemen ein Ppyr3-substituierter Propyldithiolat-[FeFe]-Komplex verwendet. Die absorptionsspektroskopischen und elektrochemischen Untersuchungen zeigten, dass eine innerdyadische elektronische Kopplung aufgrund von Konjugationsblockern innerhalb der verwendeten Brückeneinheiten wirksam verhindert wird. Die photokatalytischen Untersuchungen zeigten, dass alle dyadenhaltigen Zweikomponentensysteme (2CS) eine signifikant schlechtere Leistung zeigten als die entsprechenden bimolekularen Dreikomponentensysteme (3CS). Mithilfe der transienten Absorptionsspektroskopie konnte gezeigt werden, dass sich die 2CS während der Photokatalyse sehr ähnlich wie die zugehörigen Mehrkomponentensysteme verhalten. Das Elektron, das für den intramolekularen Transfer von der Photosensibilisatoreinheit zur Katalysatoreinheit innerhalb der Dyaden vorgesehen war, verbleibt analog zu den 3CS und trotz des kovalent gebundenen Katalysators relativ lange am Photosensibilisator. Es wird daher angenommen, dass dieser intramolekulare Elektronentransfer wahrscheinlich aufgrund der schwachen elektronischen Kopplung, die durch die verwendeten Brückeneinheiten verursacht wird, behindert wird. Stattdessen umgeht das System dies durch einen intermolekularen Transfer zu anderen Dyadenmolekülen in unmittelbarer Nähe. Darüber hinaus konnte mithilfe von Emissionslöschungsexperimenten und elektrochemischen Untersuchungen eindeutig darauf geschlossen werden, dass alle untersuchten Systeme während der Photokatalyse über den reduktiven Löschmechanismus ablaufen. KW - Fotokatalyse KW - Elektronentransfer KW - proton reduction KW - [FeFe] hydrogenase mimic KW - dyad KW - ruthenium photosensitizer KW - iridium photosensitizer KW - Protonenreduktion KW - [FeFe]-Hydrogenase Imitator KW - Dyade KW - Ruthenium-Photosensibilisator KW - Iridium-Photosensibilisator Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234537 ER - TY - JOUR A1 - Berger, Sarina M. A1 - Ferger, Matthias A1 - Marder, Todd B. T1 - Synthetic Approaches to Triarylboranes from 1885 to 2020 JF - Chemistry – A European Journal N2 - In recent years, research in the fields of optoelectronics, anion sensors and bioimaging agents have been greatly influenced by novel compounds containing triarylborane motifs. Such compounds possess an empty p‐orbital at boron which results in useful optical and electronic properties. Such a diversity of applications was not expected when the first triarylborane was reported in 1885. Synthetic approaches to triarylboranes underwent various changes over the following century, some of which are still used in the present day, such as the generally applicable routes developed by Krause et al. in 1922, or by Grisdale et al. in 1972 at Eastman Kodak. Some other developments were not pursued further after their initial reports, such as the synthesis of two triarylboranes bearing three different aromatic groups by Mikhailov et al. in 1958. This review summarizes the development of synthetic approaches to triarylboranes from their first report nearly 135 years ago to the present. KW - arylmetalate KW - boranes KW - chromophore KW - Lewis acid KW - synthetic methods Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238952 VL - 27 IS - 24 SP - 7043 EP - 7058 ER - TY - JOUR A1 - Mayr, Stefan A1 - Klein, Igor A1 - Rutzinger, Martin A1 - Kuenzer, Claudia T1 - Systematic water fraction estimation for a global and daily surface water time-series JF - Remote Sensing N2 - Fresh water is a vital natural resource. Earth observation time-series are well suited to monitor corresponding surface dynamics. The DLR-DFD Global WaterPack (GWP) provides daily information on globally distributed inland surface water based on MODIS (Moderate Resolution Imaging Spectroradiometer) images at 250 m spatial resolution. Operating on this spatiotemporal level comes with the drawback of moderate spatial resolution; only coarse pixel-based surface water quantification is possible. To enhance the quantitative capabilities of this dataset, we systematically access subpixel information on fractional water coverage. For this, a linear mixture model is employed, using classification probability and pure pixel reference information. Classification probability is derived from relative datapoint (pixel) locations in feature space. Pure water and non-water reference pixels are located by combining spatial and temporal information inherent to the time-series. Subsequently, the model is evaluated for different input sets to determine the optimal configuration for global processing and pixel coverage types. The performance of resulting water fraction estimates is evaluated on the pixel level in 32 regions of interest across the globe, by comparison to higher resolution reference data (Sentinel-2, Landsat 8). Results show that water fraction information is able to improve the product's performance regarding mixed water/non-water pixels by an average of 11.6% (RMSE). With a Nash-Sutcliffe efficiency of 0.61, the model shows good overall performance. The approach enables the systematic provision of water fraction estimates on a global and daily scale, using only the reflectance and temporal information contained in the input time-series. KW - earth observation KW - landsat KW - MODIS KW - remote sensing KW - probability KW - Sentinel-2 KW - subpixel KW - water Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242586 SN - 2072-4292 VL - 13 IS - 14 ER - TY - THES A1 - Jordan, Franziska T1 - Systematische Bildanalyse des Röntgen-Thorax bei Patienten mit akuter Herzinsuffizienz. Ergebnisse des AHF-Registers Würzburg T1 - Systematic image analysis of chest x-ray in patients with acute heart failure. Results of the AHF-Register Würzburg N2 - Im Zuge der Erstdiagnostik einer Krankenhausaufnahme bei akuter Herzinsuffizienz ist die Röntgen-Thorax-Untersuchung fester Bestandteil. Ziel dieser Arbeit war es, ihren klinischen Stellenwert und die Aufnahmequalität systematisch zu untersuchen. In der AHF-Registerstudie wurden alle am Universitätsklinikum Würzburg vorstelligen Patienten mit akuter Herzinsuffizienz konsekutiv registriert und umfassend phänotypisiert. Die Röntgen-Thorax-Befunde wurden systematisch informationsextrahiert, auf Konsistenz überprüft, katalogisiert und klassifiziert. N2 - In the course of the initial diagnosis of acute heart failure is chest x-ray an integral part. The aim of this work was to systematically research the clinical value and the image quality. All patients, who presented to the Würzburg University Hospital with acute heart failure, were consecutively registered and extensively phenotyped. The chest x-ray findings were systematically extracted, checked for consistency, cataloged and classified. KW - AHF KW - acute heart failure KW - akute Herzinsuffizienz KW - Röntgen-Thorax KW - chest-x-ray Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243324 ER - TY - THES A1 - Schneider, Dominik T1 - Systematische Videoanalyse von Verletzungen im Profibasketball der Männer T1 - Systematic video analysis of injuries in professional men's basketball N2 - Bisher gibt es nur wenige Forschungsarbeiten, die sich mit der videogestützten Analyse von Basketballverletzungen beschäftigen. In der vorliegenden Arbeit wurden Basketballverletzungen der ersten Basketballbundesliga und der zweiten Basketballbundesliga systematisch per Video analysiert, mit dem Ziel, Verletzungsmuster zu beschreiben und somit gegebenenfalls die Rate von Basketballverletzungen durch geeignete Präventionsansätze zu reduzieren. Hierbei wurden Daten hinsichtlich der Rahmenbedingungen, des Orts der Verletzung, der Spielsituation, der Auslöser und der Umstände der Verletzung an sich zu 215 Verletzungen mit Hilfe eines speziell für die videogestützte Analyse von Basketballverletzungen entwickelten Beobachtungsbogens erhoben. Es zeigte sich in 38% der erhobenen Fälle das Bewegungsmuster Landung zum Verletzungszeitpunkt, was somit das häufigste zu Verletzungen führende Bewegungsmuster war. Oft waren gerade die die athletische Spielweise des Basketballs charakterisierenden Spielaktionen (z. B. Korbleger bzw. Dunking und Shotblock) Auslöser von Verletzungen. Zudem ereigneten sich die Verletzungen im zweiten Viertel 2,1-fach häufiger und im vierten Viertel 1,9-fach häufiger im Vergleich zu den anderen beiden Vierteln. Ein weiteres wichtiges Resultat war, dass die Verletzungen in der Mehrzahl der Fälle (80%) nicht auf ein Foulspiel zurückzuführen waren. Insgesamt ergibt sich aus den Erkenntnissen die Empfehlung der Implementierung von neuromuskulären Präventionsprogrammen, welche die besonderen Verletzungsmechanismen des Basketballs miteinbeziehen. Bisherige Präventionsprogramme können aufgrund dieser Datenlage bezüglich der Bewegungsmuster, der Spielposition, des Verletzungszeitpunkts und des Kontaktmechanismus sowie der individuellen Voraussetzungen des jeweiligen Spielers verwendet werden. Die Umsetzung sollte von Trainern/-innen mitgetragen und überprüft werden. Foulregeländerungen müssen gemäß der vorliegenden Untersuchung – in Hinblick auf die Verletzungsprävention nicht durchgeführt werden. Bezüglich der Resultate hinsichtlich des Verletzungszeitpunkts könnte nach Detektion der genauen Ursachen für eine gehäufte Anzahl an Verletzungen in bestimmten Spielabschnitten durch weitere Studien eine Regeländerung mit Verlängerung der Viertelpausen erwogen werden. N2 - To date, there has been little research that has focused on video-based analysis of basketball injuries. In the present work, basketball injuries of the first and second German national basketball league were systematically analyzed by video with the aim to describe injury patterns and thus, if applicable, to reduce the rate of basketball injuries by suitable prevention approaches. For this purpose, data regarding the general conditions, the location of the injury, the game situation, the triggers and the circumstances of the injury itself were collected for 215 injuries using an observation form specially developed for the video-based analysis of basketball injuries. It appeared in 38% of the collected cases the movement pattern landing at the time of injury, which was thus the most common movement pattern leading to injuries. Often, the game actions that characterize the athletic style of basketball (e.g., lay-up or dunking and shot blocking) were the triggers of injuries. In addition, injuries occurred 2.1 times more frequently in the second quarter and 1.9 times more frequently in the fourth quarter compared to the other two quarters. Another important finding was that in the majority of cases (80%), the injuries were not due to foul play. Overall, the findings lead to the recommendation of implementing neuromuscular prevention programs that incorporate the unique injury mechanisms of basketball. Previous prevention programs can be used based on these data regarding movement patterns, playing position, time of injury, contact mechanism and the individual conditions of each player. Implementation should be shared and reviewed by coaches. According to the present study, foul rule changes with regard to injury prevention do not need to be implemented. With regard to the results concerning the time of injuries, a rule change with extension of the quarter breaks could be considered after detection of the exact causes for a clustered number of injuries in certain game sections by further studies. KW - Basketball KW - Prävention KW - Verletzung KW - Bewegungsmuster KW - Sportmedizin KW - systematische Videoanalyse Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222681 ER - TY - JOUR A1 - Adolph, Jonas E. A1 - Fleischhack, Gudrun A1 - Gaab, Christine A1 - Mikasch, Ruth A1 - Mynarek, Martin A1 - Rutkowski, Stefan A1 - Schüller, Ulrich A1 - Pfister, Stefan M. A1 - Pajtler, Kristian W. A1 - Milde, Till A1 - Witt, Olaf A1 - Bison, Brigitte A1 - Warmuth-Metz, Monika A1 - Kortmann, Rolf-Dieter A1 - Dietzsch, Stefan A1 - Pietsch, Torsten A1 - Timmermann, Beate A1 - Tippelt, Stephan T1 - Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies JF - Journal of Neuro-Oncology N2 - Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation. KW - ependymoma KW - chemotherapy KW - recurrence KW - children KW - sirolimus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308302 SN - 0167-594X SN - 1573-7373 VL - 155 IS - 2 ER - TY - THES A1 - Hafer [geb. Zailer], Elina T1 - Tagging - Development of new qNMR methods T1 - Tagging - Die Entwicklung neuer Quantifizierungmethoden in der NMR Spektroskopie N2 - High-resolution nuclear magnetic resonance (NMR) spectroscopy is used in structure elucidation and qualitative as well as quantitative examination of product components. Despite the worldwide development of numerous innovative NMR spectroscopic methods, several official methods that analyze specific substances and do not represent a holistic analysis, are still in use for the quality control of drugs, food and chemicals. Thus, counterfeit or contaminated products of inferior quality can be brought onto the market and distributed despite previous quality controls. To prevent this, three NMR spectroscopic methods have been developed within the scope of this work (1) to study the peroxide value in vegetable and animal oils, (2) for the qualitative and quantitative analysis of metal cations and (3) to determine the enantiomeric excess in chiral alcohols. In oil analysis, titration methods are used to determine the bulk quality parameters such as peroxide value, which represents the concentration of peroxides. Titrations show several drawbacks, such as the need of a large amount of sample and solvents, cross reactions and the low robustness. Thus, an alternative NMR spectroscopic method was developed to improve the peroxide analysis by using triphenylphosphine as a derivatization reagent, which reacts with peroxides in a stoichiometric ratio of 1:1 forming triphenylphosphine oxide. In the 1H-31P decoupled NMR spectrum, the signals of the unreacted triphenylphosphine and the reacted triphenylphosphine oxide are detected at 7.4 ppm and 7.8 ppm, respectively. The ratio of the two signals is used for the calculation of the peroxide concentration. 108 oil samples with a peroxide value between 1 meq/kg and 150 meq/kg were examined using the developed method. Oils with a very low peroxide value of less than 3 meq/kg showed a relative standard deviation of 4.9%, highly oxidized oils with a peroxide value of 150 meq/kg of 0.2%. The NMR method was demonstrated as a powerful technique for the analysis of vegetable and krill oils. Another 1H NMR spectroscopic method was developed for the qualitative determination of Be2+, Sr2+ and Cd2+, and for the qualitative and quantitative determination of Ca2+, Mg2+, Hg2+, Sn2+, Pb2+ and Zn2+ by using ethylenediamine tetraacetate (EDTA) as complexing agent. EDTA is a hexadentate ligand that forms stable chelate complexes with divalent cations. The known amount of added EDTA and the signal ratio of free and complexed EDTA are used to calculate the concentrations of the divalent cations, which makes the use of an internal standard obsolete. The use of EDTA with Be2+, Sr2+, Cd2+, Ca2+, Mg2+, Hg2+, Sn2+, Pb2+ and Zn2+ result in complexes whose signals are pH-independent, showing cation-specific chemical shifts and couplings in the 1H NMR spectrum that are used for identification and quantification. In the presented NMR method, the limit of quantification of the cations Ca2+, Mg2+, Hg2+, Sn2+, Pb2+, and Zn2+ was determined with 5-22 μg/mL. This method is applicable in the food and drug sectors. The third NMR spectroscopic method introduced an alternative determination of the enantiomer excess (ee) of the chiral alcohols menthol, borneol, 1-phenylethanol and linalool using phosgene as a derivatizing reagent. Phosgene reacts with a chiral alcohol to form carboxylic acid diesters, made of two identical (RR, SS) or two different enantiomers (RS, SR). These two different types of diastereomers can be examined by the difference of their chemical shifts. In the presented method, the integration values of the carbonyl signals in the 13C NMR spectrum are used for the determination of the enantiomer excess. The limit of quantification depends, among others, on the sample and on the non-labelled or 13C-labelled phosgene used for the analysis. In the case of menthol, a quantification limit of ee=99.1% was determined using non-labelled phosgene and ee=99.9% using 13C-labelled phosgene. The 13C NMR method was also applied for the quality control of the enantiomeric purity of borneol, 1-phenylethanol and linalool. The developed 13C NMR method represents a powerful alternative to Mosher’s reagent for investigating the enantiomeric excess in chiral alcohols. This work demonstrates the variety of possibilities of applications for the quantitative nuclear magnetic resonance spectroscopy in the chemical analysis of drugs, food and chemicals using tagging reactions such as derivatizations and complexations. The nuclear resonance spectroscopic methods developed in this research work represent powerful alternatives to the previously used quality control techniques. N2 - Die hochauflösende Kernresonanzspektroskopie findet heute primär Anwendung in derStrukturaufklärung und der qualitativen sowie quantitativen Untersuchung von Produkt-inhaltsstoffen. Trotz der weltweiten Entwicklung von innovativen kernresonanzspektrosko-pischen Methoden sind noch zahlreiche, offiziell anerkannte Methoden zur Qualitätskon-trolle von Arzneimitteln, Lebensmitteln und Chemikalien in Verwendung, die spezifischeSubstanzen kontrollieren und keine ganzheitliche Untersuchung darstellen. Somit könnenverunreinigte, qualitativ minderwertige oder gefälschte Produkte trotz vorheriger Quali-tätskontrollen auf den Markt gebracht und vertrieben werden. Um dies zu verhindern,wurden im Rahmen dieser Arbeit drei kernresonanzspektroskopische Methoden entwickelt,die zur (1) Bestimmung der primären Oxidation in pflanzlichen und tierischen Ölen anhandder Peroxidzahl, (2) zur qualitativen und quantitativen Analyse von Metallkationen und(3) zur Ermittlung des Enantiomerüberschusses in chiralen Alkoholen dienen.In der Ölanalytik werden Titrationsverfahren zur Bestimmung der Bulkqualitätsparameterwie auch der Peroxidzahl, welche die Konzentration an Peroxiden aufzeigt, eingesetzt. Dadie Titration neben dem Einsatz von größeren Mengen an Probenmaterial und Lösungsmit-teln, auch Kreuzreaktionen und eine geringe Robustheit aufweist, wurde eine kernreso-nanzspektroskopische Methode entwickelt, in der Triphenylphosphin als Derivatisierungs-reagenz eingesetzt wird, welches mit Peroxiden im stöchiometrischen Verhältnis von 1:1zu Triphenylphosphinoxid reagiert. Im1H-31P entkoppelten Kernresonanzspektrum wer-den die Signale des nicht reagierten Triphenylphosphins bei 7,4 ppm und des reagiertenTriphenylphosphinoxid bei 7,8 ppm detektiert. Das Verhältnis beider Signale wird in dieKonzentration der Peroxide umgerechnet. 108 Ölproben mit einer Peroxidzahl zwischen 1meq/kg und 170 meq/kg wurden mit der entwickelten Methode untersucht. Hierbei zeigtenÖle mit einer sehr geringen Peroxidzahl von weniger als 3 meq/kg eine relative Standard-abweichung von 4,9%, hochoxidierte Öle mit einer Peroxidzahl von 150 meq/kg 0,2%. Diekernresonanzspektroskopische Methode findet Anwendung in der Untersuchung von Krill-und pflanzlichen Ölen.Eine weitere1H kernresonanzspektroskopische Methode wurde zur qualitativen Analyse. Zusammenfassungvon Be2+, Sr2+und Cd2+und zur qualitatitativen sowie quantitativen Bestimmung vonCa2+, Mg2+, Hg2+, Sn2+, Pb2+und Zn2+entwickelt. Hierbei wurde Ethylendiamintetra-acetat (EDTA) als Komplexbildner verwendet. EDTA ist ein sechszähniger-Ligand, derstabile Chelatkomplexe mit zweiwertigen Kationen bildet. Die definierte Menge an EDTAund das Verhältnis von freier und komplexierter EDTA nach Zugabe der Probe werdenfür die Rückrechnung der Konzentration der Kationen verwendet. Somit ist der Einsatzeines internen Standards obsolet. EDTA komplexiert Be2+, Sr2+, Cd2+, Ca2+, Mg2+, Hg2+,Sn2+, Pb2+und Zn2+zu stabilen Komplexen, deren Signale im Protonen-Kernresonanz-spektrum pH-unabhängige und kationenspezifische chemische Verschiebungen und Kop-plungen aufweisen, die zur Identifizierung und Quantifizierung verwendet werden. DieKoaleszenz der∆undΛKonfigurationen des EDTA-Komplexes mit Be2+, Sr2+und Cd2+führt bei 298K zu einer Signalverbreiterung, die eine Quantifizierung bei den vorliegendenParametern unmöglich macht. Die Kationen Ca2+, Mg2+, Hg2+, Sn2+, Pb2+und Zn2+sindab einer Konzentration von 5-22μg/mL quantitativ in wässriger Lösung quantifizierbar.Diese Methode kann im Lebensmittel- und Arzneimittelbereich eingesetzt werden.Die dritte kernresonanzspektroskopische Methode stellt eine neue Bestimmung des Enan-tiomerüberschusses (ee) in den chiralen Alkoholen Menthol, Borneol, 1-Phenylethanol undLinalool unter Einsatz von Phosgen als Derivatisierungsreagenz vor. Phosgen reagiert miteinem chiralen Alkohol zu Carbonsäurediestern, die aus zwei gleichen (RR, SS) oder zweiunterschiedlichen Enantiomeren (RS, SR) entstehen. Diese zwei Diastereomertypen kön-nen anhand der unterschiedlichen, chemischen Verschiebungen ihrer Signale identifiziertwerden. In der vorgestellten Methode wird das Carbonylsignal integriert und zur Bes-timmung des Enantiomerenüberschusses eingesetzt. Die Bestimmungsgrenze ist hierbeiu. a. von dem eingesetzten Phosgen und der Probe abhängig. Bei Menthol wurdeeine Bestimmungsgrenze mittels nicht markiertem Phosgen von ee = 99,1% und mit-tels13C-markiertem Phosgen von ee = 99,9% ermittelt. Die13C Methode wurde zudemzur Qualitätskontrolle der Enantiomerreinheit von Borneol, 1-Phenylethanol sowie vonLinalool eingesetzt. Hierbei enthielten die käuflich erworbenen Chemikalien (-)-Borneolund (S)-1-Phenylethanol jeweils 1,7% des anderen Enantiomers (+)-Borneol bzw. (R)-1-Phenylethanol. Bei (-)-Linalool konnte ein Enantiomerüberschuss von ee = 66,4% undsomit eine größere Verunreinigung durch (+)-Linalool identifiziert werden. Bei Proben,die einen Enantiomerüberschuss von ee < 95,0% aufweisen, sollte eine potentielle, asym-metrische Induktion mittels Kalibrationskurven anhand von künstlichen Enantiomeren-mischungen vorab untersucht werden. Die entwickelte13C kernresonanzspektroskopischeMethode präsentiert eine leistungsstarke Alternative zur Analyse mittels Mosher’s Reagenzfür die Untersuchung des Enantiomerüberschusses in chiralen Alkoholen.Diese Arbeit weist eine Vielfalt an Möglichkeiten der Anwendungen der quantitativen Kern-resonanzspektroskopie in der chemischen Untersuchung von Arzneimitteln, Lebensmittelnund Chemikalien unter Einsatz von Tagging, wie Derivatisierungen und Komplexierun-gen auf. Die hierbei entwickelten kernresonanzspektroskopischen Methoden repräsentierenleistungsstarke Alternativen zu bisher eingesetzten Techniken der Qualitätskontrolle KW - NMR Spektroskopie KW - EDTA KW - Lipid-Peroxide KW - Chiralität KW - Derivsatisierung KW - Peroxidzahl KW - Enantiomerüberschuss KW - qNMR Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219583 ER - TY - JOUR A1 - Franzsico, Marcos A. S. A1 - Fantuzzi, Felipe A1 - Cardozo, Thiago M. A1 - Esteves, Pierre M. A1 - Engels, Bernd A1 - Oliveira, Ricardo R. T1 - Taming the Antiferromagnetic Beast: Computational Design of Ultrashort Mn-Mn Bonds Stabilized by N-Heterocyclic Carbenes JF - Chemistry—A European Journal N2 - The development of complexes featuring low-valent, multiply bonded metal centers is an exciting field with several potential applications. In this work, we describe the design principles and extensive computational investigation of new organometallic platforms featuring the elusive manganese-manganese bond stabilized by experimentally realized N-heterocyclic carbenes (NHCs). By using DFT computations benchmarked against multireference calculations, as well as MO- and VB-based bonding analyses, we could disentangle the various electronic and structural effects contributing to the thermodynamic and kinetic stability, as well as the experimental feasibility, of the systems. In particular, we explored the nature of the metal-carbene interaction and the role of the ancillary η\(^{6}\) coordination to the generation of Mn\(_{2}\) systems featuring ultrashort metal-metal bonds, closed-shell singlet multiplicities, and positive adiabatic singlet-triplet gaps. Our analysis identifies two distinct classes of viable synthetic targets, whose electrostructural properties are thoroughly investigated. KW - metal-metal interactions KW - ab initio calculations KW - carbene ligands KW - density functional calculations KW - manganese Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256874 VL - 27 IS - 47 ER - TY - JOUR A1 - Eiring, Patrick A1 - McLaughlin, Ryan A1 - Matikonda, Siddharth S. A1 - Han, Zhongying A1 - Grabenhorst, Lennart A1 - Helmerich, Dominic A. A1 - Meub, Mara A1 - Beliu, Gerti A1 - Luciano, Michael A1 - Bandi, Venu A1 - Zijlstra, Niels A1 - Shi, Zhen-Dan A1 - Tarasov, Sergey G. A1 - Swenson, Rolf A1 - Tinnefeld, Philip A1 - Glembockyte, Viktorija A1 - Cordes, Thorben A1 - Sauer, Markus A1 - Schnermann, Martin J. T1 - Targetable conformationally restricted cyanines enable photon-count-limited applications JF - Angewandte Chemie Internationale Edition N2 - Cyanine dyes are exceptionally useful probes for a range of fluorescence-based applications, but their photon output can be limited by trans-to-cis photoisomerization. We recently demonstrated that appending a ring system to the pentamethine cyanine ring system improves the quantum yield and extends the fluorescence lifetime. Here, we report an optimized synthesis of persulfonated variants that enable efficient labeling of nucleic acids and proteins. We demonstrate that a bifunctional sulfonated tertiary amide significantly improves the optical properties of the resulting bioconjugates. These new conformationally restricted cyanines are compared to the parent cyanine derivatives in a range of contexts. These include their use in the plasmonic hotspot of a DNA-nanoantenna, in single-molecule Förster-resonance energy transfer (FRET) applications, far-red fluorescence-lifetime imaging microscopy (FLIM), and single-molecule localization microscopy (SMLM). These efforts define contexts in which eliminating cyanine isomerization provides meaningful benefits to imaging performance. KW - biology KW - super-resolution microscopy KW - conformational restriction KW - cyanine dyes KW - DNA nanotechnology KW - fluorescent dyes KW - single-molecule fluorescence spectroscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256559 VL - 60 IS - 51 ER - TY - JOUR A1 - Wobser, Marion A1 - Roth, Sabine A1 - Appenzeller, Silke A1 - Houben, Roland A1 - Schrama, David A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Rosenwald, Andreas A1 - Maurus, Katja T1 - Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation JF - Cancers N2 - Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior. KW - mycosis fungoides KW - cutaneous T-cell-lymphoma KW - panel sequencing KW - large cell transformation KW - CD30 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250094 SN - 2072-6694 VL - 13 IS - 21 ER - TY - JOUR A1 - Pauli, Martin A1 - Paul, Mila M. A1 - Proppert, Sven A1 - Mrestani, Achmed A1 - Sharifi, Marzieh A1 - Repp, Felix A1 - Kürzinger, Lydia A1 - Kollmannsberger, Philip A1 - Sauer, Markus A1 - Heckmann, Manfred A1 - Sirén, Anna-Leena T1 - Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections JF - Communications Biology N2 - Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 mu m, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 mu m thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons. Pauli et al. develop targeted volumetric dSTORM in order to image large hippocampal mossy fiber boutons (MFBs) in brain slices. They can identify synaptic targets of individual MFBs and measured size and density of Bassoon clusters within individual untruncated MFBs at nanoscopic resolution. KW - mossy fiber synapses KW - CA3 pyrimidal cells KW - CA2+ channels KW - active zone KW - hippocampal KW - release KW - plasticity KW - proteins KW - platform KW - reveals Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259830 VL - 4 ER - TY - JOUR A1 - Linz, Christian A1 - Brands, Roman C. A1 - Kertels, Olivia A1 - Dierks, Alexander A1 - Brumberg, Joachim A1 - Gerhard-Hartmann, Elena A1 - Hartmann, Stefan A1 - Schirbel, Andreas A1 - Serfling, Sebastian A1 - Zhi, Yingjun A1 - Buck, Andreas K. A1 - Kübler, Alexander A1 - Hohm, Julian A1 - Lapa, Constantin A1 - Kircher, Malte T1 - Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [\(^{18}\)F]FDG PET/CT and MRI JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose While [\(^{18}\)F]-fluorodeoxyglucose ([\(^{18}\)F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [\(^{18}\)F]FDG and [\(^{68}\)Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV\(_{max}\)) and peak (SUV\(_{peak}\) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [\(^{18}\)F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([\(^{18}\)F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [\(^{18}\)F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted. KW - molecular imaging KW - fibroblast activation protein KW - head and neck cancer KW - PET Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307246 SN - 1619-7070 SN - 1619-7089 VL - 48 IS - 12 ER - TY - JOUR A1 - Dohrn, Maike F. A1 - Ihne, Sandra A1 - Hegenbart, Ute A1 - Medina, Jessica A1 - Züchner, Stephan L. A1 - Coelho, Teresa A1 - Hahn, Katrin T1 - Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis JF - Journal of Neurochemistry N2 - The liver‐derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild‐type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate‐limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence‐specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac‐conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood–brain barrier, but its half‐life is short and liver failure a potential side effect. Amyloid‐directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR‐amyloidosis has become a model disease for pathophysiology‐based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood–brain barrier permeability. KW - amyloid‐directed antibodies KW - ATTRv amyloidosis KW - familial amyloid polyneuropathy (FAP) KW - transthyretin KW - TTR knockdown KW - TTR stabilization Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224481 VL - 156 IS - 6 SP - 802 EP - 818 ER - TY - JOUR A1 - Reif, Magnus A1 - Tesfaselassie, Mewael F. A1 - Wolters, Maik H. T1 - Technological Growth and Hours in the Long Run: Theory and Evidence JF - Economica N2 - Over the last few decades, hours worked per capita have declined substantially in many OECD economies. Using the standard neoclassical growth model with endogenous work–leisure choice, we assess the role of trend growth slowdown in accounting for the decline in hours worked. In the model, a permanent reduction in technological growth decreases steady‐state hours worked by increasing the consumption–output ratio. Our empirical analysis exploits cross‐country variation in the timing and size of the decline in technological growth to show that technological growth has a highly significant positive effect on hours. A decline in the long‐run trend of technological growth by 1 percentage point is associated with a decline in trend hours worked in the range of 1–3%. This result is robust to controlling for taxes, which have been found in previous studies to be an important determinant of hours. Our empirical finding is quantitatively in line with the one implied by a calibrated version of the model, though evidence for the model’s implication that the effect on hours works via changes in the consumption–output ratio is rather mixed. KW - technological growth KW - working hours KW - neoclassical growth model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262801 VL - 88 IS - 352 SP - 1016 EP - 1053 ER - TY - JOUR A1 - Barlinn, J. A1 - Winzer, S. A1 - Worthmann, H. A1 - Urbanek, C. A1 - Häusler, K. G. A1 - Günther, A. A1 - Erdur, H. A1 - Görtler, M. A1 - Busetto, L. A1 - Wojciechowski, C. A1 - Schmitt, J. A1 - Shah, Y. A1 - Büchele, B. A1 - Sokolowski, P. A1 - Kraya, T. A1 - Merkelbach, S. A1 - Rosengarten, B. A1 - Stangenberg-Gliss, K. A1 - Weber, J. A1 - Schlachetzki, F. A1 - Abu-Mugheisib, M. A1 - Petersen, M. A1 - Schwartz, A. A1 - Palm, F. A1 - Jowaed, A. A1 - Volbers, B. A1 - Zickler, P. A1 - Remi, J. A1 - Bardutzky, J. A1 - Bösel, J. A1 - Audebert, H. J. A1 - Hubert, G. J. A1 - Gumbinger, C. T1 - Telemedizin in der Schlaganfallversorgung – versorgungsrelevant für Deutschland T1 - Telemedicine in stroke—pertinent to stroke care in Germany JF - Der Nervenarzt N2 - Hintergrund und Ziel Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur. Methoden Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch. Ergebnisse In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern. Diskussion Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken. N2 - Background and objective Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution. Methods The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks. Results Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1–3) as well as 225 cooperating hospitals (per network: median 9, IQR 4–17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319–2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6–14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5–8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states. Conclusion Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future. KW - Schlaganfall KW - Stroke-Unit KW - Telemedizin KW - Schlaganfall-Netzwerk KW - Umfragestudie KW - stroke KW - stroke unit KW - telemedicine KW - stroke networks KW - survey Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307752 SN - 0028-2804 SN - 1433-0407 VL - 92 IS - 6 ER - TY - JOUR A1 - Shan, Junwen A1 - Böck, Thomas A1 - Keller, Thorsten A1 - Forster, Leonard A1 - Blunk, Torsten A1 - Groll, Jürgen A1 - Teßmar, Jörg T1 - TEMPO/TCC as a Chemo Selective Alternative for the Oxidation of Hyaluronic Acid JF - Molecules N2 - Hyaluronic acid (HA)-based hydrogels are very commonly applied as cell carriers for different approaches in regenerative medicine. HA itself is a well-studied biomolecule that originates from the physiological extracellular matrix (ECM) of mammalians and, due to its acidic polysaccharide structure, offers many different possibilities for suitable chemical modifications which are necessary to control, for example, network formation. Most of these chemical modifications are performed using the free acid function of the polymer and, additionally, lead to an undesirable breakdown of the biopolymer’s backbone. An alternative modification of the vicinal diol of the glucuronic acid is oxidation with sodium periodate to generate dialdehydes via a ring opening mechanism that can subsequently be further modified or crosslinked via Schiff base chemistry. Since this oxidation causes a structural destruction of the polysaccharide backbone, it was our intention to study a novel synthesis protocol frequently applied to selectively oxidize the C6 hydroxyl group of saccharides. On the basis of this TEMPO/TCC oxidation, we studied an alternative hydrogel platform based on oxidized HA crosslinked using adipic acid dihydrazide as the crosslinker. KW - hyaluronic acid KW - oxidation KW - hydrogel formation KW - Schiff base chemistry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248362 SN - 1420-3049 VL - 26 IS - 19 ER - TY - JOUR A1 - Klaffehn, Annika L. A1 - Sellmann, Florian B. A1 - Kirsch, Wladimir A1 - Kunde, Wilfried A1 - Pfister, Roland T1 - Temporal binding as multisensory integration: Manipulating perceptual certainty of actions and their effects JF - Attention, Perception & Psychophysics N2 - It has been proposed that statistical integration of multisensory cues may be a suitable framework to explain temporal binding, that is, the finding that causally related events such as an action and its effect are perceived to be shifted towards each other in time. A multisensory approach to temporal binding construes actions and effects as individual sensory signals, which are each perceived with a specific temporal precision. When they are integrated into one multimodal event, like an action-effect chain, the extent to which they affect this event's perception depends on their relative reliability. We test whether this assumption holds true in a temporal binding task by manipulating certainty of actions and effects. Two experiments suggest that a relatively uncertain sensory signal in such action-effect sequences is shifted more towards its counterpart than a relatively certain one. This was especially pronounced for temporal binding of the action towards its effect but could also be shown for effect binding. Other conceptual approaches to temporal binding cannot easily explain these results, and the study therefore adds to the growing body of evidence endorsing a multisensory approach to temporal binding. KW - temporal processing KW - perception and action KW - multisensory processing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273195 SN - 1943-393X VL - 83 IS - 8 ER - TY - JOUR A1 - Muth, Felicitas V. A1 - Wirth, Robert A1 - Kunde, Winfried T1 - Temporal binding past the Libet clock: testing design factors for an auditory timer JF - Behavior Research Methods N2 - Voluntary actions and causally linked sensory stimuli are perceived to be shifted towards each other in time. This so-called temporal binding is commonly assessed in paradigms using the Libet Clock. In such experiments, participants have to estimate the timing of actions performed or ensuing sensory stimuli (usually tones) by means of a rotating clock hand presented on a screen. The aforementioned task setup is however ill-suited for many conceivable setups, especially when they involve visual effects. To address this shortcoming, the line of research presented here establishes an alternative measure for temporal binding by using a sequence of timed sounds. This method uses an auditory timer, a sequence of letters presented during task execution, which serve as anchors for temporal judgments. In four experiments, we manipulated four design factors of this auditory timer, namely interval length, interval filling, sequence predictability, and sequence length, to determine the most effective and economic method for measuring temporal binding with an auditory timer. KW - temporal binding KW - auditory timer KW - experimental design KW - measures KW - intentional binding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234922 VL - 53 IS - 3 ER - TY - THES A1 - Roth, Nicolas Mériadec Max André T1 - Temporal development of communities with a focus on insects, in time series of one to four decades T1 - Entwicklung von Artengemeinschaften in der Zeit mit einem Fokus auf Insekten in Zeitreihen von einer bis vier Dekaden N2 - Changes and development are fundamental principles in biocenoses and can affect a multitude of ecological processes. In insect communities phenological and density changes, changes in species richness and community composition, as well as interactions between those changes, are the most important macro processes. However, climate change and other factors like habitat degradation and loss alter these processes leading to shifts and general biodiversity declines. Even though knowledge about insect decline in central Europe increased during the last decades, there are significant knowledge gaps about the development of insect communities in certain habitats and taxa. For example, insect communities in small lentic as well as in forested habitats are under-sampled and reported to be less endangered than communities in other habitats. Furthermore, the changes within habitats and taxa are additionally influenced by certain traits, like host or feeding specialization. To disentangle these influences and to increase the knowledge about the general long-term development of insect communities, comprehensive long-term monitoring studies are needed. In addition, long-term effects of conservation strategies should also be evaluated on large time scales in order to be able to decide on a scientific base which strategies are effective in promoting possibly declining taxa. Hence, this thesis also tackles the effects of an integrative conservation strategy on wood dependent beetle and fungi, beside the development of water beetle and macro moth communities over multiple decades. In Chapter 2 I present a study on the development of water beetle communities (Dytiscidae, Haliplidae, Noteridae) in 33 water bodies in Southern Germany from 1991 to 2018. Time-standardized capture per waterbody was used during three periods: between 1991 and 1995, 2007 and 2008, and 2017 and 2018. Results showed annual declines in both species number (ca. -1%) and abundance (ca. -2%). In addition, community composition shifted over time in part due to changing pH values. Hence, the recorded changes during the 28-year study period partly reflect natural succession processes. However, since also moor-related beetle species decreased significantly, it is likely that water beetles in southern Germany are also threatened by non-successional factors, including desiccation, increased nitrogen input and/or mineralization, as well as the loss of specific habitats. The results suggest, that in small to midsize lentic waterbodies, current development should aim for constant creation of new water bodies and protection of moor waterbodies in order to protect water beetle communities on a landscape scale. In Chapter 3 I present an analysis of the development of nocturnal macro moth species richness, abundance and biomass over four decades in forests of southern Germany. Two local scale data sets featuring a coppiced oak forest as well as an oak high forest were analysed separately from a regional data set representing all forest types in the temperate zone of Central Europe. At the regional scale species richness, abundance and biomass showed annual declines of ca. 1 %, 1.3 % and 1.4 %, respectively. These declines were more pronounced in plant host specialists and in dark coloured species. In contrast, species richness increased by ca. 1.5 % annually in the coppiced forest, while no significant trends were found in the high forest. In contrast to past assumptions, insect decline apparently affects also hyper diverse insect groups in forests. Since host specialists and dark coloured species were affected more heavily by the decline than other groups, habitat loss and climate change seem to be potential drivers of the observed trends. However, the positive development of species richness in the coppiced oak forest indicates that maintaining complex and diverse forest ecosystems through active management might compensate for negative trends in biodiversity. Chapter 4 features a study specifically aiming to investigate the long-term effect of deadwood enrichment as an integrative conservation strategy on saproxylic beetles and fungi in a central European beech forest at a landscape scale. A before–after control–impact design, was used to compare assemblages and gamma diversities of saproxylic organisms (beetles and fungi) in strictly protected old-growth forest areas (reserves) and previously moderately and intensively managed forest areas. Forests were sampled one year before and a decade after starting a landscape-wide strategy of dead-wood enrichment. Ten years after the start of the dead-wood enrichment, neither gamma diversities of saproxylic organisms nor species composition of beetles did reflect the previous management types anymore. However, fungal species composition still mirrored the previous management gradient. The results demonstrated that intentional enrichment of dead wood at the landscape scale can effectively restore communities of saproxylic organisms and may thus be a suitable strategy in addition to permanent strict reserves in order to protect wood dependent organisms in Europe. In this thesis I showed, that in contrast to what was assumed and partly reported so far, also water beetles in lentic water bodies and macro moths in forests decreased in species richness, abundance and biomass during the last three to four decades. In line with earlier studies, especially dark coloured species and specialists decreased more than light-coloured species and generalists. The reasons for these declines could partly be attributed to natural processes and pollution and possibly to climate change. However, further studies, especially experimental ones, will be needed to achieve a better understanding of the reasons for insect decline. Furthermore, analyses of time series data should be interpreted cautiously especially if the number of sampling years is smaller than ten years. In addition, validation techniques such as left- and right- censoring and cross validation should be used in order to proof the robustness of the analyses. However, the lack of knowledge, we are still facing today, should not prevent scientists and practitioners from applying conservation measures. In order to prove the effectiveness of such measures, long-term monitoring is crucial. Such control of success is essential for evidence based and thus adapted conservation strategies of threatened organisms. N2 - Veränderungen und Entwicklung sind grundlegende Prinzipien in Biozönosen und können eine Vielzahl von ökologischen Prozessen beeinflussen. In Insektengemeinschaften stellen Veränderungen in der Phänologie und Dichte, Veränderungen des Artenreichtums und der Artenzusammensetzung sowie die Wechselwirkungen zwischen diesen, die wichtigsten Makroprozesse dar. Klimawandel und andere Faktoren wie der Verlust von Lebensräumen oder deren Qualitätsverschlechterung beeinflussen diese Prozesse jedoch und führen zu Veränderungen und allgemeinen Rückgängen der Biodiversität. Auch wenn die Erkenntnisse zum „Insektensterben“ in Mitteleuropa in den letzten Jahrzehnten zugenommen haben, gibt es erhebliche Wissenslücken über die Entwicklung von Insektengemeinschaften in bestimmten Lebensräumen und Taxa. Beispielsweise ist die Entwicklung von Insektengemeinschaften in kleinen, stehenden Gewässern und in Wäldern wenig erforscht. Darüber hinaus werden die Veränderungen innerhalb von Habitaten und Taxa zusätzlich durch bestimmte Merkmale, wie Wirts- oder Nahrungsspezialisierung, beeinflusst. Um diese verschiedenen Einflüsse auseinanderhalten zu können und das Wissen über die allgemeine Langzeitentwicklung von Insektengemeinschaften zu vergrößern, sind umfassende Langzeitstudien erforderlich. Darüber hinaus sollten auch die langfristigen Auswirkungen von Naturschutzstrategien über lange Zeiträume evaluiert werden, um auf wissenschaftlicher Grundlage entscheiden zu können, welche Strategien zur Förderung bedrohter Taxa wirksam sind. Daher befasst sich diese Arbeit neben der Entwicklung von Wasserkäfer- und Großschmetterlingsgemeinschaften über mehrere Jahrzehnte auch mit den Auswirkungen einer integrativen Naturschutzmaßnahme auf xylobionte Käfer und Pilze. In Kapitel 2 stelle ich eine Studie über die Entwicklung von Wasserkäfergemeinschaften (Dytiscidae, Haliplidae, Noteridae) in 33 Gewässern Süddeutschlands von 1991 bis 2018 vor. Die zeitstandardisierte Erfassung pro Wasserkörper erfolgte in drei Zeiträumen: zwischen 1991 und 1995, 2007 und 2008 sowie 2017 und 2018. Die Ergebnisse zeigten einen jährlichen Rückgang sowohl der Artenzahl (ca. -1%) als auch der Abundanz (ca. -2%). Darüber hinaus verschob sich die Artenzusammensetzung im Laufe der Zeit zum Teil aufgrund sich ändernder pH-Werte. Daraus lässt sich schlussfolgern, dass die erfassten Veränderungen während des 28- jährigen Untersuchungszeitraums teilweise natürliche Sukzessionsprozesse widerspiegeln. Da aber auch an moorige Gewässer gebundene Käferarten deutlich abgenommen haben, ist es wahrscheinlich, dass die Wasserkäfer Süddeutschlands auch durch Faktoren wie Austrocknung, erhöhten Stickstoffeintrag und/oder Mineralisierung sowie durch den Verlust spezifischer Lebensräume bedroht sind. Aufgrund dieser Entwicklungen ist es empfehlenswert, auf Landschaftsebene auf die ständige Schaffung neuer Gewässer und den besonderen Schutz von Moorgewässern zu setzen, um Wasserkäfergemeinschaften erfolgreich schützen zu können. In Kapitel 3 präsentiere ich eine Analyse der Diversitäts-, Abundanz- und Biomassenentwicklung von nachtaktiven Großschmetterlingen über vier Jahrzehnte in Wäldern Süddeutschlands. Neben einem bayernweiten Datensatz, der alle typischen Waldtypen der gemäßigten Zone Mitteleuropas beinhaltet, wurden zwei lokale, besonders regelmäßig besammelte Gebiete getrennt analysiert. In diesen Gebieten werden die Eichenwälder als Hoch- bzw. als Mittelwald bewirtschaftet. Bayernweit wiesen Artenreichtum, Abundanz und Biomasse jährliche Rückgänge von ca. 1 %, 1,3 % bzw. 1,4 % auf. Diese Rückgänge waren bei Wirtspflanzenspezialisten und bei dunkel gefärbten Arten besonders stark ausgeprägt. Im Gegensatz dazu nahm der Artenreichtum im Mittelwald jährlich um ca. 1,5 % zu, während im Hochwald keine signifikanten Trends festgestellt werden konnten. Im Gegensatz zu früheren Annahmen betrifft der Insektenrückgang offenbar auch hyperdiverse Insektengruppen im Wald. Da Wirtspflanzenspezialisten und dunkel gefärbte Arten vom Rückgang stärker betroffen waren als andere, scheinen Lebensraumverlust und Klimawandel potentielle Treiber der beobachteten Trends zu sein. Die positive Entwicklung des Artenreichtums im Mittelwald zeigt jedoch, dass der Erhalt komplexer und vielfältiger Waldökosysteme durch aktives Management, negative Biodiversitätstrends zum Teil kompensieren könnte. Kapitel 4 enthält eine Studie, die die Langzeitwirkung von Totholzanreicherung als integrative Naturschutzmaßnahme auf xylobionte Käfer und Pilze in einem mitteleuropäischen Buchenwald auf der Landschaftsebene untersucht. Dabei wurde die Gamma-Diversität und die Artenzusammensetzung dieser beiden Gruppen anhand einer Vorher-Nachher Untersuchung mit Kontrollflächen (Naturwaldreservate) untersucht. Die bewirtschafteten Flächen wurden weiterhin in zuvor mäßig und intensiv bewirtschaftete Flächen eingeteilt. Die Wälder wurden ein Jahr vor und ein Jahrzehnt nach Beginn einer Totholzanreicherungsstrategie auf Landschaftsebene beprobt. Zehn Jahre nach Beginn der Totholzanreicherung spiegelten weder die Gamma-Diversität der xylobionten Organismen noch die Artenzusammensetzung der Käfer die früheren Bewirtschaftungstypen wider, und wiesen keine Unterschiede mehr zu den Naturwaldreservaten auf. Die Pilzartenzusammensetzung spiegelte jedoch noch immer den früheren Bewirtschaftungsgradienten wider. Die Ergebnisse zeigen, dass Totholzanreicherung auf Landschaftsebene positive Effekte auf xylobionte Artengemeinschaften haben kann. Somit stellt Totholzanreicherung eine Naturschutzmaßnahme dar, die zusätzlich zu permanenten Schutzgebieten, eine Grundlage schaffen kann, um holzabhängige Organismen in Europa zu schützen. In dieser Arbeit habe ich gezeigt, dass im Gegensatz zu dem, was bisher angenommen und zum Teil berichtet wurde, auch Wasserkäfer in stehenden Gewässern und nachtaktive Großschmetterlingen in Wäldern in den letzten drei bis vier Jahrzehnten an Artenreichtum, Abundanz und Biomasse abgenommen haben. In Übereinstimmung mit anderen Studien nahmen vor allem dunkel gefärbte Arten und Spezialisten stärker ab als hell gefärbte Arten und Generalisten. Die Gründe für diese Rückgänge konnten zum Teil auf natürliche Prozesse, Umweltverschmutzung und möglicherweise auf den Klimawandel zurückgeführt werden. Es sind jedoch weitere Studien, insbesondere experimentelle, erforderlich, um die Gründe für das „Insektensterben“ besser zu verstehen. Darüber hinaus sollten Zeitreihendaten mit Vorsicht interpretiert werden, insbesondere wenn die Anzahl der besammelten Jahre kleiner als zehn Jahre ist. Darüber hinaus sollten Validierungstechniken wie Links- und Rechts-Zensierung und Kreuzvalidierung eingesetzt werden, um die Robustheit der Analysen nachzuweisen. Der Mangel an Wissen, mit dem wir heute noch konfrontiert sind, sollte Wissenschaftler und Praktiker jedoch nicht davon abhalten, Naturschutzmaßnahmen anzuwenden. Um die Wirksamkeit solcher Maßnahmen nachzuweisen, ist eine langfristige Überprüfung von entscheidender Bedeutung. Solche Erfolgskontrollen sind für evidenzbasierte und damit angepasste Erhaltungsstrategien bedrohter Organismen unerlässlich. KW - climate change KW - insects KW - temporal development KW - nature conservation KW - entomology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235499 ER - TY - JOUR A1 - Leidinger, Ludwig A1 - Vedder, Daniel A1 - Cabral, Juliano Sarmento T1 - Temporal environmental variation may impose differential selection on both genomic and ecological traits JF - Oikos N2 - The response of populations and species to changing conditions determines how community composition will change functionally, including via trait shifts. Selection from standing variation has been suggested to be more efficient than acquiring new mutations. Yet, studies on community trait composition and trait selection largely focus on phenotypic variation in ecological traits, whereas the underlying genomic traits remain understudied. Using a genome‐explicit, niche‐ and individual‐based model, we address the potential interactions between genomic and ecological traits shaping communities under an environmental selective forcing, namely temporal positively autocorrelated environmental fluctuation. In this model, all ecological traits are explicitly coded by the genome. For our experiments, we initialized 90 replicate communities, each with ca 350 initial species, characterized by random genomic and ecological trait combinations, on a 2D spatially explicit landscape with two orthogonal gradients (temperature and resource use). We exposed each community to two contrasting scenarios: without (i.e. static environments) and with temporal variation. We then analyzed emerging compositions of both genomic and ecological traits at the community, population and genomic levels. Communities in variable environments were species poorer than in static environments, and populations more abundant, whereas genomes had lower genetic linkage, mean genetic variation and a non‐significant tendency towards higher numbers of genes. The surviving genomes (i.e. those selected by variable environments) coded for enhanced environmental tolerance and smaller biomass, which resulted in faster life cycles and thus also in increased potential for evolutionary rescue. Under temporal environmental variation, larger, less linked genomes retained more variation in mean dispersal ability at the population level than at genomic