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We examine the inter-linkages between financial factors and real economic activity. We review the main theoretical approaches that allow financial frictions to be embedded into general equilibrium models. We outline, from a policy perspective, the most recent empirical papers focusing on the propagation of exogenous shocks to the economy, with a particular emphasis on works dealing with time variation of parameters and other types of nonlinearities. We then present an application to the analysis of the changing transmission of financial shocks in the euro area. Results show that the effects of a financial shock are time-varying and contingent on the state of the economy. They are of negligible importance in normal times but they greatly matter in conditions of stress.
In many European countries poverty migration and its impact on the European continent are currently widely discussed topics. Many seem to forget about grave migration problems taking place in Asia, where in Hong Kong, for example, the working and living conditions for approximately 320,000 foreign domestic workers (mostly women) are often intolerable.
With only a 2.6 Å resolution laboratory powder diffraction pattern of the θ phase of Pigment Yellow 181 (P.Y. 181) available, crystal-structure solution and Rietveld refinement proved challenging; especially when the crystal structure was shown to be a triclinic dimethylsulfoxide N-methyl-2-pyrrolidone (1:1:1) solvate. The crystal structure, which in principle has 28 possible degrees of freedom, was determined in three stages by a combination of simulated annealing, partial Rietveld refinement with dummy atoms replacing the solvent molecules and further simulated annealing. The θ phase not being of commercial interest, additional experiments were not economically feasible and additional dispersion-corrected density functional theory (DFT-D) calculations were employed to confirm the correctness of the crystal structure. After the correctness of the structure had been ascertained, the bond lengths and valence angles from the DFT-D minimized crystal structure were fed back into the Rietveld refinement as geometrical restraints (‘polymorph-dependent restraints’) to further improve the details of the crystal structure; the positions of the H atoms were also taken from the DFT-D calculations. The final crystal structure is a layered structure with an elaborate network of hydrogen bonds.
Background: Due to the large amount of data produced by advanced microscopy, automated image analysis is crucial in modern biology. Most applications require reliable cell nuclei segmentation. However, in many biological specimens cell nuclei are densely packed and appear to touch one another in the images. Therefore, a major difficulty of three-dimensional cell nuclei segmentation is the decomposition of cell nuclei that apparently touch each other. Current methods are highly adapted to a certain biological specimen or a specific microscope. They do not ensure similarly accurate segmentation performance, i.e. their robustness for different datasets is not guaranteed. Hence, these methods require elaborate adjustments to each dataset.
Results: We present an advanced three-dimensional cell nuclei segmentation algorithm that is accurate and robust. Our approach combines local adaptive pre-processing with decomposition based on Lines-of-Sight (LoS) to separate apparently touching cell nuclei into approximately convex parts. We demonstrate the superior performance of our algorithm using data from different specimens recorded with different microscopes. The three-dimensional images were recorded with confocal and light sheet-based fluorescence microscopes. The specimens are an early mouse embryo and two different cellular spheroids. We compared the segmentation accuracy of our algorithm with ground truth data for the test images and results from state-of-the-art methods. The analysis shows that our method is accurate throughout all test datasets (mean F-measure: 91%) whereas the other methods each failed for at least one dataset (F-measure≤69%). Furthermore, nuclei volume measurements are improved for LoS decomposition. The state-of-the-art methods required laborious adjustments of parameter values to achieve these results. Our LoS algorithm did not require parameter value adjustments. The accurate performance was achieved with one fixed set of parameter values.
Conclusion: We developed a novel and fully automated three-dimensional cell nuclei segmentation method incorporating LoS decomposition. LoS are easily accessible features that ensure correct splitting of apparently touching cell nuclei independent of their shape, size or intensity. Our method showed superior performance compared to state-of-the-art methods, performing accurately for a variety of test images. Hence, our LoS approach can be readily applied to quantitative evaluation in drug testing, developmental and cell biology.
Snake bite envenoming often results in disability or death of breadwinners of poor families in the rural tropics and the subtropics of Nepal. Identification of the medically relevant snake species, circumstances of venomous snake bites, prehospital care of their bites and human responses to snakes and snake bite is, therefore, crucial to enable victims or first aider to select the appropriate first aid measures, physicians to anticipate complications and to use appropriate treatment protocols as well as the local community to implement prevention strategies. Inadequate educational gaps exist in Nepal and hinder identification of snakes involved in bites. To fill this gap, I aim to provide an evidence-based list of medically relevant snake species. Snake specimens brought by patients bitten or their attendants from the tropical and subtropical regions in southeastern, southcentral, and southwestern Nepal to snake bite treatment centres over a period from 2010 through 2014, were taxonomically identified and medical records of envenoming were evaluated.
