The transcriptionfactor homeobox A9 and the endothelial function

Die postnatale Neovaskularisierung ist eine wichtige Vorraussetzung um Gewebe vor kritischer Ischämie zu schützen. Eine der Grundlagen dieses Prozesses bilden die Angiogenese, bei der neue Kapillaren durch Proliferation und Migration von Endothelzellen aus bereits vorhandenen Blutgefäßen entstehen. Ein zweiter Eckpfeiler ist die Vaskulogenese, die unter anderem durch zirkulierende endotheliale Vorläuferzellen (EPC) vermittelt wird. Homeobox-Gene der Klasse 1 (Hox) sind Transkriptionsfaktoren, die während der Embryonalentwicklung an der Organogenese und der Entwicklung des kardiovaskulären Systems beteiligt sind. Verschiedene Studien weisen darauf hin, dass Homeobox-Proteine auch im adulten Organismus bei der transkriptionellen Regulation von Genen der Angio- und Vaskulogenese eine wichtige Rolle spielen. Die in dieser Arbeit vorliegenden Ergebnisse zeigen eine essentielle Rolle von HoxA9 für die postnatale Neovaskularisierung sowie für die funktionelle Integrität von Endothelzellen und endothelialen Progenitorzellen. HoxA9-defiziente Mäuse hatten einen signifikant verringerten Blutfluss nach einer Hinterlauflauf-Ischämie. Für die reduzierte Neovaskularisierung des ischämischen Gewebes, genügte der Verlust eines einzigen HoxA9-Wildtypallels. Außerdem zeigen HoxA9-defiziente Endothelzellen in vitro eine stark gehemmte Migration sowie eine verringerte Gefäßstrukturbildung. Zusätzlich war auch deren Interaktion mit EPC im Matrigel verschlechtert. Eine Bestätigung dieser Beobachtung zeigten Untersuchungen an endothelialen Vorläuferzellen, die ebenfalls einen Verlust angiogener Funktionen bei verminderter HoxA9-Expression aufwiesen. Neben der postnatalen Neovaskularisierung konnten erste Untersuchungen embryonaler Allantois zeigen, das HoxA9 vermutlich auch in der embryonalen Gefäßbildung beteiligt ist. Diese Theorie wird durch eine nicht-Mendelsche Verteilung der postnatalen Genotypen nach Kreuzung heterozygoter HoxA9-Mäuse unterstützt. Als molekulare Ursachen der Hemmung angiogener Funktionen bei Endothelzellen, konnte die Regulation verschiedener Gene nachgewiesen werden. So ist HoxA9 für die Expression der endothelialen Stickstoffmonoxidsynthase (eNOS), des VEGF-Rezeptors 2 (VEGF-R2), der Adhäsionsmoleküle VE-Cadherin und Integrin v3 sowie des EphB4-Rezeptors von essentieller Bedeutung. Diese von HoxA9 regulierten Gene spielen für die Angio- und Vaskulogenese alle eine entscheidende Rolle. Der EphB4-Rezeptor, die eNOS und der VEGF-R2 werden durch eine direkte Bindung von HoxA9 an den jeweiligen Promotor auf transkriptioneller Ebene reguliert. Bei den Genen Integrin v3 und VE-Cadherin erfolgt die Regulation durch HoxA9 indirekt über andere Gene oder posttranskriptionell. Zusätzlich zum Nachweis der Kontrolle der Genexpression, konnte für den EphB4-Rezeptor nachgewiesen werden, dass dieser von großer Bedeutung für die HoxA9-regulierte Migration ist. Außerdem besitzt der EphB4-Promotor eine für die Regulation der EphB4-Expression durch HoxA9 wichtige Bindungsstelle. In weiteren Versuchen konnte gezeigt werden, dass HoxA9 Schubspannungs-abhängig reguliert wird und dabei auch in die Regulation der Schubspannungs-induzierten Migration und die Schubspannungs-abhängige Expression der untersuchten Zielgene von HoxA9 eingreift. Zusammenfassend zeigen die hier vorgestellten Daten, dass HoxA9 endotheliale Gene vielfältig reguliert, eine entscheidende Rolle bei der Modulation verschiedener endothelialer Funktionen spielt und essentiell für die postnatale Neovaskularisierung ist.Postnatal neovascularisation, which is important to protect tissues from critical ischemia, includes both angiogenesis and vasculogenesis. Thereby angiogenesis is due to proliferation and migration of mature endothelial cells (EC) out of pre-existing, blood vessels, whereas vasculogenesis depends on the integration of circulating endothelial progenitor cells (EPC). Homeobox morphoregulatory genes encode for transcription factors, which regulate cell proliferation and migration and play an important role in organogenesis and the development of the cardiovascular system during embryogenesis. However, previous publications and recent data of our group demonstrate also principal role of homeobox genes (Hox) for an angiogenic phenotype in the adult organism. Homeobox genes are organised in four genomic clusters with a DNA-binding motif, the homeodomain. Endothelial cells express homeobox genes from several clusters such as HoxA, HoxB and HoxD, which regulate cell adhesions molecules like N-CAM, L-CAM or putative Eph-receptors. But there is no evidence for direct regulation from Eph-receptors via Homeobox genes. In addition recent studies showed that HoxD3 induce angiogenesis in EC by expression of Integrin v3 and HoxB3 stimulate capillary structures in an animal model. An alternatively splice variant of HoxA9 was detected as an endothelial-specific homeobox gene. In addition to mature EC, EPC play an important role for adult blood vessel formation. EPC derive from hematopoietic stem cells (HSC) and are released from the bone marrow. Ectopic expression of transcription factor HoxB4 promote the differentiation from earlier primitive progenitors to definitive HSC in vitro. In addition HoxB4 have a high potency to enable high-level ex vivo HSC expansion and increase in vivo the regenerative potential of HSC to improve hematopoiesis. Laminar shear stress is an important endogenous stimulus to maintain endothelial cell function. Shear stress regulates the expression of endothelial specific proteins such as VEGF receptor 2 (KDR) and endothelial nitric oxide synthase (eNOS). Homeodomain transcription factors are master regulatory genes, which are involved in differentiation. In particular, homeobox A9 (HoxA9) promotes angiogenic functions and may act as an endothelial regulatory factor. Therefore, we investigated the role of HoxA9 for shear stress-induced gene expression. Shear stress time- and dose-dependently increased HoxA9 protein expression. Knock-down of HoxA9 by RNA interference (RNAi) in HUVEC significantly regulated eNOS, EphB4, KDR, Integrin v3 and VE-Cadherin, whereas the expression of CD31 and von Willebrand factor were unchanged. To determine a direct regulatory role of HoxA9 for eNOS, EphB4, KDR, Integrin v3 and VE-Cadherin, we analyzed the binding of HoxA9 to their promoters by chromatin-immunoprecipitation (ChIP). Wild-type HoxA9 bound to the eNOS-, EphB4-, KDR-, Integrin 3 - promoter, whereas a HoxA9 mutant lacking the DNA binding domain did not. HoxA9 did not bind the VE-Cadherin- or Integrin v-promoter. Moreover, overexpression of HoxA9 wt significantly enhanced eNOS-, EphB4-, KDR-, Integrin v3 - and VE-Cadherin - promoter activity in a luciferase assay

