Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression
Cathrin J. Czupalla
Makoto M. Taketo
Karl H. Plate
- Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.
Betriebliche Weiterbildung bei den Feuerwehren : Start einer Seminarreihe zur pädagogischen Professionalisierung
- Der vorliegende Beitrag beschäftigt sich mit den Lehrenden in der betrieblichen Weiterbildung und deren pädagogischem Professionalisierungsbedarf. Beschrieben wird ein von der Feuerwehr- und Rettungsdienstakademie der Branddirektion Frankfurt am Main (FRA) und dem Fachbereich Erziehungswissenschaften der Goethe-Universität entwickeltes Konzept zur Aus- und Weiterbildung pädagogisch tätiger FeuerwehrbeamtInnen, das 2012 erstmals umgesetzt wird. Bislang existierten hierfür weder in Deutschland noch in Österreich einheitliche Vorgaben. Ausgehend von den Bedürfnissen der Feuerwehren und geleitet von theoretischen Positionen der Erwachsenenbildung wird mit dem Konzept nicht zuletzt auch eine lernende Organisation zu verwirklichen versucht. Der Beitrag erläutert Ausgangslage, pädagogische Grundhaltung, Ziele und Ergebnisse der Voruntersuchung und skizziert die konkreten Modulinhalte und den Seminarablauf. Fazit der Autoren: Analog zu der bereits begonnenen Entwicklung in Wirtschaftsunternehmen wird das Niveau der pädagogischen Kenntnisse von lehrendem Personal auch bei den Feuerwehren steigen müssen. (DIPF/Orig.)
The formation and the geochemical and thermal evolution of the lithospheric mantle beneath the Kaapvaal craton recorded by subcalcic garnets from harzburgites and by pristine eclogites and garnet-pyroxenites
- The mantle xenoliths collected by kimberlites indicate that the subcratonic mantle underneath the Archean crust is mostly a residue of high degrees of partial melting which was subsequently reenriched. The majority of the xenoliths show cryptic metasomatism and only few modal metasomatism.
Much effort has been put into deciphering different kinds of enrichment processes within the mantle. Here, we take the approach to look into the inventory of subcalcic garnets which stem from cpx-free harzburgites and dunites. These subcalcic garnets, commonly with sinusoidal REE patterns, carry the major budget of the trace elements of their host rock. Thus, they are promising objects to study both depletion and enrichment. Most importantly, the analysis of a single grain subcalcic garnetwill provide almost all important information of the bulk rock. Our aim is to gain detailed information mainly on metasomatism on a craton wide scale by combining major, trace elements and Lu-Hf and Sm-Nd isotopic signatures from subcalcic garnets. Eventually, we will summarize the metasomatic agent(s) and processes and possibly the timing of the enrichment within the lithospheric mantle underneath the Kaapvaal craton.
Development of native electrophoretic techniques for the isolation and characterization of mitochondrial complexes
- In the first part of this work, the development of a novel two-dimensional native gel electrophoretic system (2-D BN/hrCNE) is described. This new system simplifies proteomics and biochemical analysis of mega protein complexes that are dissociated into the constituent complexes during 2-D electrophoresis, thereby reducing the complexity of the system considerably. This technique is exceptionally well suited for the in-gel detection of fluorescence-labeled proteins and the identification of individual enzymes and protein complexes by specific in-gel assays on native gels.
In the second part, a new technique for the native immunoblotting of blue native gels (NIBN) was developed. This new technique allows for the identification of conformation-specific antibodies and the discrimination of antibodies recognizing linear epitopes of denatured proteins. Identification of conformation-specific antibodies is becoming increasingly important not only for the electron microscopic identification of native proteins but also for structural investigations in general. For this purpose, a commonly used protocol for Western blotting of blue native gels was modified in such a way that the native state of proteins and protein complexes was retained throughout the complete protocol. Instead of using the denaturing methanol in Western blotting protocols, mild detergents such as Tween 20, digitonin and Brij 35 were used for the obligatory removal of protein bound Coomassie-dye.
The detection of respiratory complex I by activity staining on the blot membrane demonstrated that all three non-ionic detergents preserved the native state of complex I. The native state of the enzyme on the blot membrane was also monitored and confirmed with the help of a set of conformation-specific antibodies. NIBN can be used as a simple alternative method to the demanding native ELISA to screen for conformation-specific antibodies for structural studies. Unlike the time consuming native ELISA, NIBN does not require introduction of appropriate affinity tags and purification of the target protein by chromatography. Thus, the NIBN technique is especially useful for microscale projects and for proteins not easily accessible to genetic manipulation.