level, whereas the opposite trend emerged for biomass. Our results provide clues to how sexually‐reproducing diploid plant communities might react to variable environments and highlights the importance of genomic traits and their interaction with ecological traits for eco‐evolutionary responses to changing climates. KW - environmental variability KW - genomic traits KW - mechanistic model KW - rapid evolution KW - standing variation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238945 VL - 130 IS - 7 SP - 1100 EP - 1115 ER - TY - THES A1 - Pieper, Sabrina H. T1 - Temporal information transfer by electrical stimulation in auditory implants T1 - Zeitliche Informationsübertragung durch elektrische Stimulation bei Hörprothesen N2 - In deafness, which is caused by the malfunctioning of the inner ear, an implantation of a cochlear implant (CI) is able to restore hearing. The CI is a neural prosthesis that is located within the cochlea. It replaces the function of the inner hair cells by direct electrical stimulation of the auditory nerve fibers. The CI enables many deaf or severe hearing-impaired people to achieve a good speech perception. Nevertheless, there is a lot of potential for further improvements. Compared to normal-hearing listeners rate pitch discrimination is much worse. Rate pitch discrimination is the ability to distinguish the pitch of two stimuli with two different pulse rates. This ability is important for enjoying music as well as speech perception (in noise). Further, the small dynamic range in electrical hearing (compared to normal-hearing listeners) and therefore the small intensity resolution limits the performance of CI users. Both, rate pitch coding and dynamic range were investigated in this doctoral thesis. For the first issue, a pitch discrimination task was designed to determine the just-noticeable-difference (JND) in pitch with 200 and 400 pps as reference. Additionally to the default biphasic pulse (single pulse) the experiment was performed with double pulses. The double pulse consists out of two biphasic pulses directly after each other and a small interpulse interval (IPI) in between. Three different IPIs (15, 50, and 150 µs) were tested. The statistical analysis of JNDs revealed no significant effects between stimulation with single-pulse or double-pulse trains. A follow-up study investigated an alternating pulse train consisting of single and double pulses. To investigate if the 400 pps alternating pulse train is comparable in pitch with the 400 pps single-pulse train, a pairwise pitch comparison test was conducted. The alternating pulse train was compared with single-pulse trains at 200, 300 and 400 pps. The results showed that the alternating pulse train is for most subjects similar in pitch with the 200 pps single-pulse train. Therefore, pitch perception seemed to be dominated by the double pulses within the pulse train. Accordingly, double pulses with different amplitudes were tested. Based on the facilitation effect, a larger neuronal response was expected by stimulating with two pulses with a short IPI within the temporal facilitation range. In other studies, this effect was shown to be maximal in CIs of the manufacturer Cochlear, with first pulse amplitudes set at or slightly below the electrically evoked compound action potential (ECAP) threshold. The second pulse amplitude did not influence the facilitation effect and therefore could be choose at will. Similarly, this effect was tested in this thesis with CIs of the manufacturer MED-EL. Nevertheless, to achieve a proper signal-to-noise ratio, technical issues had to be addressed like a high noise floor, resulting in incorrect determination of the ECAP threshold. After solving this issues, the maximum facilitation effect was around the ECAP threshold as in the previous study with Cochlear. For future studies this effect could be used in a modified double pulse rate pitch experiment with the first pulse amplitude at ECAP threshold and the second pulse amplitude variable to set the most comfortable loudness level (MCL). The last study within this thesis investigated the loudness perception at two different loudness levels and the resulting dynamic range for different interphase-gaps (IPG). A larger IPG can reduce the amplitude at same loudness level to save battery power. However, it was unknown if the IPG has an influence on the dynamic range. Different IPGs (10 and 30 µs) were compared with the default IPG (2.1 µs) in a loudness matching experiment. The experiment was performed at the most comfortable loudness level (MCL) of the subject and the amplitude of half the dynamic range (50%-ADR). An upper dynamic range was calculated from the results of MCL and 50%-ADR (therefore not the whole dynamic range was covered). As expected from previous studies a larger IPG resulted in smaller amplitudes. However, the observed effect was larger at MCL than at 50%-ADR which resulted in a smaller upper dynamic range. This is the first time a decrease of this dynamic range was shown. N2 - Bei einer Taubheit, welche durch eine Schädigung des Innenohres hervorgerufen wird, ist es möglich das Gehör mittels eines Cochlea-Implantates (CI) wieder herzustellen. Das Implantat befindet sich innerhalb der Hörschnecke und ist in der Lage, die Funktion der inneren Haarzellen zu ersetzen. Dies geschieht durch direkte elektrische Stimulation der auditorischen Nervenfasern. Dadurch ermöglicht das CI Ertaubten oder stark Schwerhörigen, ein gutes Sprachverstehen zu erlangen. Dennoch gibt es weiterhin Verbesserungspotential. Im Vergleich zu Normalhörenden ist unter anderem die Tonhöhenunterscheidung stark eingeschränkt. Die Unterscheidung von Tonhöhen ist sowohl für den Musikgenuss als auch für das Sprachverstehen (im Störgeräusch) wichtig. Ebenso verfügen CI Träger über einen vergleichsweise kleinen Dynamikbereich und einer daraus resultierenden geringen Auflösung der Intensitäten. Dies kann zu einer Beeinträchtigung des Hörens führen. Sowohl die Fähigkeit der Tonhöhenunterscheidung als auch der Dynamikbereich werden in der vorliegenden Doktorarbeit untersucht. Hierfür wurde zunächst ein Tonhöhenunterscheidungs-Experiment entworfen, bei welchem der kleinste wahrnehmbare Unterschied zweier Pulsraten ermittelt wurde. Die Pulsraten 200 und 400 pps dienten als Referenzwert. Neben dem standardmäßig verwendeten Biphasischen Puls, wurden Doppelpulse genutzt. Diese bestehen aus zwei aufeinander folgenden biphasischen Pulsen gleicher Amplitude, welche durch ein kurzes interpuls Intervall (IPI) separiert sind. In dem Experiment wurden drei unterschiedliche IPIs getestet (15, 50 und 150 µs). Die Analyse des kleinesten wahrnehmbaren Tonhöhenunterschieds ergab keine signifikanten Unterschiede zwischen dem einfachen Puls und den Doppelpulsen. Ein Folgeexperiment beschäftigte sich mit einer alternierenden Pulsfolge bestehend aus dem einfachen und dem Doppelpuls. In einem paarweisen Vergleichsexperiment wurde die alternierende Pulsfolge bei 400 pps mit einem Einfachpuls bei 200, 300 und 400 pps in ihrer Tonhöhe verglichen. Es zeigte sich, dass die alternierende Pulsfolge bei 400 pps mehrheitlich mit dem Einzelpuls bei 200 pps vergleichbar war. Demzufolge scheint die Tonhöhenwahrnehmung der alternierenden Pulsfolge von dem Doppelpuls dominiert zu werden. Auf beide Experimente aufbauend, wurden Doppelpulse mit unterschiedlichen Amplituden untersucht. Basierend auf den Bahnungseffekt (Facilitation-Effekt), kann eine größere neuronale Antwort hervorgerufen werden, indem mit Doppelpulsen mit kurzem IPI stimuliert wird. In einer anderen Studie konnte anhand von CIs der Firma Cochlear gezeigt werden, dass dieser Effekt maximal war, wenn die Amplitude des ersten Pulses nahe der Schwelle zum elektrisch evozierten Summenaktionspotential (ECAP) liegt. Die Amplitude des zweiten Pulses dagegen hatte keinen Einfluss auf den „Facilitation“-Effekt und konnte beliebig gewählt werden. Dieser Effekt wurde mit CIs der Firma MED-EL in der vorliegenden Doktorarbeit nachgestellt. Es zeigte sich, dass auch hier der größte „Facilitation“-Effekt auftrat, wenn die Amplitude des ersten Pulses nahe der ECAP-Schwelle lag. In zukünftigen Studien könnte dieser Effekt für einen modifizierten Doppelpuls genutzt werden, um mit diesem das ursprüngliche Tonhöhenunterscheidungs-Experiment zu wiederholen. Dabei würde die Amplitude des ersten Pulses der ECAP-Schwelle entsprechen, während die zweite Pulsamplitude variiert wird, um den größten, möglichst angenehmen, Lautheitspegel zu erhalten. In einer letzten Studie wurde das Lautheitsempfinden bei zwei unterschiedlichen Lautheiten bei unterschiedlichen Interphasen-Gaps (IPG) untersucht und der daraus resultierende Dynamikbereich. Eine Vergrößerung des IPGs führt bei gleich bleibendem Lautheitsempfinden zu geringeren Stimulations-Amplituden und ist dadurch in der Lage die Batterie schonen. Allerdings ist der Einfluss auf den Dynamikbereich bisher unbekannt. In einem Lautheits-Experiment wurden Pulse mit verschiedenen IPGs (10 und 30 µs) mit dem standardmäßig verwendeten IPG (2.1 µs) in ihrer Lautheit angeglichen. Dieses Verfahren wurde bei MCL und der Amplitude des halben Dynamikbereichs (50%-ADR) durchgeführt. Aus den ermittelten Werten konnte ein „oberer“ Dynamikbereich zwischen MCL und 50%-ADR ermittelt werden. Es zeigte sich, dass sich die Amplituden mit größerem IPG, wie erwartet, verringerten. Jedoch zeigte sich ein stärkerer Effekt bei MCL, was eine Verringerung des Dynamikbereichs zur Folge hat. Dies ist das erste Mal, dass eine Verringerung des Dynamikbereichs gezeigt wurde. KW - Cochlear-Implantat KW - Bahnung KW - Elektrostimulation KW - temporal information transfer KW - ECAP KW - interphase gap KW - interpulse interval KW - cochlea implant KW - zeitlich Informationsübertragung Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223887 ER - TY - JOUR A1 - Navarro, Stefano A1 - Stegner, David A1 - Nieswandt, Bernhard A1 - Heemskerk, Johan W. M. A1 - Kuijpers, Marijke J. E. T1 - Temporal roles of platelet and coagulation pathways in collagen- and tissue factor-induced thrombus formation JF - International Journal of Molecular Sciences N2 - In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process. KW - coagulation KW - fibrin KW - glycoprotein VI KW - platelet receptors KW - spatiotemporal thrombus KW - thrombin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284219 SN - 1422-0067 VL - 23 IS - 1 ER - TY - JOUR A1 - Delgobo, Murilo A1 - Heinrichs, Margarete A1 - Hapke, Nils A1 - Ashour, DiyaaElDin A1 - Appel, Marc A1 - Srivastava, Mugdha A1 - Heckel, Tobias A1 - Spyridopoulos, Ioakim A1 - Hofmann, Ulrich A1 - Frantz, Stefan A1 - Ramos, Gustavo Campos T1 - Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging JF - Frontiers in Immunology N2 - The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of naïve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice. KW - CD4+ T-cells KW - myocardial aging KW - inflammaging KW - NSG animals KW - immunosenescence KW - lymphocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229612 SN - 1664-3224 VL - 12 ER - TY - BOOK A1 - Ackermann, Zeno A1 - Karremann, Isabel A1 - Malhotra, Simi A1 - Zaidi, Nishat T1 - Terrains of Consciousness: Multilogical Perspectives on Globalization N2 - TERRAINS OF CONSCIOUSNESS emerges from an Indian-German-Swiss research collaboration. The book makes a case for a phenomenology of globalization that pays attention to locally situated socioeconomic terrains, everyday practices, and cultures of knowledge. This is exemplified in relation to three topics: - the tension between ‘terrain’ and ‘territory’ in Defoe’s ‘Robinson Crusoe’ as a pioneering work of the globalist mentality (chapter 1) - the relationship between established conceptions of feminism and the concrete struggles of women in India since the 19th century (chapter 2) - the exploration of urban space and urban life in writings on India’s capital – from Ahmed Ali to Arundhati Roy (chapter 3). N2 - TERRAINS OF CONSCIOUSNESS emerges from a transnational research project in which scholars from Jamia Millia Islamia (New Delhi), the JMU Würzburg, and the University of Zurich collaborated to evolve new multilogical perspectives on what is usually referred to as globalization. The book makes a case for a PHENOMENOLOGY OF GLOBALIZATION that pays particular attention to the transformation of locally situated and individually experienced socioeconomic terrains, everyday practices, and cultures of knowledge. This perspective is exemplified in relation to three concrete research topics: - the tension between the concepts of ‘TERRAIN’ and ‘TERRITORY’ in parts one and two of Daniel Defoe’s "Robinson Crusoe as" a pioneering work of the globalist mentality (chapter 1) - the relationship between established abstract conceptions of FEMINISM and the concrete emancipatory struggles and life practices of women in India since the early 19th century (chapter 2) - the exploration of URBAN SPACE and URBAN LIFE as a socio-sensorial terrain in fictional and non-fictional writings on or of Delhi – from Ahmed Ali’s "Twilight in Delhi" (1940) to Arundhati Roy’s "The Ministry of Utmost Happiness" (2017). Throughout, the approach of Terrains of Consciousness is informed by the uncomfortable question of how the ‘liberating’ effects of globalization relate to its limiting and disrupting consequences. In these respects, it is vital to ask how globalization affects the dispossessed inhabitants of the world and its various societies. KW - Globalisierung KW - Sinne KW - Kulturtheorie KW - Literaturwissenschaft KW - Stadtforschung KW - Globalization KW - Sensory Studies KW - Phenomenology KW - Mondialization KW - Articulation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243936 SN - 978-3-95826-168-6 SN - 978-3-95826-169-3 N1 - Parallel erschienen als Druckausgabe in Würzburg University Press, 978-3-95826-168-6, 24,90 Euro. PB - Würzburg University Press CY - Würzburg ET - 1. Auflage ER - TY - THES A1 - Buss, Alexa T1 - Testung verschiedener Strategien für die Regeneration von Knorpeldefekten im Ex vivo-Testsystem T1 - Evaluation of cartilage regeneration strategies in an osteochondral ex vivo cartilage defect model N2 - Die Degeneration des Gelenkknorpels ist Hauptursache für chronische Schmerzen und eine dadurch bedingte Einschränkung der Lebensqualität. Für die Sozialversicherungssysteme ist dies mit steigenden Kosten verbunden. Gegenwärtige Behandlungsoptionen wie die Mikrofrakturierung oder die (matrix-assoziierte) Autologe Chondrozytentransplantation (M-) ACT führen zu einem minderwertigen Reparaturgewebe aus Faserknorpel mit unzureichenden mechanischen Eigenschaften an der Defektstelle. Es besteht ein Bedarf an der Entwicklung und Testung neuer Knorpeltherapien, die ein funktionelles Reparaturgewebe für nachhaltige Beschwerdefreiheit erzeugen. Das hier verwendete kürzlich etablierte osteochondrale Ex vivo-Testsystem (EVTS) eignet sich zur Evaluation unterschiedlicher zellbasierter Behandlungsansätze für die Knorpelregeneration. Aus der medialen Femurkondyle von Schweinen wurden zylindrische 8 mm große osteochondrale Explantate (OCE) isoliert. Es wurden Knorpel-Knochendefekte und reine Knorpeldefekte kreiert und mit autologen Schweine-Chondrozyten (CZ) bzw. einer Mischung aus CZ und mesenchymalen Stammzellen (MSC) gefüllt, die in Kollagen Typ I Hydrogel eingebettet waren. Nach vierwöchiger Kultivierung wurden die Proben histologisch und immunhistochemisch gefärbt (Safranin-O-Färbung, Kollagen Typ II, Aggrekan), die Zellvitalität (Lebend-Tot-Färbung) überprüft und die extrazelluläre Matrixproduktion analysiert. Nach vierwöchiger Kultur im EVTS in Normoxie und Hypoxie zeigten sich die in Kollagen-I-Hydrogel eingebetteten Zellen lebensfähig. Die Auswertung der verschiedenen Ansätze erfolgte über den standardisierten ICRS-II-Score der International Cartilage Repair Society (ICRS) mit drei unabhängigen Bewertern. Insgesamt resultierten bessere Ergebnisse im Hinblick auf die Matrixsynthese in den Monokulturen aus CZ im Vergleich zu den Co-Kulturen aus CZ und MSCs. Da dieser Unterschied nicht groß war, könnten MSCs zur Einsparung autologer CZ eine Alternative in der Behandlung von Knorpeldefekten darstellen. Hypoxie spielte eine Rolle bei reinen Knorpeldefekten, nicht bei Knorpel-Knochendefekten. Dies bestätigt die Bedeutung des physiologischen hypoxischen Milieus des Gelenkknorpels, das einen niedrigen Sauerstoffgehalt von 2-5 VII % aufweist. Die Ergebnisse zeigen, dass die unterschiedlichen Faktoren aus Zellkombination, Knorpeldefektgröße und Kultivierung in Hypoxie oder Normoxie Einfluss auf die Ausbildung der extrazellulären Matrix haben. Weiterhin fehlt jedoch das Verständnis für die genauen Mechanismen des Knorpelregenerationsverhaltens. Ex vivo-Testsysteme können dabei helfen ein weiteres Verständnis zu erlangen und entsprechende Behandlungsstrategien zu evaluieren. N2 - Degeneration of articular cartilage is a major cause of chronic pain - impairing the quality of life and rising health care costs. Current treatment options like microfracture, ACT or MACT result in fibrocartilaginous repair tissue with insufficient mechanical properties at the defect site. Hence, new cartilage therapies generating functional repair tissue need to be developed and tested. Here we used a recently established ex vivo osteochondral model to evaluate the therapeutic potential of several cell-based cartilage regeneration approaches. Reproducible cylindrical 8 mm osteochondral explants (OCE) were isolated from porcine medial condyles. Full-thickness and cartilage-only defects were created and filled with autologous porcine chondrocytes respectively a mixture of chondrocytes and mesenchymal stem cells, embedded in collagen type I hydrogel. After static culture for four weeks, samples were analyzed for cell viability (live/dead staining) and extracellular matrix production, using immunohistochemical staining (Safranin-O-staining, collagen type II, aggrecan). Embedded cells remain viable after four weeks culture in ex vivo osteochondral model. Outcome of different cartilage regeneration approaches were compared using the recommended guidelines proposed by the International Cartilage Repair Society (ICRS) and ICRS-II-score with three independent evaluators. Overall, the monocultures from CZ performed better than the co-cultures from CZ and MSCs. Since this difference was not large, MSCs could be an alternative in the treatment of cartilage defects to save autologous CZ. Hypoxia played a role in pure cartilage defects, but not in cartilage-bone defects. This confirms the importance of the physiological hypoxic milieu of the articular cartilage, which has a low oxygen content of 2-5 %. The results show that the different factors from cell combination, cartilage defect size and cultivation in hypoxia or normoxia influence the formation of the extracellular matrix. However, there is still no understanding of the exact mechanisms of cartilage regeneration behavior. Ex vivo test systems can help to gain further understanding and to evaluate appropriate treatment strategies. KW - cartilage KW - test system KW - Knorpel KW - in vitro Testsystem Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246714 ER - TY - JOUR A1 - Schlecht, Anja A1 - Vallon, Mario A1 - Wagner, Nicole A1 - Ergün, Süleyman A1 - Braunger, Barbara M. T1 - TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain JF - Biomolecules N2 - Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain. KW - heart-brain axis KW - brain-retina axis KW - neurotrophins KW - TGFβ signaling KW - myocardial infarction KW - diabetic retinopathy KW - age-related macular degeneration KW - ischemic stroke Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246159 SN - 2218-273X VL - 11 IS - 9 ER - TY - THES A1 - Wagner, Rabea Marie T1 - The Bacterial Exo- and Endo-Cytoskeleton Spatially Confines Functional Membrane Microdomain Dynamics in \(Bacillus\) \(subtilis\) T1 - Das bakterielle Außen- und Innenskelett begrenzt die Mobilität funktionaler Membranmikrodomänen in \(Bacillus\) \(subtilis\) räumlich N2 - Cellular membranes form a boundary to shield the inside of a cell from the outside. This is of special importance for bacteria, unicellular organisms whose membranes are in direct contact with the environment. The membrane needs to allow the reception of information about beneficial and harmful environmental conditions for the cell to evoke an appropriate response. Information gathering is mediated by proteins that need to be correctly organized in the membrane to be able to transmit information. Several principles of membrane organization are known that show a heterogeneous distribution of membrane lipids and proteins. One of them is functional membrane microdomains (FMM) which are platforms with a distinct lipid and protein composition. FMM move within the membrane and their integrity is important for several cellular processes like signal transduction, membrane trafficking and cellular differentiation. FMM harbor the marker proteins flotillins which are scaffolding proteins that act as chaperones in tethering protein cargo to FMM. This enhances the efficiency of cargo protein oligomerization or complex formation which in turn is important for their functionality. The bacterium Bacillus subtilis contains two flotillin proteins, FloA and FloT. They form different FMM assemblies which are structurally similar, but differ in the protein cargo and thus in the specific function. In this work, the mobility of FloA and FloT assemblies in the membrane was dissected using live-cell fluorescence microscopy techniques coupled to genetic, biochemical and molecular biological methods. A characteristic mobility pattern was observed which revealed that the mobility of both flotillins was spatially restricted. Restrictions were bigger for FloT resulting in a decreased diffusion coefficient compared to FloA. Flotillin mobility depends on the interplay of several factors. Firstly, the intrinsic properties of flotillins determine the binding of different protein interaction partners. These proteins directly affect the mobility of flotillins. Additionally, binding of interaction partners determines the assembly size of FloA and FloT. This indirectly affects the mobility, as the endo-cytoskeleton spatially restricts flotillin mobility in a size-dependent manner. Furthermore, the extracellular cell wall plays a dual role in flotillin mobility: its synthesis stimulates flotillin mobility, while at the same time its presence restricts flotillin mobility. As the intracellular flotillins do not have spatial access to the exo-cytoskeleton, this connection is likely mediated indirectly by their cell wall-associated protein interaction partners. Together the exo- and the endo-cytoskeleton restrict the mobility of FloA and FloT. Similar structural restrictions of flotillin mobility have been reported for plant cells as well, where the actin cytoskeleton and the cell wall restrict flotillin mobility. These similarities between eukaryotic and prokaryotic cells indicate that the restriction of flotillin mobility might be a conserved mechanism. N2 - Zelluläre Membranen bilden eine Barriere um das Zellinnere von dem -äußeren abzuschirmen. Das ist insbesondere bei Bakterien wichtig, einzellige Organismen, deren Membranen in direktem Kontakt zu ihrer Umgebung stehen. Die Membran muss es ermöglichen, Informationen über mögliche vorteilhafte oder schädliche Einflüsse in der Umgebung wahrzunehmen, damit die Zelle dementsprechend eine Reaktion initiieren kann. Die Informationsaufnahme und die resultierenden Reaktionen werden von Membranproteinen in Gang gesetzt, deren Organisation in der Membran Voraussetzung für ihre Funktionalität ist. Mehrere Prinzipien zur Membranorganisation sind bekannt, die alle eine heterogene Verteilung von Proteinen und Lipiden zu Grunde legen. Ein Beispiel für ein solches Prinzip sind funktionelle Membranmikrodomänen (FMM), Plattformen mit einer besonderen Lipid- und Proteinzusammensetzung. FMM bewegen sich in der Membran und ihre Integrität ist für viele zelluläre Prozesse wichtig, zum Beispiel für Signaltransduktion, Membrantransport oder zur zellulären Differenzierung. Flotilline sind Markerproteine für FMM. Sie bilden eine Art Gerüst und funktionieren als Chaperone, indem sie die sogenannten Frachtproteine in den FMM binden. Dort wird die Effizienz der Oligomerisierung oder Komplexbildung der Frachtproteine gesteigert, was für ihre Funktionalität und die ihrer assoziierten Prozesse von Bedeutung ist. In dem Bakterium Bacillus subtilis gibt es zwei Flotilline, FloA und FloT. Diese formen FMM Plattformen, die zwar strukturell ähnlich sind, sich aber in ihren Frachtproteinen und somit auch in ihren spezifischen Funktionen unterscheiden. In dieser Arbeit wurde die Mobilität der FloA- und FloT-abhängigen Plattformen in der Membran untersucht. Dafür wurden Technologien der Fluoreszenzmikroskopie mit genetischen, biochemischen und molekularbiologischen Ansätzen kombiniert. Charakteristische Bewegungsmuster wurden beobachtet, die zeigten, dass die Beweglichkeit beider Flotilline räumlich begrenzt war. Dabei war die Einschränkung für FloT größer, und dementsprechend der Diffusionskoeffizient kleiner verglichen mit FloA. Die Mobilität von FloA und FloT hängt von dem Zusammenspiel mehrerer Faktoren ab. Zum einen bestimmen intrinsische Eigenschaften der Flotillinproteine ihre Fähigkeit verschiedene Interaktionspartner zu binden. Diese wirken sich dann direkt auf die Mobilität von Flotillinen aus. Des Weiteren bestimmt die Bindung verschiedener Interaktionspartner auch die Größe der FloA- und FloT- abhängigen Plattformen. Die resultierenden Größen beeinflussen die Mobilität indirekt, da das zelluläre Innenskelett die Flotillinmobilität räumlich in größenabhängiger Weise begrenzt. Außerdem spielt das Außenskelett der Zelle, die Zellwand, eine zweifache Rolle: die Zellwandsynthese fördert die Mobilität der Flotilline, während die Zellwand an sich gleichzeitig die Mobilität der Flotilline einschränkt. Da Flotilline räumlich keine Verbindung zum Außenskelett haben, wird diese Verbindung wahrscheinlich durch ihre Zellwand-assoziierten Interaktionspartner übermittelt. Zusammenfassend beschränken das Außen- und das Innenskelett die Mobilität von FloA und FloT. In Pflanzen wurden ähnliche strukturelle Beschränkungen der Mobilität von Flotillinen durch das Aktin- Zytoskelett und die Zellwand beschrieben. Diese Ähnlichkeit zwischen prokaryotischen und eukaryotischen Zellen deutet darauf hin, dass die Beschränkung der Mobilität der Flotillin-Plattformen ein konservierter Mechanismus sein könnte. KW - Heubacillus KW - Bakterienzellwand KW - Plasmamembran KW - Zellskelett KW - Bacillus subtilis KW - functional membrane microdomains KW - membrane dynamics KW - bacterial lipid rafts KW - cytoskeleton KW - cell wall Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217458 ER - TY - JOUR A1 - Apelblat, Alexander A1 - Consiglio, Armando A1 - Mainardi, Francesco T1 - The Bateman functions revisited after 90 years — a survey of old and new results JF - Mathematics N2 - The Bateman functions and the allied Havelock functions were introduced as solutions of some problems in hydrodynamics about ninety years ago, but after a period of one or two decades they were practically neglected. In handbooks, the Bateman function is only mentioned as a particular case of the confluent hypergeometric function. In order to revive our knowledge on these functions, their basic properties (recurrence functional and differential relations, series, integrals and the Laplace transforms) are presented. Some new results are also included. Special attention is directed to the Bateman and Havelock functions with integer orders, to generalizations of these functions and to the Bateman-integral function known in the literature. KW - bateman functions KW - havelock functions KW - integral-bateman functions KW - confluent hypergeometric functions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240970 SN - 2227-7390 VL - 9 IS - 11 ER - TY - JOUR A1 - Haider, Malik Salman A1 - Ahmad, Taufiq A1 - Groll, Jürgen A1 - Scherf-Clavel, Oliver A1 - Kroiss, Matthias A1 - Luxenhofer, Robert T1 - The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging JF - European Journal of Drug Metabolism and Pharmacokinetics N2 - Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably. Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility. KW - Mitotane KW - cancer KW - adrenal gland Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270476 SN - 2107-0180 VL - 46 IS - 5 ER - TY - THES A1 - Lapuente, Juan M. T1 - The Chimpanzees of the Comoé National Park, Ivory Coast. Status, distribution, ecology and behavior T1 - Die Schimpansen im Comoé Nationalpark, Elfenbeinküste. Status, Verbreitung, Ökologie und Verhalten N2 - Although wild chimpanzees (Pan troglodytes) have been studied intensely for more than 50 years, there are still many aspects of their ecology and behavior that are not well understood. Every time that a new population of chimpanzees has been studied, new behaviors and unknown aspects of their ecology have been discovered. All this accumulated knowledge is helping us to piece together a model of how could last human and chimpanzee common ancestors have lived and behaved between seven and five million years ago. Comoé chimpanzees had never been studied in depth, until we started our research in October 2014, only a few censuses had been realized. The last surveys prior our work, stated that the population was so decimated that was probably functionally extinct. When we started this research, we had to begin with a new intensive survey, using new methods, to ascertain the real status and distribution of the chimpanzees living in Comoé National Park (CNP). During the last five years, we have realized a deep study aiming to know more about their ecology and behavior. We combined transects and reconnaissance marches (recces) with the use of camera traps, for the first time in CNP, obtaining a wealth of data that is not fully comprised in this dissertation. With this research, we determined that there is a sustainable continuous population of Western chimpanzees (Pan troglodytes verus) in CNP and the adjacent area of Mont Tingui, to the West, with a minimum of 127 weaned chimpanzees living in our main 900 km2 study area, SW of CNP. We found that this population is formed by a minimum of eight different chimpanzee communities, of which we studied seven, four of them more in detail. These chimpanzees spent much more time in the forest than in the savanna habitats. We also found that Comoé chimpanzees consumed at least 58 different food items in their dit, which they obtained both from forest and savanna habitats. Another finding was that insectivory had an important role in their diet, with at least four species of ants, three of termites and some beetle larvae. These chimpanzees also hunted at least three species of monkeys and maybe rodents and duikers and occasionally consumed the big land snails of genus Achatina. We found that, during the fruit scarcity period in the late rainy season, they intensely consumed the cambium of Ceiba pentandra, as fallback food, much more than the bark or cambium of any other tree species. Another interesting finding was that all the chimpanzees in the studied area realized this particular bark-peeling behavior and had been repeatedly peeling the trees of this species for years. This did not increase tree mortality and the damage caused to the trees was healed in two years, not reducing the growth, thus being a sustainable use of the trees. We found that Comoé chimpanzees produced and used a great variety of tools, mainly from wooden materials, but also from stone and herbaceous vegetation. Their tool repertory included stick tools to dip for Dorylus burmeisteri ants, to fish for Camponotus and Crematogaster ants, to dip for honey, mainly from Meliponini stingless bees, but sometimes from honey bees (Apis mellifera). It also included the use of stick tools to fish termites of Macrotermes subhyalinus and Odontotermes majus (TFTs), to dip for water from tree holes and investigatory probes for multiple purposes. Additionally, these chimpanzees used leaf-sponges to drink from tree holes and to collect clayish water from salt-licks. They also used stones to hit the buttresses of trees during displays, the so called accumulative stone throwing behavior and probably used stones as hammers, to crack open hard-shelled Strichnos spinosa and Afraegle paniculata fruits and Achatina snails. The chimpanzees also used objects that are not generally accepted as animal tools, for being attached to the substrate, with different purposes: they drummed buttresses of trees with hands and/or feet to produce sound during male displays and they pounded open hard-shelled fruits, Achatina snails and Cubitermes termite mounds on stone or root anvils. We finally measured the stick tools and found significant differences between them suggesting that they were specialized tools made specifically for every purpose. We studied more in detail the differences between apparently similar tools, the honey dipping tools and the water dipping tools, often with brushes made at their tips to collect the fluids. These last tools were exclusive from Comoé and have not been described at any other site. We found that total length, diameter and brush length were significantly different, suggesting that they were specialized tools. We concluded that Comoé chimpanzees had a particular culture, different from those of other populations of Western chimpanzees across Africa. Efficient protection, further research and permanent presence of research teams are required to avoid that this unique population and its culture disappears by the poaching pressure and maybe by the collateral effects of climate change. N2 - Obwohl wild lebende Schimpansen (Pan troglodytes) seit mehr als 50 Jahren intensiv untersucht werden, gibt es noch zahlreiche Aspekte ihrer Ökologie und ihres Verhaltens, die nicht gut verstanden werden. Jedes Mal, wenn eine neue Population von Schimpansen studiert wurde, wurden neue Verhaltensweisen und unbekannte Aspekte ihrer Ökologie entdeckt. All dieses gesammelte Wissen hilft uns, ein Modell zu erstellen, wie lange die gemeinsamen Vorfahren von Menschen und Schimpansen vor sieben bis fünf Millionen Jahren gelebt und sich verhalten haben könnten. Als wir im Oktober 2014 mit unserer Forschung begannen waren die Comoé-Schimpansen, bis auf einige Populations-Zensus von Schimpansen in der Elfenbeinküste, noch nie eingehend untersucht worden. Die letzte Zählung bevor unsere Arbeit began ergab, dass die Schimansenpopulation so stark dezimiert war, dass sie als funktionell ausgestorben erarchtet werden konnte. Zum Beginn unserer Forschung, führten wir zuerst mit neusten Methoden einen neuen detailierten Zensus durch, um den tatsächlichen Status und die Verteilung der im Comoé-Nationalpark (CNP) lebenden Schimpansen zu ermitteln. In den folgenden fünf Jahren haben wir zudem eine umfassende Studie durchgeführt, um mehr über ihre Ökologie und ihr Verhalten zu erfahren. Wir haben im CNP erstmals systematische Transekte und Datenerhebungen mittels Kamerafallen kombiniert, um eine Fülle von Erkenntnissen zu erhalten, die in dieser Dissertation nicht vollständig enthalten sind. Wir stellten fest, dass es in CNP und dem westlich angrenzenden Gebiet des Mont Tingui nach wie vor eine nachhaltige und kontinuierliche Population westlicher Schimpansen (Pan troglodytes verus) existiert, wobei mindestens 131 adulte (entwöhnte) Schimpansen in unserem 900 km² großen Hauptuntersuchungsgebiet südwestlich des CNP leben. Diese Population besteht aus mindestens acht verschiedenen Schimpansengruppen, von denen wir sieben untersuchten, vier davon genauer. Wir konnten zeigen dass diese Schimpansen deutlich mehr Zeit im Wald als in den angrenzenden Savannenhabitaten verbringen. Wir stellten fest, dass Comoé- Schimpansen mindestens 58 verschiedene Futtermittel aus Wald- als auch aus Savannenhabitaten nutzen. Zudem spielt der Konsum von Insekten, bestelhend aus mindestens vier Ameisen-, drei Termiten- und verschiedenene Käferlarven eine wichtige Rolle in ihrem Ernährungsreportoire. Die Comoé-Schimpansen jagen zudem mindestens drei Affena sowie möglicherweise Nagetiere und Duiker, und fraßen gelegentlich die großen Schnecken der Gattung Achatina. Wir fanden heraus, dass sie den typischen Mangel an reifen Fuechten in der \späten Regenzeit durch den intensiven Konsum der Rinde (Kambium) von Ceiba pentandra kompensieren. Alle Schimpansen im untersuchten Gebiet zeigten dieses besondere Verhalten, bei dem sie die Rinde von Ceiba Bäumen schälen. Wir konnte zeigen, dass die Schimpansen diese Bäume seit Jahren wiederholt geschält hatten, was offenbar den Bäumen keinen nachhaltigen Schaden zugefügte. Innerhalb von zwei Jahren ware die Schäden geheilt and das Wachstum nicht verringert, was schlussfolgern lässt dass die Nutzung der Baumrinde nachhaltig ist. Wir fanden heraus, dass Comoé-Schimpansen eine Vielzahl von Werkzeugen aus Vegetation aber auch Steinen herstellten und verwendeten. Das Werkzeugrepertoire umfasste Stöckchen zur Gewinning von on Ameisen der Art Dorylus burmeisteri, sowie Ameisen der Gattungen Camponotus und Crematogaster, aber auch von Bienenhonig produziert von der stachellosen Gattung Melipoa sowie von Apis mellifera. Die Schimpansen nutzen ausserdem Pflanzenwerkzeuge zum Termitenfischen von Macrotermes subhyalinus und Odontotermes majus, um an das Wasser in Baumvertiefungen zu gelangen, sowie für diverse andere Untersuchungszwecke. Zusätzlich verwenden die Comoé-Schimpansen Blattschwämme, um aus Baumlöchern zu trinken und lehmiges Wasser von den Salzlecken zu sammeln. Im Rahmen ihres Imponierverhaltens schleuden sie Steine an die Brettwurzeln spezieller grosser Bäume, ein neu entdecktes Verhalten das als akkumulatives Steinerfen bezeichnet wird. Es ist wahrscheinlich dass sie Steine auch als Hammerwerkzeuge nutzen, um hartschalige Früchte wie Strichnos spinosa und Afraegle paniculata sowie grosse Landschnecken aufzubrechen. Die Schimpansen verwenden Gegenstände auch in anderen Zusammenhängen, die nicht unbedingt als Werkzeuggebrauch definiert werden können: Sie trommlen im Rahmen vom männlichen Imponierverhalten laut mit Händen und Füßen auf die Brettwurzeln von Bäumen, und zerschmettern harte Früchte, Schneckenhäuser und Cubitermes-Termitenhügel auf Ambossen aus Gestein oder Wurzeln. Wir haben signifikante Unterschiede beim Vermessen der Stabwerkzeuge festgestellt, was darauf hindeutet, dass es sich um Spezialwerkzeuge handelt, die speziell für verschiedene Zwecke hergestellt werden. Wir haben insbesondere die Unterschiede zwischen scheinbar ähnlichen Pinselwerkzeugen für den Konsum von Flüssigkeiten (H zu verhindern, sowie die möglichen Nebeneffekte des Klimawandels zu dokumentieren.onig, Wasser) genauer untersucht. Diese Pinselwerkzeuge der Comoé-Schimpansen sind offenbar einzigartig und bislang nicht in der Literatur beschrieben. Gesamtlänge, Durchmesser und Bürstenlänge weichen je nach Verwendungszweck der Pinsel erheblich voneinander ab, was darauf hindeutet, dass es sich um Spezialwerkzeuge handelt. Wir schlussfolgern, dass die Kultur der Comoé-Schimpansen einzigartig innerhalb der der westlichen Schimpansen ist. Um diese einzigartige Population von Schimpansen effektiv zu schützen benötigt es weitere Forschung sowie die ständige Präsenz von Forschungsteams, um Wilderei KW - Chimpanzee KW - ecology KW - distribution KW - behavior KW - Comoé National Park KW - tool-use KW - primate KW - tool KW - diet KW - habitat KW - Parc National de la Comoé KW - Schimpanse KW - Verhalten Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223180 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Hayashi, Kentaro A1 - Störk, Stefan A1 - Scheper, Verena A1 - Lenarz, Thomas A1 - Förster, Carola Y. T1 - The conspicuous link between ear, brain and heart − Could neurotrophin-treatment of age-related hearing loss help prevent Alzheimer's disease and associated amyloid cardiomyopathy? JF - Biomolecules N2 - Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease. KW - Alzheimer's disease KW - amyloid cardiomyopathy KW - heart failure KW - age-related hearing loss KW - neurotrophins KW - blood–brain barrier KW - blood–labyrinth barrier KW - spiral ganglion neuron KW - BDNF KW - GDNF Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241084 SN - 2218-273X VL - 11 IS - 6 ER - TY - JOUR A1 - Zapf, Ludwig A1 - Finze, Maik T1 - The crystal structure of poly[(μ \(_3\)-imidazolato-κ \(^3\) N:N:N′)(tetrahydrofuran- κ \(^1\) O)lithium(I)], C\(_7\)H\(_{11}\)LiN\(_2\)O JF - Zeitschrift für Kristallographie - New Crystal Structures N2 - C\(_7\)H\(_{11}\)LiN\(_2\)O, monoclinic, P2\(_1\)/c (no. 14), a = 8.9067(1) angstrom, b = 8.6975(1) angstrom, c = 10.2398(1) angstrom, beta = 101.900(3)degrees, V = 770.491(15) angstrom(3), Z = 4, R-gt (F) = 0.0338, wR(ref) (F\(^2\)) = 0.0925, T = 100 K. KW - acid sphingomyelinase KW - antidepressants KW - major depression KW - regulatory T cells KW - sphingolipids Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260745 VL - 236 IS - 5 ER - TY - JOUR A1 - Staab, Torsten E. M. A1 - Lotter, Frank A1 - Mühle, Uwe A1 - Elsayed, Mohamed A1 - Petschke, Danny A1 - Schubert, Thomas A1 - Ibrahim, Alaa M. A1 - Krause-Rehberg, Reinhard A1 - Kieback, Bernd T1 - The decomposition process in high-purity Al-1.7 at.% Cu alloys with trace elements: preservation of quenched-in vacancies by In, Sn and Pb influencing the ​θ′formation JF - Journal of Materials Science N2 - Aluminium-copper alloys of the 2xxx type receive their excellent mechanical properties by the formation of copper-rich precipitates during hardening. Size, distribution and crystal structure of the formed precipitates determine the final strength of those alloys. Adding traces of certain elements, which bind to vacancies, significantly influences the decomposition behaviour, i.e. the diffusion of the copper atoms. For high-purity ternary alloys (Al-1.7 at.% Cu-X), we investigate the interaction of copper and trace element atoms (X=In, Sn, and Pb) with quenched-in vacancies by Positron Annihilation Lifetime Spectroscopy (PALS). By employing Vickers microhardness, Differential Scanning Calorimetry (DSC) and Small Angle X-Ray Scattering (SAXS) we obtain a comprehensive picture of the decomposition process: opposite to predicted binding energies to vacancies by ab-initio calculations we find during ageing at room and elevated temperature a more retarded clustering of copper in the presence of In rather than for Sn additions, while Pb, having the highest predicted binding to vacancies, shows nearly no retarding effect compared to pure Al-Cu. If the latter would be due to a limited solubility of lead, it had to be below 2 ppm. Transmission Electron Microscopy (TEM) as imaging method complements our findings. Annealing the quenched Al-1.7 at.% Cu-X-alloys containing 100 ppm In or Sn at 150∘C leads to finely distributed θ′-precipitates on the nanoscale, since due to the trace additions the formation temperature of θ′ is lowered by more than 100∘C. According to TEM small agglomerates of trace elements (In, Sn) may support the early nucleation for the θ′-precipitates. KW - Aluminium-copper KW - alloys KW - trace elements Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269103 SN - 1573-4803 VL - 56 IS - 14 ER - TY - JOUR A1 - Ramler, Jaqueline A1 - Fantuzzi, Felipe A1 - Geist, Felix A1 - Hanft, Anna A1 - Braunschweig, Holger A1 - Engels, Bernd A1 - Lichtenberg, Crispin T1 - The dimethylbismuth cation: entry into dative Bi-Bi bonding and unconventional methyl exchange JF - Angewandte Chemie International Edition N2 - The dimethyl bismuth cation, [BiMe\(_2\)(SbF\(_6\))], has been isolated and characterized. Reaction with BiMe\(_3\) allows access to the first compound featuring Bi→Bi donor–acceptor bonding. In solution, dynamic behavior with methyl exchange via an unusual S\(_E\)2 mechanism is observed, underlining the unique properties of bismuth species as soft Lewis acids with the ability to undergo reversible Bi−C bond cleavage. KW - inorganic chemistry KW - methyl exchange KW - bismuth KW - cationic species KW - electrophilic substitution KW - Lewis acidity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256543 VL - 60 ER - TY - THES A1 - Heidrich, Lea T1 - The effect of environmental heterogeneity on communities T1 - Der Einfluss von Heterogenität in Umweltbedingungen auf Artgemeinschaften N2 - How diversity of life is generated, maintained, and distributed across space and time is the central question of community ecology. Communities are shaped by three assembly processes: (I) dispersal, (II) environ-mental, and (III) interaction filtering. Heterogeneity in environmental conditions can alter these filtering processes, as it increases the available niche space, spatially partitions the resources, but also reduces the effective area available for individual species. Ultimately, heterogeneity thus shapes diversity. However, it is still unclear under which conditions heterogeneity has positive effects on diversity and under which condi-tions it has negative or no effects at all. In my thesis, I investigate how environmental heterogeneity affects the assembly and diversity of diverse species groups and whether these effects are mediated by species traits. In Chapter II, I first examine how much functional traits might inform about environmental filtering pro-cesses. Specifically, I examine to which extent body size and colour lightness, both of which are thought to reflect the species thermal preference, shape the distribution and abundance of two moth families along elevation. The results show, that assemblages of noctuid moths are more strongly driven by abiotic filters (elevation) and thus form distinct patterns in colour lightness and body size, while geometrid moths are driven by biotic filters (habitat availability), and show no decline in body size nor colour lightness along elevation. Thus, one and the same functional trait can have quite different effects on community assembly even between closely related taxonomic groups. In Chapter III, I elucidate how traits shift the relative importance of dispersal and environmental filtering in determining beta diversity between forests. Environmental filtering via forest heterogeneity had on aver-age higher independent effects than dispersal filtering within and among regions, suggesting that forest heterogeneity determines species turnover even at country-wide extents. However, the relative importance of dispersal filtering increased with decreasing dispersal ability of the species group. From the aspects of forest heterogeneity covered, variations in herb or tree species composition had overall stronger influence on the turnover of species than forest physiognomy. Again, this ratio was influenced by species traits, namely trophic position, and body size, which highlights the importance of ecological properties of a taxo-nomic group in community assembly. In Chapter IV, I assess whether such ecological properties ultimately determine the level of heterogeneity which maximizes species richness. Here, I considered several facets of heterogeneity in forests. Though the single facets of heterogeneity affected diverse species groups both in positive and negative ways, we could not identify any generalizable mechanism based on dispersal nor the trophic position of the species group which would dissolve these complex relationships. In Chapter V, I examine the effect of environmental heterogeneity of the diversity of traits itself to evalu-ate, whether the effects of environmental heterogeneity on species richness are truly based on increases in the number of niches. The results revealed that positive effects of heterogeneity on species richness are not necessarily based on an increased number of niches alone, but proposedly also on a spatially partition of resources or sheltering effects. While ecological diversity increased overall, there were also negative trends which indicate filtering effects via heterogeneity. In Chapter VI, I present novel methods in measuring plot-wise heterogeneity of forests across continental scales via Satellites. The study compares the performance of Sentinel-1 and LiDar-derived measurements in depicting forest structures and heterogeneity and to their predictive power in modelling diversity. Senti-nel-1 could match the performance of Lidar and shows high potential to assess free yet detailed infor-mation about forest structures in temporal resolutions for modelling the diversity of species. Overall, my thesis supports the notion that heterogeneity in environmental conditions is an important driv-er of beta-diversity, species richness, and ecological diversity. However, I could not identify any general-izable mechanism which direction and form this effect will have. N2 - Eine zentrale Frage in der Ökologie ist es, wie die Diversität von Artgemeinschaften generiert, aufrecht-erhalten, und über Zeit und Raum verteilt wird. Die Zusammensetzung von Artgemeinschaften wird durch drei Prozesse bestimmt, die einzelne Arten herausfiltern: (I) Ausbreitung, sowie (II) Umweltbedin-gungen und (III) Interaktionen mit anderen Arten. Heterogenität in Umweltbedingungen verändert das Zusammenspiel dieser Filterprozesse, da es die Anzahl verfügbarer Nischen erhöht und Ressourcen räum-lich aufteilt, aber auch den für die jeweilige Art verfügbaren Raum reduziert, was schlussendlich die Diver-sität der Artgemeinschaft beeinflusst. Es ist jedoch immer noch unklar, wann Heterogenität die Diversität positiv und wann negativ oder sogar überhaupt nicht beeinflusst. In dieser Dissertation werde ich der Fra-ge nachgehen, wie Heterogenität die Artzusammensetzung und Diversität verschiedenster Artengruppen beeinflusst und ob deren Reaktion auf Heterogenität durch Artmerkmale beeinflusst wird. In Kapitel II untersuche ich zunächst inwieweit funktionale Merkmale den Einfluss von Umweltbedingun-gen auf Arten widerspiegeln. Dazu untersuchte ich den Einfluss von Körpergröße und Helligkeit auf die Verbreitung und Abundanz zweier Nachtfalterfamilien entlang eines Höhengradienten. Es zeigte sich, dass Noctuidae stärker von abiotischen Filterprozessen, d.h. Höhe, betroffen waren und klare Zu- bzw. Ab-nahmen in Körpergröße und Helligkeit entlang der Höhe aufwiesen, während Geometridae eher von bioti-schen Filterprozessen, d.h. der Verfügbarkeit ihres Habitats, beeinflusst wurden und keine Merkmalsmus-ter entlang der Höhe aufwiesen. Entsprechend kann ein- und dasselbe Merkmal selbst innerhalb nah-verwandter Artgruppen unterschiedliche Effekte auf die Zusammensetzung von Arten haben. In Kapitel III erläutere ich, wie funktionelle Merkmale die relative Wichtigkeit von Ausbreitungs- und Umweltfiltern für beta-Diversität verschieben können. Sowohl innerhalb als auch zwischen den untersuch-ten Regionen beeinflusste Heterogenität in Wäldern die beta-Diversität stärker als die räumliche Distanz. Letztere wurde allerdings immer bedeutender, je schlechter die Ausbreitungsfähigkeit der jeweiligen Arten-gruppe war. Wenn die Heterogenität in Wäldern nach floristischen und strukturellen Aspekten aufgeteilt wird, so hatte erstere alles in allem einen stärkeren Einfluss auf Unterschiede zwischen Artgemeinschaften. Bei Artengruppen höheren trophischen Levels und größeren Körperbaus hatten die strukturellen Aspekte jedoch einen stärkeren Einfluss. Diese Ergebnisse verdeutlichen, dass die Artzusammensetzung von be-stimmte Merkmale beeinflusst werden kann. In Kapitel IV untersuche ich ob solche Merkmale das Level an Heterogenität festlegen, an welchen Arten-reichtum am höchsten ist. Dazu betrachtete ich mehrere Aspekte von Heterogenität in Wäldern. Obwohl Heterogenität in diesen Aspekten sowohl positive als auch negative Einfluss auf den Artenreichtum der verschiedensten Artengruppen hatte, konnten wir diese nicht anhand der Ausbreitungsfähigkeit oder des trophischen Levels der Artengruppen ableiten. In Kapitel V untersuche ich schließlich den Effekt von Heterogenität auf die Vielfalt von funktionalen Merkmalen. Dieser Ansatz soll helfen zu evaluieren, ob eventuelle Anstiege in der Artenzahl mit Hetero-genität einem Zuwachs in der Anzahl der ökologischen Nischen zurückzuführen sind. Die Ergebnisse legen nahe, dass ein Anstieg von Artenreichtum nicht dadurch beeinflusst wird, sondern auch durch ande-re Mechanismen wie die räumliche Aufteilung von Ressourcen oder durch die Schaffung von Zufluchts-räumen. Obwohl Heterogenität die ökologische Diversität überwiegend positiv beeinflusste, gab es auch einige negative Reaktionen die darauf hindeuten, dass Heterogenität auch bestimmte Merkmale aus einer Artgemeinschaft herausfiltern kann. In Kapitel VI präsentiere ich neue, Satelliten-gestützte Methoden in der Erfassung von Waldstrukturen. In dieser Studie werden die Eignung von LiDar (Lasergestützte Waldvermessungen aus der Luft) und Senti-nel-1 (Satellitenscan durch Radiowellen) verglichen, Waldstrukturen und deren Heterogenität zu messen sowie verschiedene Diversitäts-indices zu modellieren. Hierbei schnitt Sentinel-1 ähnlich gut ab wie LiDar. Somit zeigt Sentinel-1 großes Potential zukünftige Biodiversitätsaufnahmen zu unterstützen, auch aufgrund der kostenfreie Verfügbarkeit von Daten, deren globalen Abdeckung und hohen zeitlichen Auflösung. Insgesamt unterstützen die Ergebnisse meiner Arbeit die große Bedeutung von Heterogenität, insbesonde-re von Waldstrukturen, für beta-Diversität, Artenreichtum und funktionaler Diversität. Allerdings konnte keine generelle Regel identifiziert werden, nach der sich vorhersagen lassen würde welche genaue Richtung dieser Effekt haben wird. KW - Heterogenität KW - Wald KW - Artenvielfalt KW - Waldstruktur Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221781 ER - TY - JOUR A1 - Asch, Silke A1 - Kaufmann, Tobias Peter A1 - Walter, Michaela A1 - Leistner, Marcus A1 - Danner, Bernd C. A1 - Perl, Thorsten A1 - Kutschka, Ingo A1 - Niehaus, Heidi T1 - The effect of perioperative hemadsorption in patients operated for acute infective endocarditis—A randomized controlled study JF - Artificial Organs N2 - Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL‐6, IL‐1b, TNF‐α), leukocytes, C‐reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL‐6 and TNF‐α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required. KW - cytokines KW - endocarditis KW - hemadsorption KW - sepsis KW - SIRS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262681 VL - 45 IS - 11 SP - 1328 EP - 1337 ER - TY - JOUR A1 - Hauser, T. A1 - Dornberger, V. A1 - Malzahn, U. A1 - Grebe, S. J. A1 - Liu, D. A1 - Störk, S. A1 - Nauck, M. A1 - Friedrich, N. A1 - Dörr, M. A1 - Wanner, C. A1 - Krane, V. A1 - Hammer, F. T1 - The effect of spironolactone on diastolic function in haemodialysis patients JF - The International Journal of Cardiovascular Imaging N2 - Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m\(^{2}\) vs. 1.7 ± 14.1 ml/m\(^{2}\), p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m\(^{2}\) vs. + 2.7 ± 15.9 g/m\(^{2}\); p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients. KW - HFpEF KW - diastolic function KW - echocardiography KW - E/e’ KW - haemodialysis KW - spironolactone Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269033 SN - 1573-0743 VL - 37 IS - 6 ER - TY - JOUR A1 - Bartmann, Catharina A1 - Fischer, Leah-Maria A1 - Hübner, Theresa A1 - Müller-Reiter, Max A1 - Wöckel, Achim A1 - McNeill, Rhiannon V. A1 - Schlaiss, Tanja A1 - Kittel-Schneider, Sarah A1 - Kämmerer, Ulrike A1 - Diessner, Joachim T1 - The effects of the COVID-19 pandemic on psychological stress in breast cancer patients JF - BMC Cancer N2 - Background: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels preCOVID-19 pandemic. Methods: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network (R) (NCCN (R)) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23. Results: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms. Conclusions: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire"could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support. KW - COVID-19 KW - breast cancer KW - psychological distress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265802 VL - 21 ER - TY - THES A1 - Saleh, Ahmed T1 - The emerging role of stress speckle tracking in viability world T1 - Die aufkommende Rolle des Belastungs-Speckletrackings in der Vitalitätswelt N2 - Introduction: Speckle-tracking echocardiography has recently emerged as a quantitative ultrasound technique for accurately evaluating myocardial function by analyzing the motion of speckles identified. Speckle-tracking obtained under stress may offer an opportunity to improve the detection of dynamic regional abnormalities and myocardial viability. Objective: To evaluate stress speckle tracking as tool to detect myocardial viability in comparison to cardiac MRI in post-STEMI patients. Methods: 49 patients were prospectively enrolled in our 18-month’s study. Dobutamin stress echocardiography was performed 4 days post-infarction accompanied with automated functional imaging (Speckle tracking) analysis of left ventricle during rest and then during low dose stress. All patients underwent a follow up stress echocardiography at 6 weeks with speckle tracking analysis. Cardiac MRI took place concomitantly at 4 days post-infarction and 6 weeks. We carried out an assessment of re-admission with acute coronary syndrome (ACS) after one year of enrollment. Results: Investigating strain rate obtained with stress speckle tracking after revascularization predicted the extent of myocardial scar, determined by contrast-enhanced magnetic resonance imaging. A good correlation was found between the global strain and total infarct size (R 0.75, p< 0.001). Furthermore, a clear inverse relationship was found between the segmental strain and the transmural extent of infarction in each segment. (R -0.69, p<0.01). Meanwhile it provided 81.82% sensitivity and 82.6% specificity to detect transmural from non-transmural infarction at a cut-off value of -10.15. Global stress strain rate showed 80% sensitivity and 77.5% specificity at a cut-off value of -9.1 to predict hospital re-admission with ACS. A cut-off value of -8.4 had shown a 69.23% sensitivity and 73.5% specificity to predict the re-admission related to other cardiac symptoms. Conclusion: Strain rate obtained from speckle tracking during stress is a novel method of detecting myocardial viability after STEMI .Moreover it carries a promising role in post-myocardial infarction risk stratification with a reasonable prediction of reversible cardiac-related hospital re-admission. N2 - Das Strainrate unter Belastung ist eine effektive Methode zum Nachweis der Myokardviabilität nach STEMI. Darüber hinaus spielt es eine vielversprechende Rolle bei der Risikostratifizierung nach Myokardinfarkt mit einer vernünftigen Vorhersage einer reversiblen kardialen Krankenhaus-Wiederaufnahme. KW - strain rate KW - Speckle tracking KW - viability KW - echocardiography Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223447 N1 - Dieses Dokument wurde aus Datenschutzgründen - ohne inhaltliche Änderungen - erneut veröffentlicht. Die ursprüngliche Veröffentlichung war am 15.05.2019 ER - TY - THES A1 - Claßen, Alexandra T1 - The ERK-cascade in the pathophysiology of cardiac hypertrophy T1 - Die ERK-Kaskade in der Pathophysiologie der Herzhypertrophie N2 - ERK1/2 are known key players in the pathophysiology of heart failure, but the members of the ERK cascade, in particular Raf1, can also protect the heart from cell death and ischemic injury. An additional autophosphorylation (ERK1 at Thr208, ERK2 at Thr188) empowers ERK1/2 translocation to the nucleus and phosphorylation of nuclear targets which take part in the development of cardiac hypertrophy. Thereby, targeting this additional phosphorylation is a promising pharmacological approach. In this thesis, an in silico model of ERK cascade in the cardiomyocyte is introduced. The model is a semi-quantitive model and its behavior was tested with different softwares (SQUAD and CellNetAnalyzer). Different phosphorylation states of ERK1/2 as well as different stimuli can be reproduced. The different types of stimuli include hypertrophic as well as non-hypertrophic stimuli. With the introduced in-silico model time courses and synergistic as well as antagonistic receptor stimuli combinations can be predicted. The simulated time courses were experimentally validated. SQUAD was mainly used to make predictions about time courses and thresholds, whereas CNA was used to analyze steady states and feedback loops. Furthermore, new targets of ERK1/2 which partially contribute, also in the formation of cardiac hypertrophy, were identified and the most promising of them were illuminated. Important further targets are Caspase 8, GAB2, Mxi-2, SMAD2, FHL2 and SPIN90. Cardiomyocyte gene expression data sets were analyzed to verify involved components and to find further significantly altered genes after induced hypertrophy with TAC (transverse aortic constriction). Changes in the ultrastructure of the cardiomyocyte are the final result of induced hypertrophy. N2 - ERK1/2 sind bekannte Schlüsselfiguren bei der Entstehung der Herzinsuffizienz. Weitere Komponenten der ERK-Kaskade, insbesondere Raf1, können das Herz jedoch vor Zelltod und ischämischem Schaden schützen. Eine zusätzliche Autophosphorylierung von ERK1 an Thr208 bzw. von ERK2 an Thr188 ermöglicht ERK1/2 die Translokation zum Zellkern und befähigt ERK dort zur Phosphorylierung von nukleosolischen Zielproteinen, welche eine Herzmuskelhypertrophie auslösen. Daher erscheint diese zusätzliche Autophosphorylierung als eine vielversprechende pharmakologische Zielstruktur. In dieser Arbeit wird ein in-silico Modell der ERK-Kaskade im Kardiomyozyten präsentiert. Das Modell ist ein semi-quantitatives Modell und wurde mit den Programmen SQUAD und CellNetAnalyzer getestet. Verschiedene Phosphorylierungs-Zustände von ERK1/2 als auch verschiedene Stimuli (hypertrophe als auch nicht-hypertrophe) können mit dem Modell reproduziert werden. Mit dem präsentierten in-silico Modell können sowohl zeitliche Abläufe als auch synergistische und antagonistische Effekte vorhergesagt werden. Die simulierten zeitlichen Abläufe wurden durch in-vitro Experimente validiert. SQUAD wurde hauptsächlich für die Modellierung von zeitlichen Abläufen und Schwellenwerte genutzt, wohingegen CellNetAnalyzer vor allen Dingen zur Analyse von Fließgleichgewichten und Rückkopplungs-Mechanismen genutzt wurde. Darüberhinaus wurden Zielstrukturen von ERK1/2, welche zusätzlich an der Entstehung der Herzhypertrophie mitwirken, identifiziert. Diese umfassen unter anderem Caspase 8, GAB2, Mxi-2, SMAD2, FHL2 und SPIN90. Gen-Expressions-Datensätze von Kardiomyozyten nach TAC (transverse aortic constriction) wurden analysiert. Diese wurden mit den im Model vorhandenen Strukturen verglichen und signifikant veränderte Expressionslevel wurden identifiziert. Veränderungen der Ultrastruktur des Kardiomyozyten sind das Ergebnis der induzierten Hypertrophie. KW - Herzhypertrophie KW - Systembiologie KW - ERK-cascade KW - ERK-Kaskade KW - cardiac hypertrophy KW - in-silico model KW - In-silico Modell Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229664 ER - TY - JOUR A1 - Barile, Frank A. A1 - Berry, Colin A1 - Blaauboer, Bas A1 - Boobis, Alan A1 - Bolt, Herrmann M. A1 - Borgert, Christopher A1 - Dekant, Wolfgang A1 - Dietrich, Daniel A1 - Domingo, Jose L. A1 - Galli, Corrado L. A1 - Gori, Gio Batta A1 - Greim, Helmut A1 - Hengstler, Jan G. A1 - Heslop-Harrison, Pat A1 - Kacew, Sam A1 - Marquardt, Hans A1 - Mally, Angela A1 - Pelkonen, Olavi A1 - Savolainen, Kai A1 - Testai, Emanuela A1 - Tsatsakis, Aristides A1 - Vermeulen, Nico P. T1 - The EU chemicals strategy for sustainability: in support of the BfR position JF - Archives of Toxicology N2 - The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations. KW - pharmacology/toxicology KW - occupational medicine/industrial medicine KW - environmental health KW - biomedicine, general Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307154 SN - 0340-5761 SN - 1432-0738 VL - 95 IS - 9 ER - TY - JOUR A1 - Kunz, Tobias C. A1 - Rühling, Marcel A1 - Moldovan, Adriana A1 - Paprotka, Kerstin A1 - Kozjak-Pavlovic, Vera A1 - Rudel, Thomas A1 - Fraunholz, Martin T1 - The Expandables: Cracking the Staphylococcal Cell Wall for Expansion Microscopy JF - Frontiers in Cellular and Infection Microbiology N2 - Expansion Microscopy (ExM) is a novel tool improving the resolution of fluorescence microscopy by linking the sample into a hydrogel that gets physically expanded in water. Previously, we have used ExM to visualize the intracellular Gram-negative pathogens Chlamydia trachomatis, Simkania negevensis, and Neisseria gonorrhoeae. Gram-positive bacteria have a rigid and thick cell wall that impedes classic expansion strategies. Here we developed an approach, which included a series of enzymatic treatments resulting in isotropic 4× expansion of the Gram-positive pathogen Staphylococcus aureus. We further demonstrate the suitability of the technique for imaging of planktonic bacteria as well as endocytosed, intracellular bacteria at a spatial resolution of approximately 60 nm with conventional confocal laser scanning microscopy. KW - high-resolution imaging KW - endosomes KW - autophagosomes KW - host-pathogen interaction KW - expansion microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232292 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Müller, Diana A1 - Bessi, Irene A1 - Richter, Christian A1 - Schwalbe, Harald T1 - The Folding Landscapes of Human Telomeric RNA and DNA G‐Quadruplexes are Markedly Different JF - Angewandte Chemie International Edition N2 - We investigated the folding kinetics of G‐quadruplex (G4) structures by comparing the K\(^{+}\)‐induced folding of an RNA G4 derived from the human telomeric repeat‐containing RNA (TERRA25) with a sequence homologous DNA G4 (wtTel25) using CD spectroscopy and real‐time NMR spectroscopy. While DNA G4 folding is biphasic, reveals kinetic partitioning and involves kinetically favoured off‐pathway intermediates, RNA G4 folding is faster and monophasic. The differences in kinetics are correlated to the differences in the folded conformations of RNA vs. DNA G4s, in particular with regard to the conformation around the glycosidic torsion angle χ that uniformly adopts anti conformations for RNA G4s and both, syn and anti conformation for DNA G4s. Modified DNA G4s with \(^{19}\)F bound to C2′ in arabino configuration adopt exclusively anti conformations for χ. These fluoro‐modified DNA (antiTel25) reveal faster folding kinetics and monomorphic conformations similar to RNA G4s, suggesting the correlation between folding kinetics and pathways with differences in χ angle preferences in DNA and RNA, respectively. KW - folding landscapes KW - G-quadruplexes KW - kinetics KW - real-time NMR spectroscopy KW - TERRA RNA Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238917 VL - 60 IS - 19 SP - 10895 EP - 10901 ER - TY - JOUR A1 - Borges, Alyssa R. A1 - Link, Fabian A1 - Engstler, Markus A1 - Jones, Nicola G. T1 - The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids JF - Frontiers in Cell and Developmental Biology N2 - The use of glycosylphosphatidylinositol (GPI) to anchor proteins to the cell surface is widespread among eukaryotes. The GPI-anchor is covalently attached to the C-terminus of a protein and mediates the protein’s attachment to the outer leaflet of the lipid bilayer. GPI-anchored proteins have a wide range of functions, including acting as receptors, transporters, and adhesion molecules. In unicellular eukaryotic parasites, abundantly expressed GPI-anchored proteins are major virulence factors, which support infection and survival within distinct host environments. While, for example, the variant surface glycoprotein (VSG) is the major component of the cell surface of the bloodstream form of African trypanosomes, procyclin is the most abundant protein of the procyclic form which is found in the invertebrate host, the tsetse fly vector. Trypanosoma cruzi, on the other hand, expresses a variety of GPI-anchored molecules on their cell surface, such as mucins, that interact with their hosts. The latter is also true for Leishmania, which use GPI anchors to display, amongst others, lipophosphoglycans on their surface. Clearly, GPI-anchoring is a common feature in trypanosomatids and the fact that it has been maintained throughout eukaryote evolution indicates its adaptive value. Here, we explore and discuss GPI anchors as universal evolutionary building blocks that support the great variety of surface molecules of trypanosomatids. KW - cell surface proteome KW - evolution KW - GPI-anchor KW - Kinetoplastea Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249253 SN - 2296-634X VL - 9 ER - TY - RPRT A1 - Neubert, Dieter T1 - The Hidden Side of Local Self-Organisation and Self-Regulation. Elements for the Comparative Analysis of the Constitution of Self-Organised Groups T1 - Die verborgene Seite von Selbstorganisation und Selbst-regulierung. Elemente für die vergleichende Analyse der Konstituierung von selbstorganisierten Gruppen N2 - The notions self-organisation and self-regulation are at least implicitly loaded with a positive democratic connotation. The main corresponding debates on social movements, governance and civil society mostly refer to the Global North with a well-functioning state and democratic political systems. One consequence is that the less democratic and less liberal hidden side of self-organisation, seen by some critics, does not gain much attention. After a short discussion of the main theoretical approaches, the paper presents a selection of self-organised groups depicting their different values, norms, and structural features. These examples reach from democratic groups marked by solidarity to racist violent groups that are a threat to differently minded people. The analysis of these examples leads to a set of criteria for the comparative analysis of the internal structure of self-organised groups including potential membership, in- and outward orientation, underlying basic principles of social order and types of trust with related types of decision-making. These basic elements help to understand the constitution and functioning of self-organisation, which are open to a wide range of value orientation. N2 - Die Begriffe Selbstorganisation und Selbstregulierung sind zumindest implizit positiv konnotiert. Die entsprechenden Debatten zu sozialen Bewegungen, Governance und Zivilgesellschaft beziehen sich zumeist auf den Globalen Norden mit einem gut funktionierenden Staat und demokratischen politischen Systemen. Eine Folge davon ist, dass die weniger demokratische und weniger liberale verborgene Seite von Selbstor-ganisation, die durchaus von einigen kritischen Stimmen gesehen wird, auf recht wenig Interesse stößt. Nach einer kurzen Diskussion wichtiger theoretischer Ansätze, präsentiert der Beitrag eine Auswahl selbstorganisierter Gruppen und stellt ihre Werte, Normen und struktu-rellen Eigenheiten dar. Diese Beispiele reichen von demokratischen von Solidarität geprägten Gruppen bis hin zu gewalttätigen Gruppen, die eine Bedrohung für Andersdenkende sind. Die Analyse dieser Beispiele führt zu Kriterien für die vergleichende Analyse der internen Strukturen von selbstorganisierten Gruppen einschließlich ihrer potenziellen Mitgliedschaft, Innen- und Außenorientierung, grundlegenden Prinzipien der sozialen Ordnung und Typen von Vertrauen und damit verbundenen Typen der Entscheidungsfindung. Die grundlegenden Elemente helfen die Konstitution und Funktionsweise von Selbstorganisation zu verstehen, die ein breites Spektrum von Werteorientierungen umfassen können. T3 - LoSAM Working Papers - 6 KW - Selbstorganisation KW - Konstituierung KW - Regulierung KW - self-organized groups KW - hidden side KW - constitution KW - self-regulation KW - local self-governance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251493 ER - TY - JOUR A1 - Höhne, Christin A1 - Prokopov, Dmitry A1 - Kuhl, Heiner A1 - Du, Kang A1 - Klopp, Christophe A1 - Wuertz, Sven A1 - Trifonov, Vladimir A1 - Stöck, Matthias T1 - The immune system of sturgeons and paddlefish (Acipenseriformes): a review with new data from a chromosome‐scale sturgeon genome JF - Reviews in Aquaculture N2 - Sturgeon immunity is relevant for basic evolutionary and applied research, including caviar‐ and meat‐producing aquaculture, protection of wild sturgeons and their re‐introduction through conservation aquaculture. Starting from a comprehensive overview of immune organs, we discuss pathways of innate and adaptive immune systems in a vertebrate phylogenetic and genomic context. The thymus as a key organ of adaptive immunity in sturgeons requires future molecular studies. Likewise, data on immune functions of sturgeon‐specific pericardial and meningeal tissues are largely missing. Integrating immunological and endocrine functions, the sturgeon head kidney resembles that of teleosts. Recently identified pattern recognition receptors in sturgeon require research on downstream regulation. We review first acipenseriform data on Toll‐like receptors (TLRs), type I transmembrane glycoproteins expressed in membranes and endosomes, initiating inflammation and host defence by molecular pattern‐induced activation. Retinoic acid‐inducible gene‐I‐like (RIG‐like) receptors of sturgeons present RNA and key sensors of virus infections in most cell types. Sturgeons and teleosts share major components of the adaptive immune system, including B cells, immunoglobulins, major histocompatibility complex and the adaptive cellular response by T cells. The ontogeny of the sturgeon innate and onset of adaptive immune genes in different organs remain understudied. In a genomics perspective, our new data on 100 key immune genes exemplify a multitude of evolutionary trajectories after the sturgeon‐specific genome duplication, where some single‐copy genes contrast with many duplications, allowing tissue specialization, sub‐functionalization or both. Our preliminary conclusion should be tested by future evolutionary bioinformatics, involving all >1000 immunity genes. This knowledge update about the acipenseriform immune system identifies several important research gaps and presents a basis for future applications. KW - evolution KW - genomics KW - immune genes KW - immune organs KW - immune system KW - sturgeon Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239865 VL - 13 IS - 3 SP - 1709 EP - 1729 ER - TY - JOUR A1 - Kurz, Anja A1 - Zanzinger, Maren A1 - Hagen, Rudolf A1 - Rak, Kirsten T1 - The impact of cochlear implant microphone settings on the binaural hearing of experienced cochlear implant users with single sided deafness JF - European Archives of Oto-Rhino-Laryngology N2 - Objective Cochlear implantation has become a well-accepted treatment option for people with single-sided deafness (SSD) and has become a clinical standard in many countries. A cochlear implant (CI) is the only device which restores binaural hearing. The effect of microphone directionality (MD) settings has been investigated in other CI indication groups, but its impact on speech perception in noise has not been established in CI users with SSD. The focus of this investigation was, therefore, to assess binaural hearing effects using different MD settings in CI users with SSD. Methods Twenty-nine experienced CI users with SSD were recruited to determine speech reception thresholds with varying target and noise sources to define binaural effects (head shadow, squelch, summation, and spatial release from masking), sound localization, and sound quality using the SSQ12 and HISQUI19 questionnaires. Outcome measures included the MD settings “natural”, “adaptive”, and “omnidirectional”. Results The 29 participants involved in the study were divided into two groups: 11 SONNET users and 18 OPUS 2/RONDO users. In both groups, a significant head shadow effect of 7.4–9.2 dB was achieved with the CI. The MD setting “adaptive” provided a significant head shadow effect of 9.2 dB, a squelch effect of 0.9 dB, and spatial release from masking of 7.6 dB in the SONNET group. No significant summation effect could be determined in either group with CI. Outcomes with the omnidirectional setting were not significantly different between groups. For both groups, localization improved significantly when the CI was activated and was best when the omnidirectional setting was used. The groups’ sound quality scores did not significantly differ. Conclusions Adaptive directional microphone settings improve speech perception and binaural hearing abilities in CI users with SSD. Binaural effect measures are valuable to quantify the benefit of CI use, especially in this indication group. KW - single-sided deafness KW - cochlear implant KW - adaptive directional microphone setting KW - questionnaire Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231750 SN - 0937-4477 ET - corrected version ER - TY - THES A1 - Peters, Simon T1 - The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity T1 - Einfluss von Sphingolipiden auf \(Neisseria\) \(meningitidis\) und deren Bedeutung für die Pathogenität N2 - The obligate human pathogen Neisseria meningitidis is a major cause of sepsis and meningitis worldwide. It affects mainly toddlers and infants and is responsible for thousands of deaths each year. In this study, different aspects of the importance of sphingolipids in meningococcal pathogenicity were investigated. In a first step, the acid sphingomyelinase (ASM), which degrades membrane sphingomyelin to ceramide, was studied in the context of meningococcal infection. A requirement for ASM surface activity is its translocation from the lysosomal compartment to the cell surface, a process that is currently poorly understood. This study used various approaches, including classical invasion and adherence assays, flow cytometry, and classical and super resolution immunofluorescence microscopy (dSTORM). The results showed that the live, highly piliated N. meningitidis strain 8013/12 induced calcium-dependent ASM translocation in human brain microvascular endothelial cells (HBMEC). Furthermore, it promoted the formation of ceramide-rich platforms (CRPs). In addition, ASM translocation and CRP formation were observed after treating the cells with pili-enriched fractions derived from the same strain. The importance for N. meningitidis to utilize this pathway was shown by the inhibition of the calcium-dependent ASM translocation, which greatly decreased the number of invasive bacteria. I also investigated the importance of the glycosphingolipids GM1 and Gb3. The results showed that GM1, but not Gb3, plays an important role in the ability of N. meningitidis to invade HBMEC. By combining dSTORM imaging and microbiological approaches, we demonstrated that GM1 accumulated prolifically around bacteria during the infection, and that this interaction seemed essential for meningococcal invasion. Sphingolipids are not only known for their beneficial effect on pathogens. Sphingoid bases, including sphingosine, are known for their antimicrobial activity. In the last part of this study, a novel correlative light and electron microscopy approach was established in the combination with click chemistry to precisely localize azido-functionalized sphingolipids in N. meningitidis. The result showed a distinct concentration-dependent localization in either the outer membrane (low concentration) or accumulated in the cytosol (high concentration). This pattern was confirmed by mass spectrometry on separated membrane fractions. Our data provide a first insight into the underlying mechanism of antimicrobial sphingolipids. N2 - Der obligate Humanpathogen Neisseria meningitidis ist weltweit einer der Hauptursachen für Sepsis und Meningitis. Er befällt vor allem Kleinkinder und Säuglinge und ist jedes Jahr für Tausende von Todesfällen verantwortlich. In dieser Studie wurden verschiedene Aspekte der Bedeutung von Sphingolipiden bei der Pathogenität von Meningokokken untersucht. In einem ersten Schritt wurde die saure Sphingomyelinase (ASM), die Membran-Sphingomyelin zu Ceramid abbaut, im Zusammenhang mit einer Meningokokken-Infektion untersucht. Eine Voraussetzung für die Oberflächenaktivität der ASM ist ihre Translokation vom lysosomalen Kompartiment auf die Zelloberfläche, ein Prozess, der derzeit noch wenig verstanden wird. In dieser Studie wurden verschiedene Ansätze verwendet, darunter klassische Invasions- und Adhärenztests, Durchflusszytometrie sowie klassische und superauflösende Immunfluoreszenzmikroskopie (dSTORM). Die Ergebnisse zeigten, dass der lebende, hochpiliatisierte N. meningitidis Stamm 8013/12 eine kalziumabhängige ASM-Translokation in mikrovaskulären Endothelzellen des menschlichen Gehirns (HBMEC) induzierte. Des Weiteren förderte er die Bildung Ceramid-reicher Plattformen (CRPs). Zusätzlich wurden ASM-Translokation und CRP-Bildung beobachtet, nachdem die Zellen mit pili-angereicherten Fraktionen desselben Stammes behandelt worden waren. Die Bedeutung für N. meningitidis in der Pathogenese zeigte sich durch die Hemmung der Calcium-abhängigen ASM-Translokation, wodurch die Zahl der invasiven Bakterien stark reduziert wurde. Ich untersuchte auch die Bedeutung der Glykosphingolipide GM1 und Gb3. Die Ergebnisse zeigten, dass GM1, aber nicht Gb3, eine wichtige Rolle bei der Fähigkeit von N. meningitidis spielt, in Gehirnendothelzellen einzudringen. Durch die Kombination von dSTORM-Bildgebung und mikrobiologischen Ansätzen konnten wir zeigen, dass sich GM1 während der Infektion vermehrt um die Bakterien herum anreicherte und dass diese Interaktion für die Invasion von Meningokokken essenziell ist. Sphingolipide sind nicht nur für ihre positive Wirkung auf Krankheitserreger bekannt. Sphingoidbasen, einschließlich Sphingosin, sind zusätzlich für ihre antimikrobielle Aktivität bekannt. Im letzten Teil dieser Studie