Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI

Mit Anwendungen auf Erdbebennetzwerke

The aim of this thesis was the development of new algorithms for the analysis of large and complex networks with applications to earthquake networks. Earthquake networks are directed and weighted networks which model the temporal and spatial succession of earthquakes. The mapping of the interdependency between the vertices of the networks representing the location of the earthquake and the temporal succession and occurrence of earthquakes through edges between the vertices leads to a considerable complexity. Assigning (clustering) the vertices with similar edge connection profiles to the same class (cluster) opens the possibility of a better understanding of the generation and topology of the network. One model offering such a cluster assignment is the Stochastic Block Model with Poisson distributions (SBM). It is a special feature of the SBM to consider the possible interdependence of each vertex to all other vertices of the network and thus capturing the complexity of the network. This network interdependency is a major challenge for the inference of a specific SBM for a given network. The application of the Variational Bayesian EM (VBEM) algorithm was proposed as an option for the solution to this problem some years ago. The estimation of the SBM with the VBEM algorithm leads to a non-convex optimisation problem. The objective is to find the optimal number of clusters and assignments of the vertices to the clusters corresponding to a global optimum of the model selection criterion. In order to solve this optimisation problem existing VBEM algorithms often only allow the separate initialisation for different numbers of clusters. Using this batch approach, the optimisation has to be performed each time with respect to all vertices in the network and for each number of clusters. For earthquake networks or comparable large and complex networks this approach leads to unsatisfactory results with respect to quality and computation time. At this point the present thesis comes in. A new type of algorithms for VBEM inference, called the Blockloading algorithms, is proposed. These algorithms combine the search of the optimal cluster assignment of the vertices and the number of clusters according to the model selection criterion in a divisive algorithm. Starting with the assignment of all vertices to a single cluster the search for an optimum is performed by splitting and refining the existing clusters. As this optimisation only involves subsets, two new, especially adapted VBEM algorithms, the BlockVB and BlockVB++ algorithms, were developed to meet this objective. The design of the Blockloading algorithms follows the observation, that the successful search for a global optimum with means of a divisive algorithm can be performed by the identification of several favourable local optima. These local optima are similar in the sense that by correctly splitting the right clusters they can be transformed into a global optimum. The Blockloading, automatic Blockloading, no reset Blockloading and Blockloading++ algorithms were designed with regard to this observation which lead to an efficient algorithmic design which was optimised for finding favourable local optima. As large and complex networks often exhibit irregularly and sparsely connected vertices the Stochastic Block Model with irrelevant Vertices (SBMIV) was developed which explicitly models these irrelevant vertices. Building on our Blockloading algorithms, the Relevance Blockloading algorithm together with the Relevance BlockVB EM algorithm was introduced for the estimation of the SBMIV. Numerical tests of the newly developed methods were performed on synthetic networks, generated by the SBM, and an earthquake network. The newly developed Blockloading algorithms reached a previously unattained quality of the results and computation time for the clustering of the earthquake network and the synthetic networks when compared to comparable methods for the estimation of the SBM. It was demonstrated for an earthquake network that inference with the Relevance Blockloading algorithm can reliably identify irrelevant vertices. This estimation lead to an even better value of the model selection criterion than the inference of the comparable Poisson SBM which demonstrates the superiority of this approach.Ziel der Arbeit war die Entwicklung neuer Algorithmen zur Analyse von großen und komplexen