The third part aimed at identification of the immediate protein interaction partners of Cox26, a hydrophobic protein that has been identified by our group as a novel component of yeast respiratory supercomplex. Multi-dimensional electrophoretic techniques were applied to identify non-covalent and covalent protein-protein interactions of Cox26. Three-dimensional electrophoresis (BNE/BNE/SDS-PAGE) gave both qualitative and quantitative information on covalent and non-covalent interactions of Cox26 and subunits of cytochrome c oxidase (complex IV), and showed that most of the Cox26 protein was non-covalently bound to the complex IV moiety of the respirasomes. Four-dimensional electrophoresis (BNE/BNE/SDS/SDS-PAGE) applying reducing and non-reducing conditions revealed that a minor fraction of Cox26 used a single cysteine residue in the center of a predicted transmembrane helix to form a disulfide bond with the Cox2 subunit of complex IV. A structural role of Cox26 protein in the assembly/stability of respiratory strings or patches has been suggested.
The last part of this work focused on the isolation and characterization of native and morphologically intact nucleoids from bovine heart mitochondria, since only a few studies on nucleoid organization and composition have been carried out on mammalian tissues. The nucleoids appeared as distinct bands (apparent mass around 30-36 MDa) in blue native-PAGE on large pore gels. The moderate variation in particle size seems to reflect variations in the binding of loosely nucleoid-associated components like respiratory chain complexes. The estimated 30-36 MDa mass of nucleoids on native gels suggested that each nucleoid contains one mtDNA molecule provided that nucleoids contains equal amounts of DNA, protein and RNA (Miyakawa et al., 1987).
Electron microscopic analysis of native nucleoids, which was performed by Dr. Karen Davies from the Max-Planck-Institute of Biophysics, Department of Structural Biology, Frankfurt, showed homogenous pool of particles with dimensions in 85x100 nm (in negative stain) and 100x150 nm (in cryo-tomography). Some of the nucleoids showed dumbbell-shape indicating dimerization of nucleoids. Recent EM and high-resolution light microscopy analysis of mammalian nucleoids have reported that nucleoids have a size of 70 nm in average. We also observed the same size of 70 nm in cryo-tomogramms when we applied harsher treatment of the native nucleoid particles with dimensions 100x150 nm. This observation is in agreement with published nucleoid sizes from both EM and high-resolution light microscopy, if we assume that native nucleoids have been dissociated under harsher treatment.
The protein composition of bovine heart mt-nucleoids was analyzed by a number of complementary approaches to identify low and highly abundant, easily dissociating and tightly bound proteins, and to rank the 90 most abundant mt-nucleoid proteins. Native and denaturing gel electrophoresis techniques were coupled to LC-MS/MS to achieve a comprehensive protein component analysis. Qualitative MS analysis of highly purified nucleoids identified more than 400 proteins, including well known nucleoid proteins such as mitochondrial transcription factor and mtDNA-binding protein (TFAM), mitochondrial single-stranded DNA-binding protein (mtSSB), mitochondrial DNA polymerase subunit gamma-2 (POLG2) and mitochondrial helicase C26H10ORF2 protein (Twinkle). These proteins were ranked according to Mascot scores, and sorted according to presumed functional properties. A large group of proteins involved in protein synthesis comprised an almost complete set of subunits of mitochondrial ribosomes suggesting that the nucleoids contained significant amounts of mitochondrial ribosomes. Identification of sixty six proteins from the oxidative phosphorylation (OXPHOS) system comprising around 100 proteins in total suggested that OXPHOS proteins are also associated with mt-nucleoids.
Interestingly, TFAM, described as a main mtDNA packaging factor in human and other mammalian cells, was not confirmed here as a major nucleoid component from bovine heart mitochondria. Fluorescence staining of protein spots on 2-D IEF/SDS gels clearly identified TFAM, but according to the stain intensity, this protein did not rank in the list of the 90 most abundant nucleoid proteins. Western blot analysis of sucrose gradient fractions revealed an enrichment of putative TFAM isoform in nucleoid fractions. Unexpectedly, the uncharacterized mitochondrial protein Es1 was identified as the most abundant nucleoid protein in bovine heart nucleoids instead. This implicates that nucleoid organization may differ between species and tissues. A functional characterization of Es1 is required to clarify its role in mammalian nucleoids.