wurde ein neuartiger korrelativer licht- und elektronenmikroskopischer Ansatz in der Kombination mit Click-Chemie etabliert, um azidofunktionalisierte Sphingolipide in N. meningitidis genau zu lokalisieren. Das Ergebnis zeigte eine deutliche konzentrationsabhängige Lokalisation entweder in der äußeren Membran (niedrige Konzentration) oder akkumuliert im Zytosol (hohe Konzentration). Dieses Muster konnte durch einen Massenspektrometrischen Ansatz bestätigt werden. Hierfür wurde eine Separation der inneren und äußeren Membran, nach Behandlung mit der niedrigen Konzentration, etabliert. Die verschiedenen Membranfraktionen wurden anschließend auf ihren Gehalt an funktionalisierten Sphingolipiden hin untersucht und bestätigten die lokalisierung in der äußeren Membran. Unsere Daten geben einen ersten Einblick in den zugrundeliegenden Mechanismus der antimikrobiellen Sphingolipide. KW - Neisseria meningitidis KW - Sphingolipide KW - Infektion KW - Pathogenität KW - host-pathogen interaction KW - antimicrobial Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226233 ER - TY - JOUR A1 - Barrea, Luigi A1 - Vetrani, Claudia A1 - Altieri, Barbara A1 - Verde, Ludovica A1 - Savastano, Silvia A1 - Colao, Annamaria A1 - Muscogiuri, Giovanna T1 - The importance of being a ‘lark’ in post-menopausal women with obesity: a ploy to prevent type 2 diabetes mellitus? JF - Nutrients N2 - Chronotype is defined as the behavioral manifestation of circadian rhythms related to the external light–dark cycle. Evening chronotype has been associated with an increased risk of developing cardiometabolic diseases in obesity. Menopause is a lifestage associated with an increased risk of developing cardiometabolic diseases and a change in circadian rhythmicity compared to pre-menopause. However, the prevalence of chronotype categories in menopause and their role in determining menopause-related cardiometabolic risk, mostly in obesity, have not been investigated. Thus, we aimed to investigate the prevalence of chronotype categories in post-menopausal women with obesity and their role in menopause-related cardiometabolic risk. In this cross-sectional study we enrolled 49 pre-menopausal and 74 post-menopausal women with obesity. Anthropometric parameters, lifestyle habits, adherence to the Mediterranean Diet (MD), sleep quality, chronotype and the presence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) were studied. No significance differences were detected in terms of lifestyle and adherence to the MD between pre- and post-menopausal women. Chronotype was classified as morning in 66 (53.6%), evening in 20 (16.3%) and intermediate in 37 (30.1%) women. In addition, pre-menopausal women with obesity showed a significantly higher chance to have an intermediate chronotype (OR = 2.21, 95% CI 1.28–3.83; p = 0.004), whereas post-menopausal women with obesity showed a trend to have a higher morning chronotype (OR = 1.42, 95% CI 0.98–2.06; p = 0.051), although this did not reach statistical significance. No significant differences were detected in terms of prevalence of evening chronotype between the two groups. However, the evening chronotype had a significantly higher risk to have T2DM compared to the morning (OR = 17.29, 95% CI 2.40–124.27; p = 0.005) and intermediate chronotypes (OR = 30.86, 95% CI 2.05–464.32; p = 0.013) in both pre- and post-menopausal women with obesity. In conclusion, the intermediate chronotype was significantly more prevalent in pre-menopausal women with obesity compared to post-menopausal women. Evening chronotype was associated to T2DM in both pre- and post-menopause. These results support the importance of including the assessment of chronotype in the management of women with obesity in post-menopause. KW - chronotype KW - circadian rhythms KW - menopause KW - obesity KW - type 2 diabetes KW - cardiovascular diseases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248572 SN - 2072-6643 VL - 13 IS - 11 ER - TY - JOUR A1 - Ibebuchi, Chibuike Chiedozie A1 - Paeth, Heiko T1 - The Imprint of the Southern Annular Mode on Black Carbon AOD in the Western Cape Province JF - Atmosphere N2 - This study examines the relationship between variations of the Southern Annular Mode (SAM) and black carbon (BC) at 550 nm aerosol optical depth (AOD) in the Western Cape province (WC). Variations of the positive (negative) phase of the SAM are found to be related to regional circulation types (CTs) in southern Africa, associated with suppressed (enhanced) westerly wind over the WC through the southward (northward) migration of Southern Hemisphere mid-latitude cyclones. The CTs related to positive (negative) SAM anomalies induce stable (unstable) atmospheric conditions over the southwestern regions of the WC, especially during the austral winter and autumn seasons. Through the control of CTs, positive (negative) SAM phases tend to contribute to the build-up (dispersion and dilution) of BC in the study region because they imply dry (wet) conditions which favor the build-up (washing out) of pollutant particles in the atmosphere. Indeed, recent years with an above-average frequency of CTs related to positive (negative) SAM anomalies are associated with a high (low) BC AOD over southwesternmost Africa. KW - black carbon AOD KW - Western Cape KW - southern annular mode KW - circulation type KW - air quality Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248387 SN - 2073-4433 VL - 12 IS - 10 ER - TY - JOUR A1 - Unruh, Fabian A1 - Landeck, Maximilian A1 - Oberdörfer, Sebastian A1 - Lugrin, Jean-Luc A1 - Latoschik, Marc Erich T1 - The Influence of Avatar Embodiment on Time Perception - Towards VR for Time-Based Therapy JF - Frontiers in Virtual Reality N2 - Psycho-pathological conditions, such as depression or schizophrenia, are often accompanied by a distorted perception of time. People suffering from this conditions often report that the passage of time slows down considerably and that they are “stuck in time.” Virtual Reality (VR) could potentially help to diagnose and maybe treat such mental conditions. However, the conditions in which a VR simulation could correctly diagnose a time perception deviation are still unknown. In this paper, we present an experiment investigating the difference in time experience with and without a virtual body in VR, also known as avatar. The process of substituting a person’s body with a virtual body is called avatar embodiment. Numerous studies demonstrated interesting perceptual, emotional, behavioral, and psychological effects caused by avatar embodiment. However, the relations between time perception and avatar embodiment are still unclear. Whether or not the presence or absence of an avatar is already influencing time perception is still open to question. Therefore, we conducted a between-subjects design with and without avatar embodiment as well as a real condition (avatar vs. no-avatar vs. real). A group of 105 healthy subjects had to wait for seven and a half minutes in a room without any distractors (e.g., no window, magazine, people, decoration) or time indicators (e.g., clocks, sunlight). The virtual environment replicates the real physical environment. Participants were unaware that they will be asked to estimate their waiting time duration as well as describing their experience of the passage of time at a later stage. Our main finding shows that the presence of an avatar is leading to a significantly faster perceived passage of time. It seems to be promising to integrate avatar embodiment in future VR time-based therapy applications as they potentially could modulate a user’s perception of the passage of time. We also found no significant difference in time perception between the real and the VR conditions (avatar, no-avatar), but further research is needed to better understand this outcome. KW - virtual reality KW - time perception KW - avatar embodiment KW - immersion KW - human computer interaction (HCI) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259076 VL - 2 ER - TY - JOUR A1 - Breves, Priska A1 - Dodel, Nicola T1 - The influence of cybersickness and the media devices’ mobility on the persuasive effects of 360° commercials JF - Multimedia Tools and Applications N2 - With the rise of immersive media, advertisers have started to use 360° commercials to engage and persuade consumers. Two experiments were conducted to address research gaps and to validate the positive impact of 360° commercials in realistic settings. The first study (N = 62) compared the effects of 360° commercials using either a mobile cardboard head-mounted display (HMD) or a laptop. This experiment was conducted in the participants’ living rooms and incorporated individual feelings of cybersickness as a moderator. The participants who experienced the 360° commercial with the HMD reported higher spatial presence and product evaluation, but their purchase intentions were only increased when their reported cybersickness was low. The second experiment (N = 197) was conducted online and analyzed the impact of 360° commercials that were experienced with mobile (smartphone/tablet) or static (laptop/desktop) devices instead of HMDs. The positive effects of omnidirectional videos were stronger when participants used mobile devices. KW - virtual reality KW - immersive advertising KW - spatial presence KW - cybersickness KW - advertising effectiveness Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269194 SN - 1573-7721 VL - 80 IS - 18 ER - TY - JOUR A1 - Rodrigues, Johannes A1 - Marzban, Dorna A1 - Hewig, Johannes T1 - The influence of mental imagery expertise of pen and paper players versus computer gamers upon performance and electrocortical correlates in a difficult mental rotation task JF - Symmetry N2 - We investigated the influence of mental imagery expertise in 15 pen and paper role-players as an expert group compared to the gender-matched control group of computer role-players in the difficult Vandenberg and Kuse mental rotation task. In this task, the participants have to decide which two of four rotated figures match the target figure. The dependent measures were performance speed and accuracy. In our exploratory investigation, we further examined midline frontal theta band activation, parietal alpha band activation, and parietal alpha band asymmetry in EEG as indicator for the chosen rotation strategy. Additionally, we explored the gender influence on performance and EEG activation, although a very small female sample section was given. The expected gender difference concerning performance accuracy was negated by expertise in pen and paper role-playing women, while the gender-specific difference in performance speed was preserved. Moreover, gender differences concerning electro-cortical measures revealed differences in rotation strategy, with women using top-down strategies compared to men, who were using top-down strategies and active inhibition of associative cortical areas. These strategy uses were further moderated by expertise, with higher expertise leading to more pronounced activation patters, especially during successful performance. However, due to the very limited sample size, the findings of this explorative study have to be interpreted cautiously. KW - mental rotation KW - expertise in visual imagery KW - pen and paper vs. computer role-players KW - midline frontal theta band frequency activation KW - parietal alpha band frequency activation KW - gender influence KW - EEG Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252253 SN - 2073-8994 VL - 13 IS - 12 ER - TY - JOUR A1 - Kleih-Dahms, Sonja Christina A1 - Botrel, Loic A1 - Kübler, Andrea T1 - The influence of motivation and emotion on sensorimotor rhythm-based brain-computer interface performance JF - Psychophysiology N2 - While decades of research have investigated and technically improved brain–computer interface (BCI)-controlled applications, relatively little is known about the psychological aspects of brain–computer interfacing. In 35 healthy students, we investigated whether extrinsic motivation manipulated via monetary reward and emotional state manipulated via video and music would influence behavioral and psychophysiological measures of performance with a sensorimotor rhythm (SMR)-based BCI. We found increased task-related brain activity in extrinsically motivated (rewarded) as compared with nonmotivated participants but no clear effect of emotional state manipulation. Our experiment investigated the short-term effect of motivation and emotion manipulation in a group of young healthy subjects, and thus, the significance for patients in the locked-in state, who may be in need of a BCI, remains to be investigated. KW - brain-computer interface KW - sensorimotor rhythm KW - psychological variables KW - motivation KW - emotional state KW - electroencephalogram Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259664 VL - 58 IS - 8 ER - TY - THES A1 - Mokay-Rinke, Shiloe Marie T1 - The Integration of Female Refugees in Germany: Perspectives of Women and an Analysis of Federal and Selected State and City Integration Policies from 1998 to 2019 T1 - Die Integration geflüchteter Frauen in Deutschland: Sichtweisen der Betroffenen und eine Analyse der Integrationspolitik des Bundes und ausgewählter Bundesländer und Städte zwischen 1998 und 2019 N2 - The following study, The Integration of Female Refugees in Germany: Perspectives of Women and an Analysis of Federal and Selected State and City Integration Policies from 1998-2019, is focused on the qualitative analysis of integration policy in Germany regarding female refugees. The states of North Rhine-Westphalia, Bavaria, and Saxony-Anhalt have been selected for this dissertation as well as the cities of Cologne, Wuerzburg, and Magdeburg. Through an analysis and comparison of integration policies and programs on the federal and selected state and city levels the question will be answered how recognized female refugees are taken into account with the development and formulation of integration policy in Germany. The analysis is then complemented through interviews with recognized female refugees in each of the states and cities. Through analyzing the results of the interviews the question will be answered how the women view their situation and integration. Through a comparison of the findings from the policy analysis and the interviews it will then be able to decipher if integration policies and programs are truly reaching their target group, if they are effective, or what hurdles they may be producing. The goal of the study is to provide initial findings on the overall integration of recognized female refugees in Germany in connection to integration policies in order to discover potential deficits or ineffective programs and policies which can then be further researched in order to produce concrete policy suggestions. N2 - Die vorliegende Arbeit – Die Integration geflüchteter Frauen in Deutschland: Sichtweisen der Betroffenen und eine Analyse der Integrationspolitik des Bundes und ausgewählter Bundesländer und Städte zwischen 1998 und 2019 – analysiert qualitativ die Integrationspolitik Deutschlands bezüglich geflüchteter Frauen. Neben der Bundesebene wurden für eine Analyse auf Landesebene Nordrhein-Westfalen, Bayern und Sachsen-Anhalt sowie auf kommunaler Ebene Köln, Würzburg und Magdeburg beispielhaft untersucht. Durch diesen Vergleich von Gesetzen, Richtlinien und Programmen wird die Frage beantwortet, wie anerkannte geflüchtete Frauen und deren Perspektive bei der Ausgestaltung von Integrationsstrategien berücksichtigt werden. Die Analyse wird vervollständigt durch die Ergebnisse von Interviews mit anerkannten geflüchteten Frauen in den untersuchten Städten und Bundesländern. Dadurch wird die Frage beantwortet, wie die Betroffenen selbst ihren Integrationserfolg und ihre derzeitige Situation einschätzen. Durch einen Vergleich der Ergebnisse der Analyse der Integrationspolitik und der Ergebnisse der Interviews wird dann eine Einschätzung ermöglicht, inwiefern die Ansätze der Integrationspolitik tatsächlich den Bedürfnissen der Zielgruppe entsprechen, ob sie effektiv sind oder welche Schwierigkeiten sie den Betroffenen bereiten können. Das Ziel der vorliegenden Arbeit ist es, erste Einblicke zu gewinnen darüber, wie ziel- oder irreführend die bisherigen Ansätze und Richtlinien für die Integration anerkannter geflüchteter Frauen sind. Darauf aufbauend könnten folgende Studien sich verstärkt mit dem Thema beschäftigen, um letztendlich konkrete Vorschläge für eine effektivere Integrationspolitik hervorbringen zu können. KW - Organisation KW - Integration KW - Refugees KW - Female Refugees KW - Integration Policy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243047 ER - TY - JOUR A1 - Petruseva, Irina A1 - Naumenko, Natalia A1 - Kuper, Jochen A1 - Anarbaev, Rashid A1 - Kappenberger, Jeannette A1 - Kisker, Caroline A1 - Lavrik, Olga T1 - The Interaction Efficiency of XPD-p44 With Bulky DNA Damages Depends on the Structure of the Damage JF - Frontiers in Cell and Developmental Biology N2 - The successful elimination of bulky DNA damages via the nucleotide excision repair (NER) system is largely determined by the damage recognition step. This step consists of primary recognition and verification of the damage. The TFIIH helicase XPD plays a key role in the verification step during NER. To date, the mechanism of damage verification is not sufficiently understood and requires further detailed research. This study is a systematic investigation of the interaction of ctXPD (Chaetomium thermophilum) as well as ctXPD-ctp44 with model DNAs, which contain structurally different bulky lesions with previously estimated NER repair efficiencies. We have used ATPase and DNA binding studies to assess the interaction of ctXPD with damaged DNA. The result of the analysis of ctXPD-ctp44 binding to DNA containing fluorescent and photoactivatable lesions demonstrates the relationship between the affinity of XPD for DNAs containing bulky damages and the ability of the NER system to eliminate the damage. Photo-cross-linking of ctXPD with DNA probes containing repairable and unrepairable photoactivatable damages reveals differences in the DNA interaction efficiency in the presence and absence of ctp44. In general, the results obtained indicate the ability of ctXPD-ctp44 to interact with a damage and suggest a significant role for ctp44 subunit in the verification process. KW - nucleotide excision repair KW - XPD helicase KW - DNA damage KW - protein-DNA interaction KW - bulky damages recognition KW - photo-cross-linking Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231806 SN - 2296-634X VL - 9 ER - TY - JOUR A1 - Budde, Heidi A1 - Hassoun, Roua A1 - Tangos, Melina A1 - Zhazykbayeva, Saltanat A1 - Herwig, Melissa A1 - Varatnitskaya, Marharyta A1 - Sieme, Marcel A1 - Delalat, Simin A1 - Sultana, Innas A1 - Kolijn, Detmar A1 - Gömöri, Kamilla A1 - Jarkas, Muhammad A1 - Lódi, Mária A1 - Jaquet, Kornelia A1 - Kovács, Árpád A1 - Mannherz, Hans Georg A1 - Sequeira, Vasco A1 - Mügge, Andreas A1 - Leichert, Lars I. A1 - Sossalla, Samuel A1 - Hamdani, Nazha T1 - The interplay between S-glutathionylation and phosphorylation of cardiac troponin I and myosin binding protein C in end-stage human failing hearts JF - Antioxidants N2 - Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca\(^{2+}\)-activated tension and Ca\(^{2+}\) sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca\(^{2+}\) sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure. KW - myofilament proteins KW - oxidative stress KW - inflammation KW - phosphorylation KW - S-glutathionylation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242701 SN - 2076-3921 VL - 10 IS - 7 ER - TY - JOUR A1 - Avota, Elita A1 - Bodem, Jochen A1 - Chithelen, Janice A1 - Mandasari, Putri A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - The Manifold Roles of Sphingolipids in Viral Infections JF - Frontiers in Physiology N2 - Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach. KW - sphingolipid KW - ceramide KW - sphingosine-1-phosphate KW - plasma membrane KW - virus entry KW - virus replication KW - virus budding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246975 SN - 1664-042X VL - 12 ER - TY - JOUR A1 - Paudel, Rupesh A1 - Fusi, Lorenza A1 - Schmidt, Marc T1 - The MEK5/ERK5 pathway in health and disease JF - International Journal of Molecular Sciences N2 - The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway. KW - atherosclerosis KW - bone KW - cartilage KW - endothelium KW - extracellular-regulated kinase 5 KW - Krüppel-like factor KW - mechanotransduction KW - mitogen-activated protein kinase KW - stress signaling KW - tumor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261638 SN - 1422-0067 VL - 22 IS - 14 ER - TY - JOUR A1 - Sian-Hulsmann, Jeswinder A1 - Riederer, Peter T1 - The nigral coup in Parkinson's Disease by α-synuclein and its associated rebels JF - Cells N2 - The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder. KW - Parkinson's disease KW - substantia nigra KW - alpha-synuclein KW - genetics KW - iron KW - neuroinflammation KW - viruses KW - immunology KW - aging and cell death Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234073 SN - 2073-4409 VL - 10 IS - 3 ER - TY - JOUR A1 - Meir, Michael A1 - Maurus, Katja A1 - Kuper, Jochen A1 - Hankir, Mohammed A1 - Wardelmann, Eva A1 - Rosenwald, Andreas A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis, and seminoma development JF - Genes, Chromosomes & Cancer N2 - Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations. KW - germline mutation KW - GIST KW - KIT KW - mastocytosis KW - seminoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257476 VL - 60 IS - 12 ER - TY - JOUR A1 - Bakari-Soale, Majeed A1 - Ikenga, Nonso Josephat A1 - Scheibe, Marion A1 - Butter, Falk A1 - Jones, Nicola G. A1 - Kramer, Susanne A1 - Engstler, Markus T1 - The nucleolar DExD/H protein Hel66 is involved in ribosome biogenesis in Trypanosoma brucei JF - Scientific Reports N2 - The biosynthesis of ribosomes is a complex cellular process involving ribosomal RNA, ribosomal proteins and several further trans-acting factors. DExD/H box proteins constitute the largest family of trans-acting protein factors involved in this process. Several members of this protein family have been directly implicated in ribosome biogenesis in yeast. In trypanosomes, ribosome biogenesis differs in several features from the process described in yeast. Here, we have identified the DExD/H box helicase Hel66 as being involved in ribosome biogenesis. The protein is unique to Kinetoplastida, localises to the nucleolus and its depletion via RNAi caused a severe growth defect. Loss of the protein resulted in a decrease of global translation and accumulation of rRNA processing intermediates for both the small and large ribosomal subunits. Only a few factors involved in trypanosome rRNA biogenesis have been described so far and our findings contribute to gaining a more comprehensive picture of this essential process. KW - infection KW - parasite evolution KW - parasite genetics KW - RNA Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-263872 VL - 11 IS - 1 ER - TY - JOUR A1 - Eissler, Cristoph A1 - Werner, Rudolf A. A1 - Arias-Loza, Paula A1 - Nose, Naoko A1 - Chen, Xinyu A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Lapa, Constantin A1 - Buck, Andreas K. A1 - Higuchi, Takahiro T1 - The number of frames on ECG-gated \(^{18}\)F-FDG small animal PET has a significant impact on LV systolic and diastolic functional parameters JF - Molecular Imaging N2 - Objectives. This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods. \(^{18}\)F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results. Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 & PLUSMN; 57.7 mu l*, 380.8 & PLUSMN; 57.2 mu l*, 398.0 & PLUSMN; 63.1 mu l*, and 444.8 & PLUSMN; 75.3 mu l at 4, 8, 12, and 16 frames, respectively; *P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames. Conclusions. Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used. KW - Myocardial-perfusion SPECT KW - left-ventricular function KW - ejection fraction KW - MRI Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265778 VL - 2021 ER - TY - JOUR A1 - Luraghi, Silvia A1 - Inglese, Guglielmo A1 - Kölligan, Daniel T1 - The passive voice in ancient Indo-European languages: inflection, derivation, periphrastic verb forms JF - Folia Linguistica N2 - The IE languages developed different strategies for the encoding of the passive function. In some language branches, the middle voice extended to the passive function to varying extents. In addition, dedicated derivational formations arose in a number of languages, such as the Greek -ē-/-thē- aorist and the Indo-Aryan -ya-presents. Periphrastic formations involving a verbal adjective or a participle are also widely attested, and played an important role in the building of the passive paradigm in e.g. Romance and Germanic languages. As the periphrastic passive is also attested in Hittite alongside passive use of the middle, both strategies seem to be equally ancient. Some minor strategies include lexical passives and the extensive lability of verbs. A survey of possible strategies provides evidence for the rise of a disparate number of morphemes and constructions, and for their ongoing incorporation into the inflectional paradigms (paradigmaticization) of given languages, thus adding to our knowledge about cross-linguistic sources of passive morphology and grammaticalization processes involved. KW - ancient Indo-European languages KW - derivation KW - inflection KW - middle voice KW - passive KW - periphrastic forms Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-247034 SN - 0165-4004 SN - 1614-7308 VL - 55 IS - s42-s2 SP - 339 EP - 391 ER - TY - THES A1 - Hartmannsberger, Beate T1 - The pathogenicity and origin of auto-antibodies in chronic inflammatory demyelinating polyradiculoneuropathy and the identification of cutaneous biomarkers in Charcot-Marie-Tooth 1A patients T1 - Die Pathogenität und Herkunft von Auto-Antikörpern bei chronisch inflammatorischer demyelinisierender Polyradikuloneuropathie und die Identifikation von Biomarkern in Haut von Charcot-Marie-Tooth 1A Patienten N2 - Peripheral neuropathies can severely affect patients. Causes for the disease are diverse but can be classified into two main groups, acquired and hereditary. Examples for these two types are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type 1A (CMT1A). CIDP has an estimated prevalence of about 1-9:100 000. In this pathogenetically hetereo- geneous patient group about 5-10% show auto-antibodies against the node of Ranvier and present with distinct symptoms. Treatment with rituximab - a monoclonal antibody that deletes CD20 + B cells - has been shown to be effective in a majority of auto-antibody as- sociated CIDP cases. This suggests that B cells and the produced auto-antibodies might be pathogenic. Previous studies delivered evidence that auto-antibodies alone can induce nerve damage. In this study, the aim was to investigate the pathomechanism of auto-antibodies in vivo and their exact origin: For the analysis of the pathogenicity of auto-antibodies, passive transfer experiments on Lewis rats were performed with whole IgG from a patient with anti-contactin-1 (CNTN1) IgG4 auto-antibodies. IgG was infused through an intrathe- cal catheter targeting the thoracic/lumbar region of the spine over a long-term, 3-week period. In a previous study of our group, the IgG from the same patient has been re- ported to have mild pathogenic effects when applied intraneurally into the sciatic nerve of Lewis rats. In this study however, binding of auto-antibodies to nerve roots could not be detected. Neither evaluation of electrophysiological properties after the injection period nor motor and sensory skills tested throughout the injection period showed differences when compared to animals infused with control IgG. This suggests that in the chronic intrathecal protocol anti-CNTN1 auto-antibodies did not have a pathogenic effect. In peripheral blood, four B cell subsets capable to produce antibodies were previously described: memory B cells, plasmablasts (PBs), B1 cells and CD20 + CD38 hi cells. For the identification of the B cell subsets that produce auto-antibodies, purification and sort protocols as well as an enzyme-linked immuno spot (ELISpot) assay for IgG and IgM were established successfully. Since unstimulated B cell subsets produced very small amounts of IgG and IgM, peripheral blood mononuclear cells (PBMCs) were stimulated with IL-2 and R848 for 72 h prior to sorting. While the memory B cell frequency decreased after stimulation, the frequency of CD20 + CD38 hi cells increased and the overall number of antibody-secreting cells was increased. When stimulating patient PBMCs for 10 days though, detection of anti-neurofascin-155 (NF155) auto-antibodies in supernatants by enzyme-linked immunosorbent assay (ELISA) was possible in two out of three patient samples. Even though cell sorting was feasible after 10 days of stimulation, detection of auto-antibodies could not be accomplished using antigen-specific ELISpot. Although the implementation of the cell sorting and purification protocol was successful, further adjustments of the antigen-specific ELISpot need to be performed. However, we could show that after 10 days of stimulation auto-antibody detection is possible by ELISA which helps to pre-screen if patient PBMC contain auto-reactive B cells. CMT1A has an estimated prevalence of 1:5000 and is caused by a duplication of the peripheral myelin protein 22 kDa (PMP22) gene. Patients suffer from distal weakness and muscle wasting leading even to wheelchair-dependency in some cases. Although different treatment options for CMT1A have been tested in previous clinical trials, none of them have been successful. In this study, the aim was to identify objective and reproducible outcome measures that assess the actual nerve damage in a large cohort of CMT1A patients by analyzing a series of parameters. Glabrous skin samples were collected from 48 CMT1A, 7 CIDP and 16 small fiber neuropathy patients and 45 healthy controls. 