In Nepal, the epidemiology of snake bite is poorly known. Here I describe the ecological circumstances of proven krait (Bungarus spp.) and Russell´s Viper (Daboia russelii) bites to elucidate and examine, whether environmental circumstances or human behaviour contributed to envenoming. In a cross-sectional study, data about prehospital care, environmental circumstances of 46 krait and 10 Russell´s Viper bites were evaluated. Patients were interviewed using structured interview forms. Snake bite prone communities were surveyed to test people´s knowledge on snakes and their attitude towards venomous snakes in general.
Of 349 snakes involved in bites, 199 (57%) specimens were found to be medically relevant venomous snakes that included 11 species belonging to six genera and two families. Among them, Naja naja (n = 76, 22%), Bungarus caeruleus (n = 65, 19%) and Trimeresusurs albolabris (n = 10, 3%) were the most widely distributed snakes. Daboia russelii (n = 10, 3%) was found to be restricted to the southwestern part of Nepal. For B. walli, a previously poorly known species, 13 voucher specimens represent the first country records of this species as well as the first documented cases of involvement in snake bite envenoming by this species in Nepal.
Numerous snake bites (33%) occurred at night, during the rainy season, and are mainly due to Bungarus species, particularly B. caeruleus. Bites of cobras and Russell’s Vipers are a risk at daytime. Evaluation of data regarding the place where the bite happened, indicates that the snake bite risks appear to be as high in residential areas, in and around houses, as in rural areas. In cases of kraits (n = 46), 61% of the bites occurred while the victim was sleeping indoors, those of Russell´s Vipers mainly during agricultural activities in the fields. Analysis of socio-demographic data revealed that both krait and viper bites predominantly affected farmers or their family members. However, snake bites involved also people of higher socio-economic status, which suggests that it is not a health problem of poor people only living in the rural areas of Nepal.
A small number of snake bite victims (n = 7) sought help from traditional healers, but most patients went to hospitals for medical treatment using motorbikes (65%) or were transferred by ambulance cars (22%). As a first aid measure, most patients (78%) had used a tourniquet, which is of doubtful value and has often severe sequelae, instead of applying the WHO recommended pressure immobilisation bandage or local compression pad. The overall case fatality rate was calculated to be 10%, but up to 17% in cases of Bungarus spp. bites.
Rural community people were found to be extremely afraid of snakes, a major reason for indiscriminate killing of even harmless snakes, e.g., Lycodon aulicus, which were wrongly considered to be venomous. This is mainly due to the poor knowledge on snakes in general and on their role in providing ecological services, which may eventually lead to a decline in snake populations and even the extinction of rare species.
The results of the present study strongly emphasize that snake bite is an important public health issue in Nepal. There is an urgent need to improve the knowledge of people on snakes and to try changing their attitudes towards these reptiles, in addition to documenting the biodiversity and distribution of medically relevant snakes, the epidemiology and circumstances of their bites. Avoiding high-risk behaviour (e.g., killing of snakes), using screened doors and windows are some of the suggested measures preventing snake bite. Early and accurate identification of the snakes involved should help physicians to apply timely treatment, eventually referring the patient to the appropriate hospital. This also has important implications in developing public health and conservation strategies, to the benefit of the people of Nepal.
Demographic change belongs to the mega-trends of the 20th and the 21st century. The ongoing aging process in major industrialized countries gives rise to the relative scarcity of raw labor and the relative abundance of physical capital. Standard macroeconomic models suggest that this depresses asset returns and increases wages which, in turn, provides incentives for more human capital accumulation. This thesis quantifies the macroeconomic effects of demographic change and reveals the importance of human capital adjustments for price and welfare effects within and across generations. Chapter 1 investigates the distributions of income, skills, and welfare in the German economy along the inter- and the intra-generational dimension. It shows that demographic change leads to a more capital- and skill-intensive economy and that high-school households loose compared to college households in terms of welfare. Chapter 2 disentangles the effect of demographic change on returns to risk-free and risky assets in the U.S. and measures the net effect on the equity premium. It shows that both returns decline while the equity premium increases slightly. Endogenous human capital adjustments are crucial for relatively small effects. Chapter 3 develops a method for computing transitional dynamics in heterogeneous agent models with aggregate risk if these transitions are induced by exogenous deterministic dynamics such as demographic change. The application of the method to a simple illustrative example shows a large reduction in total computing time while approximation errors are small.