Strongly correlated ultracold bosons in an optical lattice
- In this thesis, we have investigated strongly correlated bosonic gases in an optical lattice, mostly based on a bosonic version of dynamical mean field theory and its real-space extension. Emphasis is put on possible novel quantum phenomena of these many-body systems and their corresponding underlying physics, including quantum magnetism, pair-superfluidity, thermodynamics, many-body cooling, new quantum phases in the presence of long-range interactions, and excitational properties. Our motivation is to simulate manybody phenomena relevant to strongly correlated materials with ultracold lattice gases, which provide an excellent playground for investigating quantum systems with an unprecedented level of precision and controllability. Due to their high controllability, ultracold gases can be regarded as a quantum simulator of many-body systems in solid-state physics, high energy astrophysics, and quantum optics. In this thesis, specifically, we have explored possible novel quantum phases, thermodynamic properties, many-body cooling schemes, and the spectroscopy of strongly correlated many-body quantum systems. The results presented in this thesis provide theoretical benchmarks for exploring quantum magnetism in upcoming experiments, and an important step towards studying quantum phenomena of ultracold gases in the presence of long-range interactions.
Entwicklung einer digitalen Korpusanwendung zur türkeitürkischen Dialektologie
- Inhalt dieser Arbeit ist die Entwicklung einer digitalen Korpusanwendung zur türkeitürkischen Dialektologie, in welcher der Inhalt des in Kapitel 3.1 beschriebenen Wörterbuchs komplett enthalten und umfangreich durchsuchbar sein soll. Da das Dialektwörterbuch insgesamt 126.468 Einträge enthält, ist eine manuelle Recherche darin äußerst zeitintensiv und unkomfortabel. Selbst die Suche innerhalb einer digitalen Version, die z. B. in einer Word-Datei gespeichert sein kann, ist nicht komfortabel möglich, sobald Optionen bzw. Einschränkungen getätigt werden sollen, wie z. B. die Beschränkung der Ergebnisse auf das Vorkommen in einer bestimmten Provinz. Daher ist es das Ziel der Entwicklung, den Anwendern folgende Suchmöglichkeiten zu bieten: Das Wörterbuch soll entweder komplett im Volltext durchsucht werden können, oder nur innerhalb des Lemmas1. Dabei soll jeweils die Angabe einer oder mehrerer Provinzen möglich sein, sodass die Suchergebnisse nur jene Einträge beinhalten, in denen Suchbegriff und Provinz in der gleichen Zeile enthalten sind. Die Treffer der Suche sollen farbig hervorgehoben sein, damit insbesondere bei großen Wörterbucheinträgen nicht manuell nach den darin enthaltenen Suchbegriffen gesucht werden muss, sondern diese dem Anwender direkt auffallen. Außerdem ist es wünschenswert, mittels Platzhaltern und sogenannten Coversymbolen nach Wortformen und phonetisch bedingten Allomorphen suchen zu können. Letzteres ist für Linguisten, die sich mit dem Türkischen beschäftigen, bei der Eingabe der Suchbegriffe äußerst praktisch, da das Türkische eine vokalharmonische Sprache ist, in der phonetisch bedingte Varianten üblicherweise durch die Schreibung mit Coversymbolen dargestellt werden: z. B. -lAr für die Pluralallomorphe -lar und -ler...
Germination performance of native and non-native Ulmus pumila populations
Henrik von Wehrden
- Germination is a crucial step for invasive plants to extend their distribution under different environmental conditions in a new range. Therefore, information on germination characteristics of invasive plant species provides invaluable knowledge about the factors which might contribute to the invasion success. Moreover, intra-specific comparisons under controlled conditions will show if different responses between non-native and native populations are caused by evolutionary changes or by phenotypic plasticity towards different environmental influences. This paper focuses on the germination of native and non-native Ulmus pumila populations. We expected that non-native populations would be characterized by their higher final germination percentage and enhanced germination rate, which might indicate an influence due to corresponding climatic conditions. Germination experiments with a moderate and a warm temperature treatment did not reveal significant differences in final germination percentage. However, seeds from the North American non-native range germinated significantly faster than native seeds (p < 0.001). Additionally, mean time to germination in both ranges was significantly negatively correlated with annual precipitation (p = 0.022). At the same time, this relationship is stronger in the native range whereas mean time to germination in nonnative populations seems to be less influenced by climatic conditions. Different germination responses of the North American populations could be caused by a fast evolutionary change mediating a higher tolerance to current climatic conditions in the non-native range. However, our findings could also be caused by artificial selection during the introduction process and extensive planting of U. pumila in its non-native range. Nevertheless, we assume that the faster germination rate of non-native populations is one potential explanation for the invasion success of U. pumila in its new range since it might provide a competitive advantage during colonization of new sites.
