Identifizierung und Charakterisierung von Maturin als neues Zielprotein in der Pathogenese der kardialen Hypertrophie aus Genexpressionsanalysen der Hypertrophen Kardiomyopathie

Pathologische kardiale Hypertrophie tritt als Anpassungsmechanismus auf anhaltende Überbeanspruchung des Herzmuskels auf und bedeutet für die Betroffenen mittel- und langfristig eine Einschränkung von Belastbarkeit und Lebensqualität sowie eine gesteigerte Mortalität. Zwar sind mittlerweile vielfältige molekulare Mechanismen bekannt, welche das Krankheitsbild verursachen und aggravieren können. Jedoch sind die therapeutischen Möglichkeiten nach wie vor unzureichend. Ziel dieser Arbeit war es daher, in einem „bedside-to-bench“-Ansatz die differentielle Regulation ausgewählter Gene aus einer Microarray-Analyse von humanen HCM-Gewebeproben in experimentellen Hypertrophiemodellen zu überprüfen und nähere Hinweise auf deren Funktion zu liefern. In diesem Zusammenhang konnten wir c7orf41/Maturin identifizieren, welches in Modellversuchen zur Hypertrophie in der Zellkultur und auch in vivo signifikant herabreguliert war. Die adenovirale Überexpression von Maturin bewirkt eine Induktion des fetalen hypertrophen Genprogrammes sowie eine Zunahme der Zellgröße von NRVCM. Maturin ist in diesen Zellen perinukleär lokalisiert, was auf eine Anreicherung im Endoplasmatischen Retikulum hindeuten könnte. Analog hierzu konnte die Expression des Gens durch Auslösung von ER-Stress deutlich induziert werden. Überexpression von Maturin führt jedoch zu keiner Veränderung in der Expression der zentralen ER-Stressgene. Weiterhin konnte in Hungerversuchen in vitro und in vivo eine Induktion von Maturin beobachtet werden, was eine Verbindung zum Prozess der Autophagie vermuten lässt. Sowohl ER-Stress bzw. die Unfolded Protein Response als auch die Autophagie sind mittlerweile als möglicherweise bedeutende molekulare Mechanismen an der Entstehung einer Vielzahl kardialer Pathologien, u.a. auch der Hypertrophie, bekannt. Es konnte in dieser Dissertation gezeigt werden, dass Maturin in hypertrophierten Maus- und Rattenkardiomyozyten vermindert exprimiert wird, eine artifizielle Überexpression des Gens jedoch zur Induktion von Hypertrophie führt. Dieser Effekt wird möglicherweise über eine Beteiligung des Maturin-Proteins an ER-Stress und Autophagie hervorgerufen und stellt eine Basis für künftige Forschung zu diesem bislang nur wenig charakterisierten Gen dar

Mediators and Cytokines in Persistent Allergic Rhinitis and Nonallergic Rhinitis with Eosinophilia Syndrome

Background: Patients with nonallergic rhinitis with eosinophilia syndrome (NARES) show typical symptoms of persistent allergic rhinitis (PAR). The aim of the present study was to compare nasal cytokine patterns between NARES and PAR. Methods: Nasal secretions of 31 patients suffering from NARES, 20 patients with PAR to house dust mite and 21 healthy controls were collected using the cotton wool method and analyzed for interleukin (IL)-1 beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 beta (MIP-1 beta) by Bio-Plex Cytokine Assay as well as eosinophil cationic protein (ECP) and tryptase by UniCAP-FEIA. Results: NARES and PAR presented elevated levels of tryptase, while ECP was markedly increased solely in NARES compared to both the controls and PAR. Elevated levels of IL-1 beta, IL-17, IFN-gamma, TNF-alpha and MCP-1 were found in NARES compared to the controls as well as PAR. MIP-1 beta was elevated in NARES and PAR, while IL-4, IL-6 and G-CSF showed increased levels in NARES, and IL-5 was elevated in PAR only. Conclusions: In patients with NARES and PAR, eosinophils and mast cells appear to be the pivotal cells of inflammation, reflected by high levels of tryptase and ECP as well as IL-5 and GM-CSF as factors for eosinophil migration and survival. The elevated levels of proinflammatory cytokines in NARES may indicate the chronic, self-perpetuating process of inflammation in NARES which seems to be more pronounced than in PAR. IL-17 might be a factor for neutrophilic infiltration or be responsible for remodeling processes in NARES. Copyright (C) 2012 S. Karger AG, Base