Netzwerken mit Anwendung auf Erdbebennetzwerke. Erdbebennetzwerke sind gerichtete und gewichtete Netzwerke, welche die zeitliche und räumliche Abfolge von Erdbeben abbilden. Die Abbildung der wechselseitigen Abhängigkeit zwischen den Knoten des Netzwerks, welche den Ort des Erdbebens beschreiben, und der zeitlichen Abfolge und dem Auftreten von Erdbeben durch Kanten zwischen den Knoten führt zu erheblicher Komplexität. Um die Entstehung und Topologie des Netzwerks besser zu verstehen, bietet sich das Zusammenfassen (Clustern) von Knoten mit ähnlichen Kantenverbindungsprofilen in derselben Klasse (Cluster) an. Ein Modell für solche Zusammenfassungen ist das Stochastische Block Modell mit Poisson Verteilungen (SBM). Das SBM hat die Besonderheit, dass es die mögliche wechselseitige Abbängigkeit von jedem Knoten zu allen anderen Knoten berücksichtigt, und so die Komplexität des Netzwerks erfasst. Diese wechselseitige Abhängigkeit ist gleichzeitig eine besondere Herausforderung für ein Lösungsverfahren zur Schätzung des konkreten SBMs für ein gegebenes Netzwerk. Vor einigen Jahren wurde der Variational Bayesian EM (VBEM) Algorithmus als Option zur Lösung dieses Problems vorgestellt. Die Schätzung eines SBM mit dem VBEM Algorithmus führt auf ein nicht-konvexes Optimierungsproblem. Dabei ist die optimale Anzahl der Cluster und Zuordnung der Knoten zu den Clustern zu finden, die einem globalen Optimum des Modellauswahlkriteriums entsprechen. Zur Lösung dieses Optimierungsproblems erlaubten bisherige VBEM Algorithmen allerdings häufig nur die getrennte Anwendung für verschiedene Anzahlen von Clustern. Dabei wird die Optimierung jedesmal in Abhängigkeit von allen Knoten des gesamten Netzwerks und für jede Clusterzahl neu durchgeführt. Dieses Vorgehen führt jedoch für Erdbebennetzwerke oder vergleichbar große und komplexe Netzwerke zu unzureichenden Ergebnissen in Bezug auf die Qualität und Rechengeschwindigkeit. Genau an dieser Stelle setzt die vorliegende Arbeit an. Es wird eine neue Art von Algorithmen zur Anwendung von VBEM Algorithmen, sogenannte Blockloading Algorithmen vorgestellt, welche die Suche nach der optimalen Clusterzuordnung der Knoten und der Anzahl der Cluster gemäß des Modellauswahlkriteriums in einem Unterteilungalgorithmus kombinieren. Ausgehend von der Zuordnung aller Knoten zu einem einzigen Cluster wird ein Optimum durch das Aufteilen und Verfeinern der bestehenden Cluster gesucht. Da in dieser Optimierung nur Teilmengen der Knoten berücksichtigt werden, wurden mit den BlockVB und BlockVB++ Algorithmen zwei neue, dafür speziell angepasste VBEM Algorithmen entwickelt. Das Design der Blockloading Algorithmen folgt der Beobachtung, dass die erfolgreiche Suche nach einem globalen Optimum mit einem Unterteilungsalgorithmus durch die Identifizierung mehrerer günstiger lokaler Optima erfolgen kann. Diese lokalen Optima sind sich in dem Sinne ähnlich, dass sie alle durch das richtige Aufteilen der richtigen Cluster in ein globales Optimum überführt werden können. Mit den Blockloading, automatic Blockloading, no reset Blockloading und Blockloading++ Algorithmen wird diese Beobachtung durch ein effizientes algorithmisches Design berücksichtigt, welches für das Auffinden geeigneter lokaler Optima optimiert wurde. Da komplexe und große Netzwerke häufig unregelmäßig und wenig verbundene Knoten aufweisen, wurde zusätzlich das Stochastische Block Modell mit irrelevanten Knoten (SBMIV) entwickelt, welches irrelevante Knoten gesondert zu berücksichtigen erlaubt. Aufbauend auf den Blockloading und BlockVB Algorithmen wurde der Relevance Blockloading Algorithmus mit dem Relevance BlockVB EM Algorithmus zur Schätzung des SBMIV vorgestellt. Anhand von synthetischen Netzwerken, die mit dem SBM erzeugt wurden, und einem Erdbebennetzwerk wurden numerische Tests der entwickelten Methoden durchgeführt. Im Vergleich zu vergleichbaren Berechnungsmethoden zur Schätzung des SBMs waren die neu entwickelten Blockloading Algorithmen in der Lage, sowohl das Erdbebennetzwerk als auch die synthetische Netzwerke in bisher nicht erreichter Qualität und Geschwindigkeit zu clustern. Anhand des Erdbebennetzwerks konnte zusätzlich gezeigt werden, dass der neue Relevance Blockloading Algorithmus bei der Schätzung eines SBMIV zuverlässig irrelevante Knoten identifizieren kann. Dies führte sogar zu einem besseren Wert des Modellauswahlkriteriums als die Schätzung des vergleichbaren Poisson-SBM, was die Überlegenheit dieses Ansatzes demonstriert