Plant invasions in China: an emerging hot topic in invasion science
- China has shown a rapid economic development in recent decades, and several drivers of this change are known to enhance biological invasions, a major cause of biodiversity loss. Here we review the current state of research on plant invasions in China by analyzing papers referenced in the ISI Web of Knowledge. Since 2001, the number of papers has increased exponentially, indicating that plant invasions in China are an emerging hot topic in invasion science. The analyzed papers cover a broad range of methodological approaches and research topics. While more that 250 invasive plant species with negative impacts have been reported from China, only a few species have been considered in more than a handful of papers (in order of decreasing number of references: Spartina alterniflora, Ageratina adenophora, Mikania micrantha, Alternanthera philoxeroides, Solidago canadensis, Eichhornia crassipes). Yet this selection might rather reflect the location of research teams than the most invasive plant species in China. Considering the previous achievements in China found in our analysis research in plant invasions could be expanded by (1) compiling comprehensive lists of non-native plant species at the provincial and national scales and to include species that are native to one part of China but non-native to others in these lists; (2) strengthening pathways studies (primary introduction to the country, secondary releases within the country) to enhance prevention and management; and (3) assessing impacts of invasive species at different spatial scales (habitats, regions) and in relation to conservation resources.
An inventory of invasive alien species in China
- Invasive alien species (IAS) are a major global challenge requiring urgent action, and the Strategic Plan for Biodiversity (2011–2020) of the Convention on Biological Diversity (CBD) includes a target on the issue. Meeting the target requires an understanding of invasion patterns. However, national or regional analyses of invasions are limited to developed countries. We identified 488 IAS in China’s terrestrial habitats, inland waters and marine ecosystems based on available literature and field work, including 171 animals, 265 plants, 26 fungi, 3 protists, 11 procaryots, and 12 viruses. Terrestrial plants account for 51.6% of the total number of IAS, and terrestrial invertebrates (104 species) for 21.3%. Of the total numbers, 67.9% of plant IAS and 34.8% of animal IAS were introduced intentionally. All other taxa were introduced unintentionally despite very few animal and plant species that invaded naturally. In terms of habitats, 64.3% of IAS occur on farmlands, 13.9% in forests, 8.4% in marine ecosystems, 7.3% in inland waters, and 6.1% in residential areas. Half of all IAS (51.1%) originate from North and South America, 18.3% from Europe, 17.3% from Asia not including China, 7.2% from Africa, 1.8% from Oceania, and the origin of the remaining 4.3% IAS is unknown. The distribution of IAS can be divided into three zones. Most IAS are distributed in coastal provinces and the Yunnan province; provinces in Middle China have fewer IAS, and most provinces in West China have the least number of IAS. Sites where IAS were first detected are mainly distributed in the coastal region, the Yunnan Province and the Xinjiang Uyghur Autonomous Region. The number of newly emerged IAS has been increasing since 1850. The cumulative number of firstly detected IAS grew exponentially.
A conceptual framework for prioritization of invasive alien species for management according to their impact
Tamara B. Robinson
- The number of invasive alien species is increasing and so are the impacts these species cause to the environment and economies. Nevertheless, resources for management are limited, which makes prioritization unavoidable. We present a prioritization framework which can be useful for decision makers as it includes both a scientific impact assessment and the evaluation of impact importance by affected stakeholders. The framework is divided into five steps, namely 1) stakeholder selection and weighting of stakeholder importance by the decision maker, 2) factual description and scoring of changes by scientists, 3) evaluation of the importance of impact categories by stakeholders, 4) calculation of weighted impact categories and 5) calculation of final impact score and decision making. The framework could be used at different scales and by different authorities. Furthermore, it would make the decision making process transparent and retraceable for all stakeholders and the general public.