The timing of polyphase Miocene tectonics in Northern Romania

This study addresses the polyphase Miocene tectonic evolution in the Maramures area (northern Romania) by combining field observations, stratigraphic arguments and fission-track analysis (Tischler et al. in press). Fission-track analysis has been carried out on basement samples from the Rodna horst, situated in the East Carpathians (Bucovinvian nappes). This area was affected by Cretaceous medium- to low-grade metamorphism, followed by post-collisional exhumation and renewed moderate thermal overprint due to the deposition of Eocene to Early Miocene sediments. Based on paleostress analyses of mesoscale structures, three main tectonic phases can be disdinguished in the study area, all of which are postdate the earliest Miocene (Aquitanian, 20.5 Ma). In late Early Miocene (Burdigalian) the Pienide nappes, nonmetamorphic flysch series, were emplaced onto the Paleogene to Early Miocene sedimentary cover of the Bucovinian nappes...conferenc

Atmospheric rivers in CMIP5 climate ensembles downscaled with a high-resolution regional climate model

Atmospheric rivers (ARs) are important drivers of hazardous precipitation levels and are often associated with intense floods. So far, the response of ARs to climate change in Europe has been investigated using global climate models within the CMIP5 framework. However, the spatial resolution of those models (1–3∘) is too coarse for an adequate assessment of local to regional precipitation patterns. Using a regional climate model with 0.22∘ resolution, we downscaled an ensemble consisting of 1 ERA-Interim (ERAI) reanalysis data hindcast simulation, 9 global historical, and 24 climate scenario simulations following greenhouse gas emission scenarios RCP2.6, RCP4.5, and RCP8.5. The performance of the climate model to simulate AR frequencies and AR-induced precipitation was tested against ERAI. Overall, we find a good agreement between the downscaled CMIP5 historical simulations and ERAI. However, the downscaled simulations better represented small-scale spatial characteristics. This was most evident over the terrain of the Iberian Peninsula, where the AR-induced precipitation pattern clearly reflected prominent east–west topographical elements, resulting in zonal bands of high and low AR impact. Over central Europe, the models simulated a smaller propagation distance of ARs toward eastern Europe than obtained using the ERAI data. Our models showed that ARs in a future warmer climate will be more frequent and more intense, especially in the higher-emission scenarios (RCP4.5, RCP8.5). However, assuming low emissions (RCP2.6), the related changes can be mostly mitigated. According to the high-emission scenario RCP8.5, AR-induced precipitation will increase by 20 %–40 % in western central Europe, whereas mean precipitation rates increase by a maximum of only 12 %. Over the Iberian Peninsula, AR-induced precipitation will slightly decrease (∼6 %) but the decrease in the mean rate will be larger (∼15 %). These changes will lead to an overall increased fractional contribution of ARs to heavy precipitation, with the greatest impact over the Iberian Peninsula (15 %–30 %) and western France (∼15 %). Likewise, the fractional share of yearly maximum precipitation attributable to ARs will increase over the Iberian Peninsula, the UK, and western France. Over Norway, average AR precipitation rates will decline by −5 % to −30 %, most likely due to dynamic changes, with ARs originating from latitudes > 60∘ N decreasing by up to 20 % and those originating south of 45∘ N increasing. This suggests that ARs over Norway will follow longer routes over the continent, such that additional moisture uptake will be impeded. By contrast, ARs from >60∘ N will take up moisture from the North Atlantic before making landfall over Norway. The found changes in the local AR pathway are probably driven by larger-scale circulation changes such as a change in dominating weather regimes and/or changes in the winter storm track over the North Atlantic