In conclusion our data show, that Flightless I function is essential for striated muscle development in zebrafish. Myofibrillar bundling and focal adhesion formation represent the basis for this development, and are ultimately a prerequisite for cardiac trabeculation. Future analysis of Actin polymerization in trabeculation will provide addition knowledge about the sensitivity of the developing and adult heart to a disequilibrium in F-actin versus G-actin availability.
In this study we found a novel ErbB2-dependent cardiomyocyte maturation process which affects both cardiac chambers. It will be of great interest to further study the nature of the Memo1-GFP cell-cell junctions and other junction proteins in order to unravel the significance of this maturation process for heart development.
Interestingly we found, that memo1bns4 homozygous mutant animals, which we generated with CRISPR/Cas9 technology, develop indistinguishable from siblings, suggesting that zygotic memo1 expression is dispensable for zebrafish development. Future studies will address the question if maternal zygotic memo1bns4 mutants will develop a heart or vascular phenotype as reported form Memo1 knockout mice or as observed in memo1 morphants in this study.
In cultured C2 mouse skeletal muscle cells the Golgi-apparatus relocalizes dependent on centrosomal proteins and independent of microtubules. We describe here that zebrafish cardiomyocytes have a similar Golgi-complex distribution suggesting a similar differentiation-dependent reorganization. This striated muscle specific, fragmented Golgi distribution might be an advantage for these cells in order to shuttle vesicles through the densely packed sarcomere structures. Future studies could address the timing of the Golgi-reorganization in cardiomyocytes during development and possibly use this Golgi-zebrafish line as a tool to study cardiomyocyte maturation in disease models and in heart regeneration.
The knowledge of three-dimensional structures of biomolecules is fundamental for the understanding of their function. Nuclear magnetic resonance (NMR) spectroscopy represents besides X-ray crystallography one of the two most widely used techniques to study macromolecules at atomic resolution. Its application has long been a laborious task that could take months and required the expertise of an experienced scientist, however, owing to the tremendous effort that has been put into the development of respective computer algorithms, structure determination by NMR spectroscopy of small- to medium sized proteins is nowadays routinely performed. CYANA is one widely used software package, which combines the majority of individual steps towards a three-dimensional structure. The most common application of the program, however, restricts to the combined automated NOE assignment and structure calculation based on NOESY peak lists and an existing chemical shift assignment. Completely automated structure determination starting from NMR spectra is to date technically possible with CYANA, however, not yet routinely applied. In order to achieve this long-term goal, the individual steps need to become more robust with regard to data imperfections such as peak overlap, spectral artifacts or a limited amount of NMR data. The work presented in this thesis should be placed within the context of increasing the reliability and improving the accuracy of structures determined by CYANA on the basis of solution- as well as solid-state NMR data.
The chapter “Systematic evaluation of combined automated NOE assignment and structure calculation with CYANA” comprises an extensive study on the robustness of the combined automated NOE assignment and structure calculation algorithm based on experimental solution NMR data sets that were modified in multiple ways to mimic different kinds of data imperfections. The results show that the algorithm is remarkably robust with regard to imperfections of the NOESY peak lists and the chemical shift tolerances but susceptible to lacking or erroneous resonance assignments, in particular for nuclei that are involved in many NOESY cross peaks.
In the chapter “Peakmatch – A simple and robust tool for peaklist matching” a method to achieve self-consistency of the chemical shift referencing among a set of peak lists is presented. The Peakmatch algorithm matches a set of peak lists to a specified reference peak list, neither of which have to be assigned, by optimizing an assignment-free match-score function. The algorithm has been extensively tested on the basis of experimental NMR data sets of five different proteins. The results show that peak lists from many different types of spectra can be matched reliably as long as they contain at least two corresponding dimensions.
NMR structures are represented by bundles of conformers whose spread indicates the precision of the atomic coordinates. However, there is as yet no reliable measure of structural accuracy, i.e. how close NMR conformers are to the “true” structure. Instead, the precision of structure bundles is widely (mis)interpreted as a measure of structural quality. Attempts to increase the precision thus often yield tight structure bundles where the precision overestimates the accuracy. To overcome this problem, the chapter “Increased reliability of NMR protein structures by consensus structure bundles” introduces a new protocol for NMR structure determination with the software package CYANA that produces bundles of conformers with a realistic precision that is throughout a large number of test data sets a much better estimate of the structural accuracy than the precision of conventional structure bundles.