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

Currently, the authorisation process for plant protection products (PPPs) relies on the testing of acute and topological toxicity only. Contrastingly, the evaluation of active substances includes a more comprehensive set of toxicity studies. Nevertheless, mixture effects of active ingredients and co-formulants may result in increased toxicity. Therefore, we investigated effects of surface active co-formulants on the toxicity of two PPPs focussing on qualitative and quantitative toxicokinetic effects on absorption and secretion. The respective products are based on the active substances abamectin and fluroxypyr-meptyl and were tested for cytotoxicity in the presence or absence of the corresponding surfactants and co-formulants using Caco-2 cells. In addition, the effect of co-formulants on increased cellular permeation was quantified using LC-MS/MS, while potential kinetic mixture effects were addressed by fluorescence anisotropy measurements and ATPase assays. The results show that surface active co-formulants significantly increase the cytotoxicity of the investigated PPPs, leading to more than additive mixture effects. Moreover, analytical investigations show higher efflux ratios of both active substances and the metabolite fluroxypyr upon combination with certain concentrations of the surfactants. The results further point to a significant and concentration-dependent inhibition of Pgp transporters by most of the surfactants as well as to increased membrane fluidity. Altogether, these findings strongly support the hypothesis that surfactants contribute to increased cytotoxicity of PPPs and do so by increasing the bioavailability of the respective active substances

Single Component and Compound Monolayers of CuPc and PTCDA on a Ag(110) Surface

This work is motivated by the recent international effort to create an experimentally self-sustained dynamo. The dynamo effect, whose existence was proposed by Larmor at the beginning of the 20th century, is believed to be the explanation for the magnetic field of Earth and other celestial bodies due to the flow of a conducting fluid. In order to numerically study the von Kármán flow, which models the configuration of the dynamo experiment implemented at Cadarache, we have developed a new numerical approach for solving the magnetohydrodynamic equations in potential formulation in a finite cylindrical geometry. The poloidal-toroidal decomposition has been used to ensure the solenoidal character of the velocity and magnetic fields. We use the influence matrix technique to impose the boundary conditions for the velocity and the continuity between the internal and external magnetic fields. The computational power of the code, which is the result of the MPI-based parallelization, enabled us to investigate two problems concerning turbulence in cylindrical geometry: axisymmetric turbulence and a bifurcation between turbulent flows.Ce travail est motivé par l'effort international actuel de créer expérimentalement une dynamo fluide auto-entretenue. L'effet dynamo, dont l'existence a été prevu par Larmor au début du XXème siècle, est considéré comme étant responsable de la production du champ matnétique terrestre et d'autres objets célestes par l'intermédiaire de l'écoulement d'un fluide conducteur. Afin d'étudier numériquement l'écoulement de von Kármán, qui modélise la configuration d'une expérience dynamo mise en place à Cadarache, nous avons développé une approche numérique originale permettant la résolution des équations magnétohydrodynamiques dans une géométrie dylindrique en formulation potentielle. La décomposition en potentiels poloïdal et toroïdal a été utilisée pour garantir la nature solénoïdale des champs de vitesse et magnétique. Nous utilisons la technique de la matrice d'influence pour satisfaire aux conditions aux limites et aux conditions de continuité du champ magnétique à la paroi du cylindre. La grande puissance de calcul, résultant de la parallélisation MPI du code, a presmis de l'appliquer deux problèmes concernant la turbulence dans la géométrie cylindrique : la turbulence axisymétrique et une bifurcation entre états turbulents