Cytokine patterns in nasal secretion of non-atopic patients distinguish between chronic rhinosinusitis with or without nasal polys

Background: Being one of the most common nasal diseases, chronic rhinosinusitis (CRS) is subdivided into CRS with nasal polyps (NP) and CRS without nasal polyps (CRSsNP). CRSsNP presents itself with a T(H)1 milieu and neutrophil infiltration, while NP is characterised by a mixed T(H)1/T(H)2 profile and an influx of predominantly eosinophils, plasma cells and mast cells. For the purpose of discovering disease-specific cytokine profiles, the present study compares levels of mediators and cytokines in nasal secretions between CRSsNP, NP, and healthy controls. Methods: The study included 45 participants suffering from NP, 48 suffering from CRSsNP and 48 healthy controls. Allergic rhinitis constituted an exclusion criterion. Nasal secretions, sampled using the cotton wool method, were analysed for IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, IL-8, GM-CSF, G-CSF, IFN-gamma, MCP-1, MIP-1 alpha, MIP-1 beta, eotaxin, and RANTES, and for ECP and tryptase, using Bio-Plex Cytokine assay or ELISA, respectively. Results: Elevated levels of IL-5, IL-17, G-CSF, MCP-1, MIP-1 alpha, MIP-1 beta, ECP, and tryptase, as well as decreased levels of IL-10, IL-12, IL-13, and IFN-gamma were detected in NP. CRSsNP presented increased levels of RANTES and MIP-1 beta while IL-13 was decreased. No differences between the three groups were found for IL-4, IL-8, GM-CSF, and eotaxin. Conclusions: The present work suggests a disequilibrium of T(H)1 and T(H)2, together with a down-regulation of regulatory T lymphocytes and up-regulated T(H)17 in NP. Moreover, elevated levels of diverse mediators represent the activation of various inflammatory cells in this disease entity. The inflammation in CRSsNP, however, is only weakly depicted in nasal secretions. Therefore, cytokines in nasal secretions may provide helpful information for differential diagnosis

Baltic Sea ecosystem response to various nutrient load scenarios in present and future climates

The Baltic Sea is a shallow, semi-enclosed brackish sea suffering like many other coastal seas from eutrophication caused by human impact. Hence, nutrient load abatement strategies are intensively discussed. With the help of a high-resolution, coupled physical-biogeochemical circulation model we investigate the combined impact of changing nutrient loads from land and changing climate during the 21st century as projected from a global climate model regionalized to the Baltic Sea region. Novel compared to previous studies are an extraordinary spin-up based upon historical reconstructions of atmospheric, nutrient load and runoff forcing, revised nutrient load scenarios and a comparison of nutrient load scenario simulations with and without changing climate. We found in almost all scenario simulations, with differing nutrient inputs, reduced eutrophication and improved ecological state compared to the reference period 1976–2005. This result is a long-lasting consequence of ongoing nutrient load reductions since the 1980s. Only in case of combined high-end nutrient load and climate scenarios, eutrophication is reinforced. Differences compared to earlier studies are explained by the experimental setup including nutrient loads during the historical period and by the projected nutrient loads. We found that the impact of warming climate may amplify the effects of eutrophication and primary production. However, effects of changing climate, within the range of considered greenhouse gas emission scenarios, are smaller than effects of considered nutrient load changes, in particular under low nutrient conditions. Hence, nutrient load reductions following the Baltic Sea Action Plan will lead to improved environmental conditions independently of future climate change.publishedVersio

Uncertainties in projections of the baltic sea ecosystem driven by an ensemble of global climate models