Neural correlates of personality dimensions and affective measures during the anticipation of emotional stimuli

Neuroticism and extraversion are proposed personality dimensions for individual emotion processing. Neuroticism is correlated with depression and anxiety disorders, implicating a common neurobiological basis. Extraversion is rather inversely correlated with anxiety and depression. We examined neural correlates of personality in relation to depressiveness and anxiety in healthy adult subjects with functional magnetic resonance imaging during the cued anticipation of emotional stimuli. Distributed particularly prefrontal but also other cortical regions and the thalamus were associated with extraversion. Parieto-occipital and temporal regions and subcortically the caudate were correlated with neuroticism and affective measures. Neuroticism-related regions were partially cross-correlated with anxiety and depression and vice versa. Extraversion-related activity was not correlated with the other measures. The neural correlates of extraversion compared with those of neuroticism and affective measures fit with concepts of different neurobiological bases of the personality dimensions and point at predispositions for affective disorder

Polymer-grade bio-monomers from oleochemicals by combining homogeneous catalysis and selective product crystallization in an integrated process

The homogeneously catalyzed methoxycarbonylation of bio-based methyl 10-undecenoate (C11-DME) produces linear 1,12-dimethyl dodecanedioate (l-C12-DME). Subsequent selective product crystallization from the reaction mixture with downstream filtration and washing allows for the generation of the bio-monomer in polymer grade quality (>99.9%). This effective purification enables its direct use, e.g., for bio-based polyamides, without further purification. It separates the expensive homogeneous catalyst dissolved in the liquid phase in its active state for efficient catalyst recycling. We present the complex interactions of process parameters regarding reaction and crystallization-based purification in an integrated catalyst recycling process. Furthermore, we demonstrate that purification of l-C12-DME with >99.9% purity over multiple consecutive recycling runs is possible. However, as the crystallization is highly sensitive towards changing concentrations of by-products and particularly unreacted substrates, this high purity is only achieved by maintaining a stable composition in the reaction mixture using a newly developed system for precise conversion control in the reaction step

Novel Smartphone Interventions Improve Cognitive Flexibility and Obsessive-Compulsive Disorder Symptoms in Individuals with Contamination Fears.