Modification of the PTCDA-Ag bond by forming a heteromolecular bilayer film

The understanding of the fundamental physical properties of metal-organic and organic-organic interfaces is crucial for improving the performance of organic electronic devices. This is particularly true for (multilayer) systems containing several molecular species due to their relevance for donor-acceptor systems. A prototypical heteromolecular bilayer system is copper-II-phthalocyanine (CuPc) on 3,4,9,10-perylene-tetra-carboxylic-dianhydride (PTCDA) on Ag(111). In an earlier work we have reported a commensurate registry between both organic layers and an enhanced charge transfer from the Ag substrate into the organic bilayer film [Phys. Rev. Lett. 108, 106103 (2012)], which both indicate an unexpectedly strong intermolecular interaction across the organic-organic interface. Here we present new details regarding electronic and geometric structure for the same system. In particular, we provide evidence that the enhanced charge transfer from the substrate into the organic bilayer does not involve CuPc electronic states, hence, there is no significant charge transfer into the second organic layer. Furthermore, we report vertical bonding distances revealing a shortening of the PTCDA-Ag(111) distance upon CuPc adsorption. Thus, electronic and geometric properties (charge transfer and bonding distance, respectively) both indicate a strengthening of the PTCDA-Ag(111) bond upon CuPc adsorption. We explain these findings—in particular the correlation between CuPc adsorption and increased charge transfer into PTCDA—in a model involving an intermolecular screening mechanism

Copper Phthalocyanine Monolayers and Multilayers on Ag(110) and Ag(111) Surfaces

Organic semiconductors and their potential for applications in electronic devices such as solar cells and organic light emitting diodesmake them interesting for fundamental research. Especially interfaces between different organic layers, e.g. PTCDA and CuPc, are subjects of experiments. To create a basis for the understanding of heteroorganic systems, the corresponding homomolecular phases are investigated regarding their geometric and electronic structure upon adsorption on a metal surface. While homomolecular phases of PTCDA on different noble metal surfaces are well-studied, less is known about adsorption and ordering of CuPc. Here we present a combined study employing (SPA)LEED, STM, STS and ARUPS to CuPc monolayers and multilayers adsorbed on the Ag(110) and Ag(111) surfaces

Single Component and Compound Monolayers of CuPc and PTCDA on a Ag(110) Surface

Organic semiconductors are of great interest for research due to their potential application in organic electronics. Organic layers of one component on top of a metal crystal have been studied for decades. Recently binary and multinary molecular films also have come into focus, e.g., for the application in organic p-n junctions and all-organic solar cells. Traditionally, (111) surfaces of Ag, Au and Cu single crystals were used for experimental studies. Here we report on the structure of ordered monolayers of CuPc and PTCDA on a Ag(110) surface, both single component and compound. Scanning Tunneling Microscopy and Low Energy Electron Diffraction were used

Single Component and Compound Monolayers of CuPc and PTCDA on a Ag(110) Surface

Organic semiconductors are of great interest for research due to their potential application in organic electronics. Organic layers of one component on top of a metal crystal, traditionally, (111) surfaces of Ag, Au and Cu single crystals, have been studied for decades. Here, we report on the structure of ordered monolayers of CuPc and PTCDA on a Ag(110) surface, both single component and compound.The geometric arrangement and the electronic structure of the n-type semiconducting molecule PTCDA adsorbed on Ag(110) are well known. [1,2,3] On the contrary, the structure of the p-type semiconducting molecule CuPc on the same Ag(110) surface has been investigated only rarely, mainly by Low Energy Electron Diffraction (LEED) and Photoemission Spectroscopy (PES). [4,5] Wewill offer further results on this sample system gained by Angle-Resolved Photoemission Spectroscopy (ARUPS) and Orbital Tomography (OT).Recently, binary and multinary molecular film also have come into focus, e.g. for the application in organic p-n junctions and all-organic solar cells. We will present results obtained by LEED, ARUPS and OT on a laterally mixed layer of CuPc and PTCDA on Ag(110). In order to complete our investigations, in the next step Scanning Tunneling Microscopy and Scanning Tunneling Spectroscopy (STM, STS) will be applied to the mixed monolayer of CuPc and PTCDA on Ag(110) as well as to the monolayer ofpure CuPc on Ag(110).[1] Willenbockel et al., NJP 15 033017, 2013[2] Puschnig et al., PRB 84 235427, 2011[3] Ziroff et al., PRL 104 233004, 2010[4] Schäfer et al., Adv. Funct. Mat. 11 193, 2001[5] Song at al., JoP: Cond. Matt. 19 136002, 200