Solid-state NMR is a powerful technique to study molecules which are not amenable to either solution NMR or X-ray crystallography. Despite the reporting of individual atomic resolution structures of membrane proteins and amyloid fibrils based on solid-state NMR data, the application is far from routine. One major obstacle that hinders structure determination by solid-state NMR is the overall lower quality of the solid-state NMR spectra. It is therefore necessary to increase the robustness of the computer algorithms in order to improve the results when using lower quality solid-state NMR spectra. The chapter “Structure calculations of the model protein GB1 from solid-state NMR data” presents structure calculations on the basis of a set of two-dimensional solid-state NMR experiments of the model protein GB1. The most important result obtained from these test calculations is that the limitation of structural accuracy can be attributed to inaccurate distance information resulting from the limited correlation between peak intensities and distance, which is especially severe in spin diffusion-based solid-state NMR experiments.
The chapter “Full relaxation matrix-based correction of relayed polarization transfer for solid-state NMR structure calculation” therefore introduces a method which corrects experimental peak intensities for spin diffusion in order to improve the distance information from solid-state NMR spectra. The results show that the structural accuracy can be significantly improved when using the corrected distance information, however, strongly dependent on the preliminary structural model that is required as input for the method.
Stechmücken (Dipteren: Culicidae) sind weltweit mit über 3500 Arten und mit Ausnahme der arktischen Regionen ubiquitär vertreten. Die medizinische Relevanz dieser Tiergruppe, begründet durch die hämatophage Lebensweise der Weibchen, erschloss sich bereits Ende des 19. Jh. und hat bis heute Bestand. Jedes Jahr sterben rund 600.000 Menschen an den Folgen der Malaria und fast 100 Mio. Menschen infizieren sich mit dem Denguefieber. Zwar beziehen sich diese Zahlen fast ausschließlich auf die Entwicklungsländer, aber im Zuge des Klimawandels und des immer stärkeren Welthandels kommt es auch in Europa und den USA immer wieder zu Ausbrüchen vorher nicht relevanter Krankheiten. So hat sich das West-Nil- Virus seit 1999 in Nordamerika rasant verbreitet. Im Jahr 2013 gab es dort rund 2500 Fälle, von denen 119 zum Tod führten. In Europa traten hingegen Krankheiten wie das Chikungunyafieber (Italien 2007) oder das Denguefieber (Frankreich 2010/2013) auf. Die Gründe für diese Ausbrüche sind vor allem in der Einschleppung neuer Vektorspezies und Krankheitserreger sowie in den veränderten Wirtspräferenzen einheimischer Stechmückenarten zu suchen. Das Wissen um das Vektorpotential der in Deutschland heimischen Stechmücken konnte vor allem durch die seit 2009 initiierten Monitoring-Programme stetig erweitert werden. Auch die Veränderung der heimischen Fauna durch invasive Arten wie Ochlerotatus japonicus japonicus oder Aedes albopictus wird intensiv erforscht. Dennoch ist hinsichtlich der Biologie, Ökologie sowie Genetik vieler Arten noch immer wenig bekannt.
Die vorliegende Dissertation, welche auf Basis von vier (ISI-) Einzelpublikationen kumulativ angefertigt wurde, beschäftigte sich mit der Analyse der genetischen Variabilität sowie der Zoogeographie der untersuchten Arten und der Etablierung einer schnellen und kostengünstigen Methode zur Artdiagnostik. Besonderes Augenmerk wurde bei den Analysen auf die beiden heimischen Arten Culex pipiens und Culex torrentium sowie die invasive Art Ochlerotatus japonicus japonicus gelegt. Ziel war es, die noch bestehenden Wissenslücken zu füllen, um zukünftige Monitoring-Programme besser koordinieren sowie Analysen zur Vektorkompetenz und Genetik dieser Arten gezielter durchführen zu können.