One type of obsessive-compulsive disorder (OCD) is characterized by contamination fears and compulsive cleansing. Few effective treatments are available for this debilitating condition. Compulsive symptoms, such as excessive washing, are believed to be mediated by cognitive inflexibility-arguably the most striking cognitive impairment in OCD. In this study, we investigated the effects of two novel smartphone interventions on cognitive flexibility and OCD symptoms in healthy individuals with OCD-like contamination fears. In the first intervention, participants watched a brief video recording of themselves engaging in handwashing on a smartphone, four times a day, for a total of one week (N = 31). The second intervention was similar except that participants watched themselves repeatedly touching a disgust-inducing object (N = 31). In a third (control) "intervention", participants watched themselves performing sequential hand movements (N = 31). As hypothesized, the two smartphone interventions, unlike the control, improved cognitive flexibility; as assessed on the Intradimensional-Extradimensional Set Shifting task (a sensitive marker of cognitive flexibility). The two interventions, unlike the control, also improved OCD symptoms (measured with the Obsessive-Compulsive Inventory-Revised and Yale-Brown Obsessive-Compulsive Scale). Finally, we found high levels of adherence to the interventions. These findings have significant clinical implications for OCD

Über das Auftreten und die Verbreitung von Crypturaphis grassii Silvestri, 1935 und Neotoxoptera formosana (Takahashi, 1921) (Hemiptera, Aphididae) in Deutschland

Es wird über die Nachweise und die Ausbreitung der zwei nichtwirtswechselnden Blattlausarten Crypturaphis grassii Silvestri, 1935 und Neotoxoptera formosana (Takahashi, 1921) in Deutschland berichtet. Auf hohe Besiedelungsdichte reagiert die monophage, nur Alnus cordata besiedelnde C. grassii mit der verstärkten Produktion von geflügelten Morphen, die eine schnelle Ausbreitung ermöglichen. Diese Reaktion ist stark reduziert bei der polyphagen, zahlreiche Taxa des Genus Allium L. besiedelnden N. formosana, deren Ausbreitung hauptsächlich vom anthropogenen Transport besiedelter Wirtspflanzen abhängig ist

Evidence for Efimov quantum states in an ultracold gas of cesium atoms

Systems of three interacting particles are notorious for their complex physical behavior. A landmark theoretical result in few-body quantum physics is Efimov's prediction of a universal set of bound trimer states appearing for three identical bosons with a resonant two-body interaction. Counterintuitively, these states even exist in the absence of a corresponding two-body bound state. Since the formulation of Efimov's problem in the context of nuclear physics 35 years ago, it has attracted great interest in many areas of physics. However, the observation of Efimov quantum states has remained an elusive goal. Here we report the observation of an Efimov resonance in an ultracold gas of cesium atoms. The resonance occurs in the range of large negative two-body scattering lengths, arising from the coupling of three free atoms to an Efimov trimer. Experimentally, we observe its signature as a giant three-body recombination loss when the strength of the two-body interaction is varied. We also detect a minimum in the recombination loss for positive scattering lengths, indicating destructive interference of decay pathways. Our results confirm central theoretical predictions of Efimov physics and represent a starting point with which to explore the universal properties of resonantly interacting few-body systems. While Feshbach resonances have provided the key to control quantum-mechanical interactions on the two-body level, Efimov resonances connect ultracold matter to the world of few-body quantum phenomena.Comment: 18 pages, 3 figure

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization

Improving insect conservation management through insect monitoring and stakeholder involvement

In recent years, the decline of insect biodiversity and the imminent loss of provided ecosystem functions and services has received public attention and raised the demand for political action. The complex, multi-causal contributors to insect decline require a broad interdisciplinary and cross-sectoral approach that addresses ecological and social aspects to find sustainable solutions. The project Diversity of Insects in Nature protected Areas (DINA) assesses insect communities in 21 nature reserves in Germany, and considers interactions with plant diversity, pesticide exposure, spatial and climatic factors. The nature reserves border on agricultural land, to investigate impacts on insect diversity. Part of the project is to obtain scientific data from Malaise traps and their surroundings, while another part involves relevant stakeholders to identify opportunities and obstacles to insect diversity conservation. Our results indicate a positive association between insect richness and biomass. Insect richness was negatively related to the number of stationary pesticides (soil and vegetation), pesticides measured in ethanol, the amount of area in agricultural production, and precipitation. Our qualitative survey along with stakeholder interviews show that there is general support for insect conservation, while at the same time the stakeholders expressed the need for more information and data on insect biodiversity, as well as flexible policy options. We conclude that conservation management for insects in protected areas should consider a wider landscape. Local targets of conservation management will have to integrate different stakeholder perspectives. Scientifically informed stakeholder dialogues can mediate conflicts of interests, knowledge, and values to develop mutual conservation scenarios