Many coastal seas worldwide are affected by human impacts such as eutrophication causing, inter alia, oxygen depletion, and extensive areas of hypoxia. Depending on the region, global warming may reinforce these environmental changes by reducing air-sea oxygen fluxes, intensifying internal nutrient cycling, and increasing river-borne nutrient loads. The development of appropriate management plans to effectively protect the marine environment requires projections of future marine ecosystem states. However, projections with regional climate models commonly suffer from shortcomings in the driving global General Circulation Models (GCMs). The differing sensitivities of GCMs to increased greenhouse gas concentrations affect regional projections considerably. In this study, we focused on one of the most threatened coastal seas, the Baltic Sea, and estimated uncertainties in projections due to climate model deficiencies and due to unknown future greenhouse gas concentration, nutrient load and sea level rise scenarios. To address the latter, simulations of the period 1975–2098 were performed using the initial conditions from an earlier reconstruction with the same Baltic Sea model (starting in 1850). To estimate the impacts of climate model uncertainties, dynamical downscaling experiments with four driving global models were carried out for two greenhouse gas concentration scenarios and for three nutrient load scenarios, covering the plausible range between low and high loads. The results suggest that changes in nutrient supply, in particular phosphorus, control the long-term (centennial) response of eutrophication, biogeochemical fluxes and oxygen conditions in the deep water. The analysis of simulated primary production, nitrogen fixation, and hypoxic areas shows that uncertainties caused by the various nutrient load scenarios are greater than the uncertainties due to climate model uncertainties and future greenhouse gas concentrations. In all scenario simulations, a proposed nutrient load abatement strategy, i.e., the Baltic Sea Action Plan, will lead to a significant improvement in the overall environmental state. However, the projections cannot provide detailed information on the timing and the reductions of future hypoxic areas, due to uncertainties in salinity projections caused by uncertainties in projections of the regional water cycle and of the mean sea level outside the model domain.publishedVersio

Gradient-based estimation of Manning's friction coefficient from noisy data

We study the numerical recovery of Manning's roughness coefficient for the diffusive wave approximation of the shallow water equation. We describe a conjugate gradient method for the numerical inversion. Numerical results for one-dimensional model are presented to illustrate the feasibility of the approach. Also we provide a proof of the differentiability of the weak form with respect to the coefficient as well as the continuity and boundedness of the linearized operator under reasonable assumptions using the maximal parabolic regularity theory.Comment: 19 pages, 3 figure

Towards a Rule-based Manufacturing Integration Assistant

Recent developments and steadily declining prices in ICT enable an economic application of advanced digital tools in wide areas of manufacturing. Solutions based on concepts and technologies of the “Internet of Things” or “cyber physical systems” can be used to implement monitoring as well as self-organization of production, maintenance or logistics processes. However, integration of new digital tools in existing heterogeneous manufacturing IT systems and integration of machines and devices into manufacturing environments is an expensive and tedious task. Therefore, integration issues on IT and manufacturing level significantly prevent agile manufacturing. Especially small and medium-sized enterprises do not have the expertise or the investment possibilities to realize such an integration. To tackle this issue, we present the approach of the Manufacturing Integration Assistant - MIALinx. The objective is to develop and implement a lightweight and easy-to-use integration solution for small and medium-sized enterprises based on recent web automation technologies. MIALinx aims to simplify the integration using simple programmable, flexible and reusable “IF-THEN” rules that connect occurring situations in manufacturing, such as a machine break down, with corresponding actions, e.g., an automatic maintenance order generation. For this purpose, MIALinx connects sensors and actuators based on defined rules whereas the rule set is defined in a domain-specific, easy-to-use manner to enable rule modeling by domain experts. Through the definition of rule sets, the workers’ knowledge can be also externalized. Using manufacturing-approved cloud computing technologies, we enable robustness, security, and a low-effort, low-cost integration of MIALinx into existing manufacturing environments to provide advanced digital tools also for small and medium-sized enterprises