40-µm cryosections from the lateral part of the index finger were double-labeled using immunoflu- orescence to investigate cutaneous innervation. The disease severity which was assessed using the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2) and ranged between mild to severe (3-27) correlated with age in CMT1A patients. Furthermore, the intraepidermal nerve fiber density (IENFD) was reduced in CMT1A patients in comparison to controls and correlated negatively with the disease severity. In controls however, the IENFD correlated inversely with age. Meissner corpuscle density tended to be reduced and correlated inversely with age in CMT1A patients. This was not observed in healthy controls though. Compared to controls, Merkel cell density was also reduced in CMT1A, while the fraction of denervated Merkel cell was increased and correlated with age. Further differences were revealed concerning the node of Ranvier. Paranodes were shortened and the fraction of long nodes was decreased in CMT1A patients compared to controls. These data suggest that the IENFD, the Meissner corpuscle and Merkel cell densities are possible candidates for outcome measures as they are associated with disease severity or age of patients. However, a reliable statement about the suitability as a marker for disease progression can not be made in this study since only six CMT1A patients agreed to give a follow-up biopsy two years later. N2 - Polyneuropathien können Patienten schwer betreffen. Krankheitsursachen sind vielfältig, können jedoch in zwei Hauptgruppen unterteilt werden. Sie können erworben oder genetisch bedingt sein. Beispiele für diese zwei Klassen sind die chronisch inflammatorische demyelinisierende Polyradikuloneuropathie (CIDP) und Charcot-Marie-Tooth-Erkrankung Typ 1A (CMT1A). CIDP hat eine geschätzte Häufigkeit von etwa 1-9:100 000. 5-10% der Patienten dieser pathogenetisch heterogenen Gruppe weisen Auto-Antikörper gegen den Ranvier’schen Schnürring auf und zeigen Symptome, die sich von anderen CIDP-Patienten unterscheiden. Es wurde gezeigt, dass die Behandlung mit Rituximab - einem monoklonalen Antiköper, der CD20+ B-Zellen deletiert - bei der Mehrheit der Auto-Antikörper-assoziierten CIDP-Fälle wirksam ist. Das deutet darauf hin, dass B-Zellen und die produzierten Auto-Antikörper pathogenetisch sein könnten. Frühere Studien liefern Beweise, dass Auto-Antikörper allein Nervenschädigungen verursachen können. Ziel dieser Studie war es, den Pathomechanismus der Auto-Antikörper in vivo zu untersuchen und deren genaue Herkunft zu ermitteln: Um die Pathogenität von Auto-Antikörpern zu ermitteln, wurden Passiv-Transfer-Versuche an Lewis Ratten mit Gesamt-IgG einer Patientin mit anti-CNTN1 IgG4 Auto-Antikörpern durchgeführt. Das IgG wurde mittels eines intrathekalen Katheters, der am thorakalen/lumbalen Abschnitt der Wirbelsäule endete, über eine langzeitige, 3-wöchige Zeitspanne injiziert. Eine frühere Studie unserer Arbeitsgruppe hat gezeigt, dass das IgG derselben Patientin milde pathogenetische Effekte hatte, als diese intraneural in den Ischiasnerv von Lewis Ratten appliziert wurden. In dieser Studie jedoch konnten keine Bindungen von Auto-Antikörpern an die Nervenwurzel ermittelt werden. Patienten-Tiere zeigten keine Unterschiede zu Tieren auf, die mit Kontroll-IgG behandelt wurden, weder in der Untersuchung von elektrophysiologischen Eigenschaften nach der Injektionszeit noch bezüglich motorischer und sensorischer Fähigkeiten, die auch während der Injektionszeit getestet wurden. Dies deutet darauf hin, dass anti-CNTN1 Auto-Antikörper keinen pathogenetischen Effekt bei Anwendung des chronischen, intrathekalen Protokolls hatten. In peripherem Blut wurden vier B-Zell-Subgruppen beschrieben, die fähig sind, Antikörper zu produzieren: Gedächtnis-B-Zellen, Plasmablasten, B1-Zellen und CD20+ CD38hi B-Zellen. Um die Auto-Antikörper-produzierenden B-Zell-Subtypen zu identifizieren, wurden Protokolle zur Anreicherung und zum Sortieren sowie zum ELISpot für IgG und IgM erfolgreich etabliert. Da die Produktion von IgG- und IgM-Antikörpern in unstimulierten B-Zell-Subtypen sehr gering war, wurden mononukleäre Zellen des peripheren Blutes (PBMCs, peripheral blood mononuclear cells) mit IL-2 und R848 vor dem Sorten für 72 h stimuliert. Während die Häufigkeit von Gedächtnis-B-Zellen nach der Stimulation abnahm, ist die Häufigkeit von CD20+ CD38hi B-Zellen gestiegen und die Gesamtzahl an Antikörper-sezernierenden Zellen hat zugenommen. Wurden Patienten PBMCs jedoch für 10 Tage stimuliert, konnten Auto-Antikörper in Überständen mittels ELISA in zwei von drei Patientenproben ermittelt werden. Obwohl das Sorten nach 10-tägiger Stimulation immernoch durchführbar war, war die Detektion von Auto-Antikörper durch antigenspezifischen ELISpot nicht erfolgreich. Trotz der gelungenen Etablierung der Anreicherungs- und Sortierungsprotokolle müssen weitere Einstellarbeiten am antigenspezifischen ELISpot-Protokoll vorgenommen werden. Trotzdem konnten wir zeigen, dass die Detektion von Auto-Antikörpern nach 10-tägiger PBMC-Stimulation mittels ELISA möglich ist, was dabei hilft zu ermitteln, ob Patienten-PBMCs auto-reaktive B-Zellen enthalten. CMT1A hat eine geschätzte Häufigkeit von etwa 1:5000 und wird durch eine Duplikation des PMP22-Gens (peripheral myelin protein 22 kDa) verursacht. Patienten leiden unter distaler Schwäche und Muskelschwund, was in manchen Fällen sogar zu Rollstuhlabhängigkeit führen kann. Obwohl verschiedene Behandlungsmöglichkeiten für CMT1A in früheren Studien getestet wurden, ist keine von ihnen erfolgreich gewesen. Das Ziel dieser Studie war es, objektive und reproduzierbare Outcome-Parameter, die den tatsächlichen Nervenschaden bemessen, in einer großen Kohorte von CMT1A-Patienten zu identifizieren, wozu eine Reihe an Parametern analysiert wurde. Von 48 CMT1A-, 7 CIDP- und 16 small fiber neuropathy- Patienten und 45 gesunden Kontrollen wurden unbehaarte Hautproben der lateralen Region des Zeigefingers entnommen. An diesen wurden Doppelfluoreszenzfärbungen vorgenommen, um die kutane Innervation zu untersuchen. Der Krankheitsgrad der CMT1A-Gruppe, der durch den Charcot-Marie-Tooth Neuropathy Score version 2 eingestuft wurde, erstreckte sich von mild bis schwer (3-27) und korrelierte mit dem Alter der Patienten. Zudem war die intraepidermale Nervenfaserdichte (IENFD) reduziert in CMT1A-Patienten im Vergleich mit gesunden Kontrollen und korrelierte invers mit dem Krankheitsgrad der Patienten. In gesunden Kontrollen korrelierte jedoch die IENFD invers mit dem Alter. Die Dichte der Meissner-Körperchen neigte zu Abnahme in CMT1A-Patienten und korrelierte negativ mit deren Alter, was nicht in gesunden Kontrollen beobachtet wurde. Im Vergleich mit gesunden Kontrollen war die Dichte der Merkel-Zellen ebenfalls verringert in CMT1A, während der Anteil von denervierten Merkel-Zellen erhöht war und mit dem Alter korrelierte. Weitere Unterschiede wurden am Ranvier’schen Schnürring festgestellt. Paranodale Regionen waren verkürzt und der Anteil von langen Schnürringen war erhöht in CMT1A-Patienten im Vergleich zu den Kontrollen. Diese Daten deuten darauf hin, dass die IENFD, die Dichten der Meissner-Körperchen und Merkel-Zellen potentielle Kandidaten für Outcome-Parameter sind, da sie entweder mit dem Krankheitsgrad oder dem Alter zusammenhängen. Jedoch kann in dieser Studie keine verlässliche Aussage über die Eignung dieser Parameter als Marker für den Krankheitsfortschritt gemacht werden, da zwei Jahre später nur sechs CMT1A-Patienten zu einer Folgebiopsie eingewilligt haben. KW - CMT1A KW - polyradiculoneuropathy KW - Charcot-Marie-Tooth 1A KW - skin KW - autoantibody KW - skin biopsy KW - B cells KW - CIDP Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211451 ER - TY - THES A1 - Filin, Daniel T1 - The Princes’ War in South Germany 1458-1463 T1 - Der Fürstenkrieg in Süddeutschland (1458-1463) N2 - The Princes’ War in South Germany (1458-1463) was the biggest military collision in the German lands in the middle of the fifteenth century. The most prominent princes of southern Germany participated in this struggle. Due to its significant scope, this conflict provides a valuable case study for achieving a better understanding of the conditions at the heart of the Holy Roman Empire at the sunset of the Middle Ages. The purpose of this study was to fill an existing gap in the modern research literature and provide a comprehensive up-to date monograph on the subject. The study was realized mainly on the basis of archival work and primary sources. Thousands of letters and documents exchanged between the princes, their advisors and the city representatives were carefully studied and analysed. Extensive use of printed sources as well as scientific literature also greatly facilitated this research. The first part of the dissertation provides a detailed description of the war itself and the events that led to it. In the initial phase of the struggle, Albrecht Achilles used his position as the imperial captain to advance his own interests. His actions enraged both Duke Ludwig and Elector Friedrich and made the war unavoidable. For more than two years two major coalitions of princes exchanged blows but as the dust settled the status quo ante bellum was restored in the eastern theatre of actions, while at the western front Elector Friedrich forced each of his opponents to make serious concessions. The second part of the dissertation is devoted to honor and reputation. It explores how these two constituents affected the actions and decision-making of the princes. The lack of a powerful arbiter allowed each of the princes to interpret the meaning of “right” and “justice” as most suited him, although they hardly intentionally misused these terms. Thus, more often than not, the important actors seemed to believe in the appropriateness of their deeds. Nevertheless, despite frequent emotional response, in the competition between emotions and cold calculation the latter usually prevailed. The conflict showed the confines of each of its major participants and the modus operandi of the Empire that prevented change and was tuned to keep the old order of things. N2 - Der Fürstenkrieg in Süddeutschland (1458-1463) war die größte militärische Auseinandersetzung in den deutschen Landen in der Mitte des fünfzehnten Jahrhunderts. An diesem Kampf nahmen die bedeutendsten Fürsten Süddeutschlands teil. Aufgrund seines bedeutenden Umfangs stellt dieser Konflikt eine wertvolle Fallstudie dar, um ein besseres Verständnis für die Verhältnisse im Herzen des Heiligen Römischen Reiches am Ausgang des Mittelalters zu erlangen. Das Ziel dieser Studie war es, eine bestehende Lücke in der modernen Forschungsliteratur zu schließen und eine umfassende, aktuelle Monographie zu diesem Thema bereitzustellen. Die Studie wurde hauptsächlich auf der Grundlage von Archivarbeit und Primärquellen realisiert. Tausende von Briefen und Dokumenten, die zwischen den Fürsten, ihren Beratern und den Vertretern der Städte ausgetauscht wurden, wurden sorgfältig studiert und analysiert. Die umfangreiche Nutzung gedruckter Quellen sowie wissenschaftlicher Literatur erleichterte diese Forschung ebenfalls sehr. Der erste Teil der Dissertation liefert eine detaillierte Beschreibung des Krieges selbst und der Ereignisse, die zu ihm führten. In der Anfangsphase des Kampfes nutzte Albrecht Achilles seine Position als kaiserlicher Hauptmann, um seine eigenen Interessen durchzusetzen. Sein Handeln erzürnte sowohl Herzog Ludwig als auch Kurfürst Friedrich und machte den Krieg unausweichlich. Mehr als zwei Jahre lang lieferten sich zwei große Fürstenkoalitionen einen Schlagabtausch, doch als sich der Staub gelegt hatte, wurde auf dem östlichen Kriegsschauplatz der Status quo ante bellum wiederhergestellt, während Kurfürst Friedrich an der Westfront jeden seiner Gegner zu ernsthaften Zugeständnissen zwang. Der zweite Teil der Dissertation ist der Ehre und dem Ansehen gewidmet. Es wird untersucht, wie diese beiden Bestandteile das Handeln und die Entscheidungsfindung der Fürsten beeinflussten. Das Fehlen eines mächtigen Schiedsrichters erlaubte es jedem der Fürsten, die Bedeutung von "Recht" und "Gerechtigkeit" so zu interpretieren, wie es ihm am besten passte, obwohl sie diese Begriffe kaum absichtlich missbrauchten. So schienen die wichtigen Akteure meistens an die Angemessenheit ihrer Taten zu glauben. Dennoch, trotz häufiger emotionaler Ansprache, setzte sich im Wettstreit zwischen Emotionen und kalter Berechnung meist letztere durch. Der Konflikt zeigte die Grenzen der einzelnen Hauptbeteiligten und den Modus Operandi des Imperiums, der Veränderungen verhinderte und auf die Beibehaltung der alten Ordnung der Dinge abgestimmt war. KW - Fürstenkrieg <1458-1463> KW - Bavarian War KW - Bayern KW - Geschichte 1458-1463 KW - conflict KW - honour KW - honor KW - Ludwig der Reiche KW - reputation KW - War in south Germany KW - Emperor Friedrich III KW - 1458-1463 KW - Elector of Brandenburg KW - emotions KW - Princes' War in South Germany KW - Duke Ludwig the Rich KW - the Elector Friedrich KW - Albrecht Achilles KW - Count Ulrich Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231236 ER - TY - JOUR A1 - Kelm, Matthias A1 - Germer, Christoph-Thomas A1 - Schlegel, Nicolas A1 - Flemming, Sven T1 - The revival of surgery in Crohn's disease — early intestinal resection as a reasonable alternative in localized ileitis JF - Biomedicines N2 - Crohn's disease (CD) represents a heterogeneous and complex disease with no curative therapeutic option available to date. Current therapy is mainly antibody-based focusing on the immune system while other treatment alternatives such as surgery are considered to be “last options”. However, medical therapy for CD results in mild to severe side effects in a relevant amount of patients and some patients do not respond to the medication. Following that, quality of life is often significantly reduced in this patient cohort, thus, therapeutic alternatives are urgently needed. Updated evidence has revealed that surgery such as ileocecal resection (ICR) might be a potential therapeutic option in case of localized terminal ileitis since resection at early time points improves quality of life and significantly reduces the postoperative need for immunosuppressive medication with low rates of morbidity. In addition, new surgical approaches such as Kono-S anastomosis or inclusion of the mesentery result in significantly reduced rates of disease recurrence and reoperation. Based on the new evidence, the goal of this review is to provide an update on the role of surgery as a reasonable alternative to medical therapy in the interdisciplinary treatment of patients with CD. KW - surgery KW - Crohn's disease KW - terminal ileitis KW - inflammatory bowel disease KW - surgical outcome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246296 SN - 2227-9059 VL - 9 IS - 10 ER - TY - JOUR A1 - Brych, Mareike A1 - Murali, Supriya A1 - Händel, Barbara T1 - The Role of Blinks, Microsaccades and their Retinal Consequences in Bistable Motion Perception JF - Frontiers in Psychology N2 - Eye-related movements such as blinks and microsaccades are modulated during bistable perceptual tasks. However, if they play an active role during internal perceptual switches is not known. We conducted two experiments involving an ambiguous plaid stimulus, wherein participants were asked to continuously report their percept, which could consist of either unidirectional coherent or bidirectional component movement. Our main results show that blinks and microsaccades did not facilitate perceptual switches. On the contrary, a reduction in eye movements preceded the perceptual switch. Blanks, on the other hand, thought to mimic the retinal consequences of a blink, consistently led to a switch. Through the timing of the blank-introduced perceptual change, we were able to estimate the delay between the internal switch and the response. This delay further allowed us to evaluate that the reduction in blink probability co-occurred with the internal perceptual switch. Additionally, our results indicate that distinct internal processes underlie the switch to coherent vs. component percept. Blanks exclusively facilitated a switch to the coherent percept, and only the switch to coherent percept was followed by an increase in blink rate. In a second study, we largely replicated the findings and included a microsaccade analysis. Microsaccades only showed a weak relation with perceptual switches, but their direction was correlated with the perceived motion direction. Nevertheless, our data suggests an interaction between microsaccades and blinks by showing that microsaccades were differently modulated around blinks compared with blanks. This study shows that a reduction in eye movements precedes internal perceptual switches indicating that the rate of blinks can set the stage for a reinterpretation of sensory input. While a perceptual switch based on changed sensory input usually leads to an increase in blink rate, such an increase was only present after the perceptual switch to coherent motion but absent after the switch to component percept. This provides evidence of different underlying mechanism or internal consequence of the two perceptual switches and suggests that blinks can uncover differences in internal percept-related processes that are not evident from the percept itself. KW - eye movements KW - spontaneous eye blink KW - microsaccade rate KW - microsaccade direction KW - bistable perception KW - ambiguous plaid 4 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235217 SN - 1664-1078 VL - 12 ER - TY - THES A1 - Kalb, Jacqueline T1 - The role of BRCA1 and DCP1A in the coordination of transcription and replication in neuroblastoma T1 - Die Rolle von BRCA1 und DCP1A in der Koordination von Transkription und Replikation im Neuroblastom N2 - The deregulation of the MYC oncoprotein family plays a major role in tumorigenesis and tumour maintenance of many human tumours. Because of their structure and nuclear localisation, they are defined as undruggable targets which makes it difficult to find direct therapeutic approaches. An alternative approach for targeting MYC-driven tumours is the identification and targeting of partner proteins which score as essential in a synthetic lethality screen. Neuroblastoma, an aggressive entity of MYCN-driven tumours coming along with a bad prognosis, are dependent on the tumour suppressor protein BRCA1 as synthetic lethal data showed. BRCA1 is recruited to promoter regions in a MYCN-dependent manner. The aim of this study was to characterise the role of BRCA1 in neuroblastoma with molecular biological methods. BRCA1 prevents the accumulation of RNA Polymerase II (RNAPII) at the promoter region. Its absence results in the formation of DNA/RNA-hybrids, so called R-loops, and DNA damage. To prevent the accumulation of RNAPII, the cell uses DCP1A, a decapping factor known for its cytoplasmatic and nuclear role in mRNA decay. It is the priming factor in the removal of the protective 5’CAP of mRNA, which leads to degradation by exonucleases. BRCA1 is necessary for the chromatin recruitment of DCP1A and its proximity to RNAPII. Cells showed upon acute activation of MYCN a higher dependency on DCP1A. Its activity prevents the deregulation of transcription and leads to proper coordination of transcription and replication. The deregulation of transcription in the absence of DCP1A results in replication fork stalling and leads to activation of the Ataxia telangiectasia and Rad3 related (ATR) kinase. The result is a disturbed cell proliferation to the point of increased apoptosis. The activation of the ATR kinase pathway in the situation where DCP1A is knocked down and MYCN is activated, makes those cells more vulnerable for the treatment with ATR inhibitors. In summary, the tumour suppressor protein BRCA1 and the decapping factor DCP1A, mainly known for its function in the cytoplasm, have a new nuclear role in a MYCN-dependent context. This study shows their essentiality in the coordination of transcription and replication which leads to an unrestrained growth of tumour cells if uncontrolled. N2 - Die MYC Onkoproteine spielen in einer Vielzahl humaner Tumore eine entscheidende Rolle und sind in fast allen Fällen dereguliert. Aufgrund ihrer Struktur und Lokalisation im Zellkern gelten sie für die Arzneimittelentwicklung als therapeutisch schwer angreifbar. Der Ansatz der synthetischen Lethalität ist es, Partnerproteine zu finden, die gerade für MYC-getriebene Tumore essenziell sind und diese zu inhibieren. Neuroblastome, die in einer besonders aggressiven Entität durch eine MYCN-Amplifikation getrieben sind und damit mit einer schlechten Prognose einhergehen, sind abhängig vom Tumorsupressor BRCA1, wie Daten zur synthetischen Lethalität zeigten. BRCA1 wird in Abhängigkeit von MYCN zu Promotoren rekrutiert. Diese Arbeit diente daher der Charakterisierung der Funktionalität von BRCA1 im Neuroblastom. BRCA1 verhindert die Akkumulation von RNA Polymerase II (RNAPII) in der Promoterregion. Ist BRCA1 nicht präsent, führt dies zur Bildung von DNA/RNA-Hybriden, sogenannten R-loops, und zu DNA Schäden. Um die Akkumulation von RNAPII zu verhindern, nutzt die Zelle DCP1A, einen Decapping Faktor, der sowohl im Cytoplasma als auch im Nukleus eine Rolle im mRNA Abbau spielt. DCP1A entfernt den schützenden 5’CAP der mRNA, wodurch diese von Exonukleasen abgebaut wird. BRCA1 ist notwendig für die Chromatin Bindung von DCP1A und die Rekrutierung zu RNAPII. Zellen mit einer akuten Aktivierung des MYCN Onkoproteins zeigen eine erhöhte Abhängigkeit von DCP1A. DCP1A verhindert eine Deregulation der Transkription, um Transkription mit Replikation erfolgreich zu koordinieren. Andernfalls führt dies beim Verlust von DCP1A zur Blockierung von Replikationsgabeln und der Aktivierung der Ataxia telangiectasia and Rad3 related (ATR) Kinase führt. In der Folge ist das Zellwachstum gestört und Zellen gehen vermehrt in Apoptose. Die Aktivierung des ATR Signalweges beim Verlust von DCP1A und MYCN Aktivierung verhindert vorerst den Zelltod, wodurch diese Zellen jedoch sensitiver auf die Inhibition von ATR reagieren. Zusammenfassend lässt sich sagen, dass BRCA1 als Tumorsupressor und DCP1A als Decapping Faktor, hauptsächlich beschrieben als cytoplasmatisches Protein, eine entscheidende nukleäre Rolle in der Situation einer akuten Aktivierung von MYCN spielen. Dort sind sie essenziell um Transkription mit Replikation zu koordinieren und damit zu einem ungebremsten Wachstum der Tumorzellen beizutragen. KW - Neuroblastom KW - N-Myc KW - Gen BRCA 1 KW - Transkription KW - neuroblastoma KW - BRCA1 KW - Decapping KW - MYCN KW - transcription/replication conflicts Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248711 ER - TY - THES A1 - Rüdt von Collenberg, Cora Freifrau T1 - The role of Ciliary Neurotrophic Factor in hippocampal synaptic plasticity and learning T1 - Die Rolle von Ciliary Neurotrophic Factor bei hippocampaler synaptischer Plastizität und Lernen N2 - Ciliary neurotrophic factor (Cntf) acts as a differentiation and survival factor for different types of neurons and glial cells. It is expressed by peripheral Schwann cells and astrocytes in the central nervous system and mediates its effects via a receptor complex involving CntfRα, LifRß and gp130, leading to downstream activation of Stat3. Recent studies by our group have shown that Cntf modulates neuronal microtubule dynamics via Stat3/stathmin interaction. In a mouse model for motor neuron disease, i.e. pmn, Cntf is able to rescue axonal degeneration through Stat3/stathmin signaling. While these findings suggest a role of Cntf in controlling axonal functions in the neuromuscular system, additional data indicate that Cntf might also play a role in synaptic plasticity in the hippocampus. Electrophysiological recordings in hippocampal organotypic cultures and acute slices revealed a deficit in long-term potentiation (LTP) in Cntf -/- mice. This deficit was rescued by 24 h stimulation with Cntf, combined with an acute application of Cntf during LTP-measurements indicating that Cntf is both necessary and sufficient for hippocampal LTP, and possibly synaptic plasticity. Therefore, Cntf knockout mice were investigated to elucidate this possible role of Cntf in hippocampal LTP and synaptic plasticity. First, we validated the presence of Cntf in the target tissue: in the hippocampus, Cntf was localized in Gfap-positive astrocytes surrounding small blood vessels in the fissure and in meningeal areas close to the dentate gyrus. Laser micro-dissection and qPCR analysis showed a similar distribution of Cntf-coding mRNA validating the obtained immunofluorescent results. Despite the strong LTP deficit in organotypic cultures, in vivo behavior of Cntf -/- mice regarding hippocampus-dependent learning and anxiety-related paradigms was largely inconspicuous. However, western blot analysis of hippocampal organotypic cultures revealed a significant reduction of pStat3 levels in Cntf -/- cultures under baseline conditions, which in turn were elevated upon Cntf stimulation. In order to resolve and examine synaptic structures we turned to in vitro analysis of cultured hippocampal neurons which indicated that pStat3 is predominantly located in the presynapse. In line with these findings, presynapses of Cntf -/- cultures were reduced in size and when in contact to astrocytes, contained less pStat3 immunoreactivity compared to presynapses in wildtype cultures. In conclusion, our findings hypothesize that despite of a largely inconspicuous behavioral phenotype of Cntf -/- mice, Cntf appears to have an influence on pStat3 levels at hippocampal synapses. In a next step these two key questions need to be addressed experimentally: 1) is there a compensatory mechanism by members of the Cntf family, possibly downstream of pStat3, which explains the in vivo behavioral results of Cntf -/- mice and can likewise account for the largely inconspicuous phenotype in CNTF-deficient humans? 2) How exactly does Cntf influence LTP through Stat3 signaling? To unravel the underlying mechanism further experiments should therefore investigate whether microtubule dynamics downstream of Stat3 and stathmin signaling are involved in the Cntf-induced modulation of hippocampal synaptic plasticity, similar to as it was shown in motoneurons. N2 - Ciliary neurotrophic factor (Cntf) wirkt als Differenzierungs- und Überlebensfaktor für verschiedene Arten von Neuronen und Gliazellen. Es wird von peripheren Schwann´schen Zellen und Astrozyten des zentralen Nervensystems exprimiert und vermittelt seine Effekte über einen Rezeptorenkomplex, der aus CntfRα, LifRß und gp130 besteht, und zu einer nachfolgenden Aktivierung von Stat3 führt. Jüngste Studien unserer Arbeitsgruppe haben gezeigt, dass Cntf neuronale Mikrotubulidynamik über Stat3/stathmin Interaktion modulieren kann. In pmn Mäusen, einem Mausmodell für Motoneuronenerkrankungen, ist Cntf in der Lage, durch Stat3/Stathmin Signaltransduktion die zugrundeliegende axonale Degeneration wieder aufzuheben. Während diese Ergebnisse eine Rolle von Cntf bei der Kontrolle axonaler Funktionen im neuromuskulären System postulieren, deuten zusätzliche Daten darauf hin, dass Cntf ebenfalls eine Funktion bei synaptischer Plastizität im Hippocampus ausübt. Elektrophysiologische Messungen in hippocampalen organotypischen Kulturen und akuten Schnitten zeigen ein Defizit in der Langzeitpotenzierung (LTP) bei Cntf -/- Mäusen. Dieses Defizit konnte durch eine 24 stündige Stimulation mit Cntf, in Kombination mit akuter Zugabe von Cntf während der LTP Messungen, kompensiert werden. Dies weist darauf hin, dass Cntf sowohl notwendig als auch ausreichend für hippocampale LTP und möglicherweise synaptische Plasizität ist. Deshalb wurden Cntf knockout Mäuse untersucht, um diese putative Rolle von Cntf bei hippocampaler LTP und synaptischer Plastizität zu untersuchen. Zunächst haben wir die Lokalisation von Cntf in unserem Zielgewebe bestätigt: im Hippocampus war Cntf sowohl in Gfap-positiven Astrocyten lokalisiert, die kleine Blutgefäße in der Fissur umschließen, als auch in Gfap-positiven Astrocyten nahe des Gyrus dentatus. Lasermikrodissektion und qPCR-Analysen zeigten eine ähnliche Verteilung von Cntf kodierender mRNA, und bestätigten somit die durch Immunoflureszenz-Färbung erworbenen Ergebnisse. Trotz des starken LTP Defizits in organotypischen Kulturen zeigten jedoch Cntf -/- Mäuse in Hippocampus-abhängigen lern- und angstbedingten Verhaltensparadigmen keinen offensichtlichen Phänotyp. Allerdings zeigten Western Blot Analysen hippocampaler Kulturen eine signifikante Reduktion der pStat3 Level in Cntf -/- Kulturen unter Kontrollbedingungen, die nach Cntf Zugabe wieder erhöht werden konnten. Um synaptische Strukturen besser darstellen und evaluieren zu können, wurden hippocampale Neurone in vitro kultiviert, in denen Stat3 überwiegend in Präsynapsen lokalisiert war. In Übereinstimmung mit diesen Beobachtungen zeigten Cntf -/- Präsynapsen eine geringere Größe und enthielten, verglichen zu Präsynapsen in Wildtypkulturen, weniger pStat3 Immunreaktivität, gerade dann, wenn sie sich in Kontakt mit Astrozyten befanden. Zusammenfassend weisen unsere Befunde darauf hin, dass Cntf – trotz eines weitgehend unaufälligen Verhaltensphänotyps bei Cntf -/- Mäusen – einen Einfluss auf den Level von pStat3 an hippokampalen Synapsen zu haben scheint. In einem nächsten Schritt sollten die folgenden zwei Schlüsselfragen experimentell geklärt werden: 1) gibt es einen kompensierenden Mechanismus, über welchen Mitglieder der Cntf Familie wirken könnten – möglicherweise nachfolgend von pStat3 – und welcher das Verhalten der Cntf -/- Mäuse, sowie den größtenteils unauffälligen Phänotyp bei CNTF defizienten Menschen erklären könnte? 2) Wie genau wirkt sich Cntf induziertes pStat3 auf LTP aus? Um diesen zugrundeliegenden Mechanismus aufzuklären, sollten weitere Experimente untersuchen, ob pStat3 und Stathmin abhängige Mikrotubulidynamik in der durch Cntf induzierten Modulation hippocampaler Plastizität eine Rolle spielt – ähnlich, wie es in Motoneuronen bereits gezeigt wurde. KW - Hippocampus KW - Ciliary neurotrophic factor KW - hippocampus KW - synaptic plasticity KW - learning KW - Hippocampus KW - synaptische Plastizität KW - Lernen Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206646 ER - TY - THES A1 - Kumari, Khushbu T1 - The role of lipid transfer proteins (LTPs) during the fertilization process in Arabidopsis thaliana T1 - Untersuchungen zur Rolle von Lipidtransferproteinen (LTPs) während des Befruchtungsprozesses in Arabidopsis thaliana N2 - Double fertilization is a defining characteristic of flowering plants (angiosperms). As the sperm cells of higher plants are non-motile, they need to be transported to the female gametophyte via the growing pollen tube. The pollen-tube journey through the female tissues represents a highly complex process. To provide for successful reproduction it demands intricate communication between the cells of the two haploid gametophytes - the polar growing pollen tube (carrying the two non-motile sperm cells) and the ovule (hosting the egg cell/synergid cells). The polar growth of the pollen tube towards the female gamete is guided by different signaling molecules, including sugars, amino acids and peptides. Some of these belong to the family of lipid transfer proteins (LTPs), which are secreted cysteine-rich peptides. Depending on the plant species several lines of evidence have also suggested potential roles for LTPs during pollen germination or pollen-tube guidance. Although Arabidopsis thaliana has 49 annotated genes for LTPs, several of which are involved in plant immunity and cell-to-cell communication, the role of most members of this family during fertilization is unknown. The aim of this project was therefore to systematically identify LTPs which play a role in the fertilization process in A. thaliana, particularly during pollen tube guidance. To identify candidate proteins, the expression profile of LTPs in reproductive tissue was investigated. This was accomplished by in-silico bioinformatic analysis using different expression databases. Following confirmion of these results by qRT-PCR analysis, seven Type-I nsLTPs (LTP1, LTP2, LTP3, LTP4, LTP5, LTP6 and LTP12) were found to be exclusively expressed in pistils. Except for LTP12, all other pistil expressed LTPs were transcriptionally induced upon pollination. Using reporter-based transcriptional and translational fusions the temporal and spatial expression patterns together with protein localizations for LTP2, 3, 4, 5, 6, and 12 were determined in planta. Stable transgenic plants carrying PromLTP::GUS constructs of the six different LTP candidates showed that most of LTPs were expressed in the stigma/stylar region and were induced upon pollination. With respect to protein localization on the cellular level, they split into two categories: LTP2, LTP5 and LTP6 were localized in the cell wall, while LTP3, LTP4 and LTP12 were specifically targeted to the plasma membrane. For the functional characterization of the candidate LTPs, several T-DNA insertion mutant plant lines were investigated for phenotypes affecting the fertilization process. Pollen development and quality as well as their in-vitro germination rate did not differ between the different single ltp mutant lines and wildtype plants. Moreover, in-vivo cross pollination experiments revealed that tube growth and fertilization rate of the mutant plants were similar to wildtype plants. Altogether, no discernible phenotype was evident in other floral and vegetative parts between different single ltp mutant lines and wildtype plants. As there was no distinguishable phenotype observed for single ltp-ko plants, double knock out plants of the two highly homologous genes LTP2 (expressed in the female stigma, style and transmitting tract) and LTP5 (expressed in the stigma, style, pollen pollen-tube and transmitting tract) were generated using the EPCCRISPR-Cas9 genome editing technique. Two ltp2ltp5 mutant transgenic-lines (#P31-P2 and #P31-P3) with frameshift mutations in both the genes could be established. Further experiments showed, that the CRISPR/Cas9-mediated knock-out of LTP2/LTP5 resulted in significantly reduced fertilization success. Cell biological analyses revealed that the ltp2ltp5 double mutant was impaired in pollen tube guidance towards the ovules and that this phenotype correlated with aberrant callose depositions in the micropylar region during ovule development. Detailed analysis of in-vivo pollen-tube growth and reciprocal cross pollination assay suggested that, the severely compromised fertility was not caused by any defect in development of the pollen grains, but was due to the abnormal callose deposition in the embryo sac primarily concentrated at the synergid cell near the micropylar end. Aberrant callose deposition in ltp2ltp5 ovules pose a complete blockage for the growing pollen tube to change its polarity to enter the funiculus indicating funicular and micropylar defects in pollen tube guidance causing fertilization failure. Our finding suggests that female gametophyte expressed LTP2 and LTP5 play a crucial role in mediating pollen tube guidance process and ultimately having an effect on the fertilization success. In line with the existence of a N-terminal signal peptide, secreted LTPs might represent a well-suited mobile signal carrier in the plant’s extracellular matrix. Previous reports suggested that, LTPs could act as chemoattractant peptide, imparting competence to the growing pollen tube, but the molecular mechanism is still obscure. The results obtained in this thesis further provide strong evidence, that LTP2/5 together regulate callose homeostasis and testable models are discussed. Future work is now required to elucidate the detailed molecular link between these LTPs and their potential interacting partners or receptors expressed in pollen and synergid cells, which should provide deeper insight into their functional role as regulatory molecules in the pollen tube guidance mechanism. N2 - Die ‚doppelte Befruchtung‘ ist ein charakteristisches Merkmal von Blütenpflanzen (Angiospermen). Da im Gegensatz zu vielen anderen Organismen die Spermien höherer Pflanzen nicht beweglich sind, müssen sie über den wachsenden Pollenschlauch zum weiblichen Gametophyten transportiert werden. Die je nach Pflanze durchaus lange Reise des Pollenschlauchs durch das weibliche Gewebe ist ein sehr komplexer Vorgang. Um eine erfolgreiche Reproduktion zu gewährleisten, ist eine fein abgestimmte Kommunikation zwischen den Zellen der beiden haploiden Gametophyten erforderlich - dem polar wachsenden Pollenschlauch (welcher die beiden nicht beweglichen Spermien trägt) und der Samenanlage (in der sich die Eizellen und Synergiden befinden). Das polare Wachstum des Pollenschlauchs in Richtung des weiblichen Gameten wird von verschiedenen Signalmolekülen gesteuert, darunter Zucker, Aminosäuren und Cystein-reiche Peptide (CRPs). Einige dieser Signalmoleküle gehören zur Familie der Lipidtransferproteine (LTPs), welche ebenfalls zur Klasse der CRPs gehören. Abhängig von der Pflanzenart deuten mehrere Hinweise auf eine mögliche Rolle von LTPs während der Pollenkeimung oder der Pollenschlauch-Navigation hin. Obwohl das Genom von Arabidopsis thaliana für mehr als 49 annotierte LTP-Gene kodiert, von denen einige an der ‚angeborenen Immunitätsreaktion‘ von Pflanzen sowie der Kommunikation von Zelle zu Zelle beteiligt sind, ist die physiologische Rolle der meisten Mitglieder dieser Familie während des Befruchtungsvorgangs bisher unbekannt. Ziel dieses Projekts war es daher, systematisch solche LTPs zu identifizieren, die eine Rolle bei der Befruchtung von A. thaliana spielen, insbesondere bei der Navigation des Pollenschlauchs zur Eizelle. Um diese LTP Proteine zu identifizieren, wurde zunächst das Expressionsprofil von LTPs in reproduktiven Gewebe untersucht. Dies wurde durch bioinformatische ‚in-silico‘ Analyse unter Verwendung verschiedener Expressionsdatenbanken erreicht. Nach Bestätigung dieser Ergebnisse durch qRT-PCR- Analyse wurde festgestellt, dass sieben Typ-I-LTPs (LTP1, LTP2, LTP3, LTP4, LTP5, LTP6 und LTP12) präferentiell im Stempel exprimiert werden. Mit Ausnahme von LTP12 wurden darüber hinaus alle anderen Stempel-exprimierten LTPs nach Bestäubung auf transkriptioneller Ebene induziert. Unter Verwendung von Reporter-basierten Transkriptions- und Translationsfusionen wurden die zeitlichen und räumlichen Expressionsmuster zusammen mit Proteinlokalisationen für LTP2, 3, 4, 5, 6 und 12 ‚in planta‘ bestimmt. Stabile transgene Pflanzen, die PromLTP::GUS-Konstrukte der sechs verschiedenen LTP- Kandidaten exprimierten, zeigten, dass die meisten LTPs in der Stigma/Stylar-Region abundant waren und tatsächlich bei der Bestäubung induziert wurden. Die anschließende Proteinlokalisierung auf zellulärer Ebene klassifizierte diese LTPs in zwei Kategorien: LTP2, LTP5 und LTP6 wurden in der Zellwand lokalisiert, während LTP3, LTP4 und LTP12 spezifisch an der Plasmamembran lokalisierten. Zur funktionellen Charakterisierung der Kandidaten-LTPs wurden mehrere T-DNA- Insertionsmutanten auf Phänotypen hinsichtlich des Befruchtungsprozesses untersucht. Die Pollenentwicklung sowie die ‚in-vitro‘ Keimrate des Pollens unterschieden sich dabei nicht zwischen den verschiedenen LTP-Mutantenlinien und Wildtyp-Pflanzen. Darüber hinaus ergaben ‚in-vivo‘ Kreuzbestäubungsexperimente, dass das Pollenschlauchwachstum und die Befruchtungsrate der mutierten Pflanzen im Vergleich zu Wildtyp-Pflanzen ähnlich waren. Insgesamt war kein erkennbarer Phänotyp in der Blütenentwickung oder der vegetativen Entwicklung zwischen verschiedenen LTP-Einzel-Mutanten und Wildtyp-Pflanzen erkennbar. Aufgrund möglicher funktioneller Redundanz, und der Tatsache, dass für einzelne LTP ‚knock- out‘ Pflanzen kein unterscheidbarer Phänotyp beobachtet wurde, wurden Verlustmutanten der beiden hoch homologen und ko-exprimierten Gene LTP2 und LTP5 unter Verwendung der EPC-CRISPR-Cas9-Genomeditiertechnik erzeugt. Zwei ltp2ltp5-mutierte transgene Linien (# P31-P2 und # P31-P3) mit In-Frame-Mutationen in beiden Genen konnten dabei etabliert werden. Weitere Experimente zeigten, dass das CRISPR/Cas9-vermittelte Ausschalten von LTP2 und LTP5 zu einem signifikant verringerten Befruchtungserfolg in diesen Linien führte. Zellbiologische Analysen ergaben, dass die ltp2ltp5 Doppelmutante in der Pollenschlauch- Navigation zu den Ovulen hin beeinträchtigt war und dass dieser Phänotyp mit Kalloseablagerungen in der Region der Mikropyle während der Ovulen-Entwicklung in diesen Linien korrelierte. Eine detaillierte Analyse des ‚in-vivo‘ Wachstums der Pollenschläuche sowie eines wechselseitigen Bestäubungstests ergab, dass die stark beeinträchtigte Befruchtung nicht durch einen Entwicklungsdefekt im männlichen Gametophyten, dem Pollen, verursacht wurde. Stattdessen konnte die beeinträchtigte Befruchtung auf die abnormale Kalloseabscheidung im weiblichen Gametophyten, dem Embryosack, zurückgeführt werden. Interessanterweise, konzentrierte sich die Kalloseabscheidung in der ltp2ltp5 Doppelmutante hauptsächlich im Bereich der Synergiden, am mikropylaren Ende des Embryosacks. Für den wachsenden Pollenschlauch stellen diese im Vergleich zum Wildtyp untypischen Kalloseablagerungen in ltp2ltp5-Mutanten in der Nähe der Eizellen möglicherweise eine Blockade für die Perzeption von Ovulen-Signalen dar. Dies behindert die erforderliche Richtungsänderung des polar gerichteten Wachstums und somit die Fähigkeit des Pollenschlauchs, entlang des Funikulus zu wachsen und in die Mikropyle eindringen zu können. Diese Beobachtung zeigt, dass funikuläre und mikropylare Defekte in der Pollenschlauch-Navigation den Befruchtungserfolg vermindern. Die Ergebnisse dieser Dissertation legen nahe, dass der weibliche Gametophyt, in welchem LTP2 und LTP5 exprimiert werden, eine entscheidende Rolle bei der Regulation der Pollenschlauch-Navigation spielt und letztendlich auch einen messbaren Einfluss auf den Befruchtungserfolg hat. Aufgrund der Existenz eines N-terminalen Signalpeptids und der damit verbundenen Sekretion in den Apoplasten könnten LTPs als Signalmoleküle in der extrazellulären Matrix der Pflanze fungieren. Frühere Arbeiten deuteten bereits an, dass LTPs als chemoattraktive Peptide wirken könnten und dem wachsenden Pollenschlauch die Kompetenz verleihen könnten, die Signale der Eizellen wahrzunehmen. Der zugrundeliegende molekulare Mechanismus ist jedoch noch immer unbekannt. Die in dieser Dissertation erzielten Ergebnisse liefern jedoch starke Hinweise darauf, dass LTP2/5 zusammen die Homöostase der Kallosebildung regulieren. Mögliche Modelle zur Aktivität von LTPs im Kontext der Regulation der Kallose-Homöostase werden vorgestellt und diskutiert. Zukünftige Arbeiten sind nun erforderlich, um die detaillierte molekulare Verbindung zwischen diesen LTPs und ihren potenziellen Interaktionspartnern oder Rezeptoren, die in Pollen- und Synergidzellen exprimiert werden, aufzuklären. Diese sollten einen tieferen Einblick in die funktionelle Rolle von LTP2 und LTP5 als regulatorische Moleküle für die Pollenschlauch- Navigation geben. KW - Fertilization in angiosperm KW - Lipid Transfer Protein Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199613 ER - TY - THES A1 - Becker, Isabelle Carlotta T1 - The role of megakaryocytes and platelets in vascular and osteogenic development T1 - Die Rolle von Megakaryozyten und Thrombozyten in vaskulärer und osteogener Entwicklung N2 - Platelets, small anucleate cell fragments in the blood stream, derive from large precursor cells, so-called megakaryocytes (MK) residing in the bone marrow (BM). In addition to their role in wound healing, platelets have been shown to play a significant role during inflammatory bleeding. Above all, the immunoreceptor tyrosine-based activation motif (ITAM) receptors GPVI as well as CLEC-2 have been identified as main regulators of vascular integrity. In addition to ITAM-bearing receptors, our group identified GPV as another potent regulator of hemostasis and thrombosis. Surprisingly, concomitant lack of GPV and CLEC-2 deteriorated blood-lymphatic misconnections observed in Clec2-/- mice resulting in severe edema formation and intestinal inflammation. Analysis of lymphatic and vascular development in embryonic mesenteries revealed severely defective blood-lymph-vessel separation, which translated into thrombocytopenia and increased vascular permeability due to reduced tight junction density in mesenteric blood vessels and consequent leakage of blood into the peritoneal cavity. Recently, platelet granule release has been proposed to ameliorate the progression of retinopathy of prematurity (ROP), a fatal disease in newborns leading to retinal degradation. The mechanisms governing platelet activation in this process remained elusive nonetheless, which prompted us to investigate a possible role of ITAM signaling. In the second part of this thesis, granule release during ROP was shown to be GPVI- and partly CLEC-2-triggered since blockade or loss of these receptors markedly deteriorated ROP progression. Proplatelet formation from MKs is highly dependent on a functional microtubule and actin cytoskeleton, the latter of which is regulated by several actin-monomer binding proteins including Cofilin1 and Twinfilin1 that have been associated with actin-severing at pointed ends. In the present study, a redundancy between both proteins especially important for the guided release of proplatelets into the bloodstream was identified, since deficiency in both proteins markedly impaired MK functionality mainly due to altered actin-microtubule crosstalk. Besides ITAM-triggered activation, platelets and MKs are dependent on inhibitory receptors, which prevent overshooting activation. We here identified macrothrombocytopenic mice with a mutation within Mpig6b encoding the ITIM-bearing receptor G6b-B. G6b-B-mutant mice developed a severe myelofibrosis associated with sex-specific bone remodeling defects resulting in osteosclerosis and -porosis in female mice. Moreover, G6b-B was shown to be indispensable for MK maturation as verified by a significant reduction in MK-specific gene expression in G6b-B-mutant MKs due to reduced GATA-1 activity. N2 - Blutplättchen, die kleinsten Zellen des hämatopoetischen Systems, werden von großen Vorläuferzellen, den Megakaryozyten (MKs), im Knochenmark gebildet. Neben ihrer Rolle bei der Blutstillung und Wundheilung sind Thrombozyten außerdem maßgeblich daran beteiligt, Blutungen in Entzündungsprozessen zu verhindern. Insbesondere den immuno- receptor tyrosine-based activation motif (ITAM) Rezeptoren GPVI und CLEC-2 wird eine tragende Rolle in der Aufrechterhaltung der vaskulären Integrität zugeschrieben. Neben den ITAM-Rezeptoren konnten wir auch für den Thrombozytenrezeptor GPV eine Funktion in Hämostase und Thrombose identifizieren. Erstaunlicherweise führte ein gleichzeitiger Verlust von GPV und CLEC-2 zu einer dramatischen Verstärkung der Blut- Lymphgefäß-Fehlbildungen, die bereits in CLEC-2-defizienten Mäusen beschrieben wurde, sodass die Tiere eine starke Ödembildung in den Extremitäten sowie Entzündungen des Dünndarms aufwiesen. Eine vertiefte Analyse der vaskulären Strukturen in Mesenterien während der Embryonalentwicklung offenbarte zusätzliche Defekte in der Blut- und Lymphgefäßtrennung in CLEC-2/GPV-defizienten Mäusen. Diese Deformationen führten zu Thrombozytopenie, Anämie und einer erhöhten vaskulären Permeabilität in adulten Mäusen, was sich auf eine reduzierte tight-junction-Dichte in Mesenterien und Darmgewebe zurückführen ließ, die zu einem Austritt von Blut in die Peritonealhöhle führte. In einer kürzlich veröffentlichten Publikation wurde Plättchengranula eine Rolle in der Auflösung retinopathischer Gefäßmissbildungen zugeschrieben. Retinopathia praema- turorum (ROP) ist eine Krankheit in Frühgeborenen, die aufgrund von Sauerstoffunter- schieden vor und nach Geburt zu Netzhautablösung und Blindheit führen kann. Die exakten Mechanismen, die hierbei zu Thrombozytenaktivierung und nachfolgender Degranulierung beitragen, sind bisher allerdings nicht bekannt. Da eine tragende Rolle von ITAM Rezeptoren in der Aufrechterhaltung vaskulärer Integrität insbesondere in krankhaftem Gewebe zuvor bereits aufgezeigt wurde, untersuchten wir die Entwicklung von Vaso-obliteration und Neovaskularisierung in CLEC-2 und GPVI-depletierten oder defizienten Mäusen und konnten einen Beitrag beider Rezeptoren zur Progression von ROP nachweisen. Die Produktion von Thrombozyten aus MKs ist stark von einem funktionalen Mikrotubuli- und Aktin-Zytoskelett abhängig. Aktinpolymerisation wird substanziell von unterschiedlichen Aktin-bindenden Proteinen reguliert, von denen Cofilin1 und Twinflin1 ein Abtrennen der Filamente induzieren. Wir konnten nun eine funktionale Redundanz beider Proteine in murinen MKs aufzeigen, die insbesondere für ein geregeltes Abschnüren von Thrombozyten in die Blutbahn essentiell ist und von einem Crosstalk zwischen Aktin- und Mikrotubuli- Zytoskeletts abhängig ist, der durch Twinfilin1 und Cofilin1 aufrechterhalten wird. Neben ITAM-induzierter Thrombozytenaktivierung spielt auch die Inhibition derselbigen durch immunoreceptor tyrosine-based inhibition motif (ITIM)-Rezeptoren eine große Rolle in MKs und Plättchen, da diese eine überschießende Aktivierung verhindern. Wir konnten in der vorliegenden Arbeit eine Spontanmutation in Mpig6b, das für den ITIM-Rezeptor G6b-B codiert, in stark makrothrombozytopenen, wildtypischen Mäusen identifizieren. Außer in der stark reduzierten Thrombozytenzahl manifestierte sich die Mutation des Weiteren in einer massiven Myelofibrose, die mit einer geschlechtsspezifischen Osteosklerose und -porose in weiblichen Mäusen einherging. Überraschenderweise konnten wir zudem einen dramatischen Reifungsblock in G6b-B-mutierten MKs feststellen, der insbesondere in einer reduzierten Expression des Transkriptionsfaktors GATA-1 begründet lag. KW - Megakaryozyt KW - Thrombozyt KW - Megakaryocyte KW - platelets KW - bone marrow KW - hematopoiesis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-210241 ER - TY - JOUR A1 - Meister, Julia A1 - Garbe, Philipp A1 - Trappe, Julian A1 - Ullmann, Tobias A1 - Es-Senussi, Ashraf A1 - Baumhauer, Roland A1 - Lange-Athinodorou, Eva A1 - El-Raouf, Amr Abd T1 - The Sacred Waterscape of the Temple of Bastet at Ancient Bubastis, Nile Delta (Egypt) JF - Geosciences N2 - Sacred water canals or lakes, which provided water for all kinds of purification rites and other activities, were very specific and important features of temples in ancient Egypt. In addition to the longer-known textual record, preliminary geoarchaeological surveys have recently provided evidence of a sacred canal at the Temple of Bastet at Bubastis. In order to further explore the location, shape, and course of this canal and to find evidence of the existence of a second waterway, also described by Herodotus, 34 drillings and five 2D geoelectrical measurements were carried out in 2019 and 2020 near the temple. The drillings and 2D ERT surveying revealed loamy to clayey deposits with a thickness of up to five meters, most likely deposited in a very low energy fluvial system (i.e., a canal), allowing the reconstruction of two separate sacred canals both north and south of the Temple of Bastet. In addition to the course of the canals, the width of about 30 m fits Herodotus’ description of the sacred waterways. The presence of numerous artefacts proved the anthropogenic use of the ancient canals, which were presumably connected to the Nile via a tributary or canal located west or northwest of Bubastis. KW - ancient Egypt KW - Tell Basta KW - sacred lakes KW - Herodotus KW - ERT KW - drilling KW - Isheru Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246129 SN - 2076-3263 VL - 11 IS - 9 ER -