Es konnte gezeigt werden, dass Cx. pipiens und Cx. torrentium deutliche Unterschiede in ihren Populationsstrukturen aufwiesen welche auf verschiedene evolutive Prozesse hindeuten. Die geringere genetische Variabilität in Cx. pipiens lässt auf positive Selektion durch z.B. Insektizidresistenz im Zuge durchgeführter Bekämpfungsmaßnahmen oder die Infektion mit Wolbachien schließen. Die analysierte Populationsstruktur von Cx. torrentium spricht hingegen für eine geringe Ausbreitung, wodurch der genetische Austausch reduziert wurde und so die untersuchten Populationen genetisch stärker voneinander abwichen. Des Weiteren ließen die Analysen des Cytochrom c Oxidase Untereinheit 1-Fragmentes (cox1) Rückschlüsse auf die Zoogeographie dieser Arten in Deutschland zu - wobei beide Arten über das Untersuchungsgebiet verteilt waren, Cx. torrentium jedoch in den neuen Bundesländern weniger häufig nachgewiesen wurde als in den alten und eine geringere gefangene Individuenzahl aufwies. Basierend auf der ökologischen Nischenmodellierung konnten potentiell neue Verbreitungsgebiete für die Art Ochlerotatus japonicus japonicus identifiziert werden. Als klimatisch besonders günstig zeigten sich dabei Südhessen, das Saarland sowie nördliche Teile Nordrhein-Westfalens. Mit Hilfe der etablierten Methode der direct-PCR wird in Zukunft eine schnellere und kostengünstigere Identifizierung von Stechmücken erfolgen können, welche aufgrund bestimmungsrelevanter Merkmale nicht mehr morphologisch zu identifizieren sind.
Um das Wissen über die Stechmücken in Deutschland fortlaufend zu intensivieren, ist sowohl das Weiterführen der Monitoring-Programme als auch die molekularbiologische Aufarbeitung der Proben nötig. Durch die Anwendung neuer Techniken und weiterer molekularer Marker wird es möglich sein, weitere Krankheitserreger sowie genetische Besonderheiten der heimischen Stechmückenfauna nachzuweisen. Aber auch die Überwachung invasiver Stechmückenarten durch die Modellierung potentieller Verbreitungsgebiete und die Anwendung molekularbiologischer Analysemethoden zum Detektieren der Arten und möglicher Krankheitserreger wird ein wichtiger Bestandteil der weiteren Forschung sein.
Die Parkinson Erkrankung ist die zweithäufigste neurodegenerative Erkrankung in industrialisierten Ländern. Die charakteristischen Symptome sind schwere Beeinträchtigungen des Bewegungsablaufes welche auf den Verlust dopaminerger Neurone der Substantia nigra und der damit einhergehenden Reduktion des striatalen Dopamin Gehaltes zurückzuführen sind. Alpha-Synuklein (SNCA) ist ein Protein welches zum einen mit sporadischen aber auch mit idiopathischen Erkrankungen assoziiert ist. Mutationen welche einen Funktionsgewinn von SNCA zur Folge haben konnten mit autosomal dominanten Varianten der Parkinson Erkrankung assoziiert werden und genetische Veränderungen an beiden Genenden agieren als Risikofaktor für sporadische Formen der Erkrankung. Des Weiteren wird SNCA als Hauptbestandteil der Lewy Körperchen gefunden, einem pathologischen Kennzeichen der parkinsonschen Erkrankung. Die charakteristischen Bewegungsstörungen können mittels L-DOPA, einer metabolischen Vorstufe von Dopamin, behandelt werden. Neben dem enorm positiven Effekt auf die Bewegungsstörungen, geht die Behandlung mit L-DOPA jedoch auch mit ernsten Nebenwirkungen einher, welche als Levodopa induzierte Dyskinesien (LID) beschrieben werden.
Ziel der Arbeit war die Analyse von Effekten eines SNCA Funktionsgewinns sowie des Pink1 Funktionsverlustes auf molekulare Signalwege der synaptischen Plastizität unter Verwendung dreier PD Mausmodelle (A53T-SNCA überexprimierendes Modell (PrPmtA), Pink1KO Modell sowie A53T-SNCA + Pink1KO Doppelmutante (DM)). Es wurden Kandidatengene welche eine Rolle für synaptische Plastizität spielen in 6 Monate alten Mäusen aller drei PD Mauslinien untersucht. Die Analyse von PrPmtA zeigte erhöhte mRNA Spiegel von Glutamatrezeptor-Untereinheiten und von Kandidatengenen welche eine Rolle bei der synaptischen Signalweiterleitung spielen, sowie reduzierte mRNA Spiegel von IEGs und Transkriptionsfaktoren. Die Analyse der DM zeigte nur geringe Expressionsänderungen der Glutamatrezeptor-Untereinheiten und die Analyse von IEGs und Transkriptionsfaktoren zeigte erneut reduziert mRNA Spiege. In Pink1KO Tieren konnten nur minimale Expressionsveränderungen der Kandidatengene gefunden werden, was den Schluss zulässt, dass die zuvor beschriebenen Expressionsveränderungen in PrPmtA und DM Mäusen eindeutig auf den SNCA Funktionsgewinn zurückzuführen sind. Um frühe Effekte des SNCA Funktionsgewinns zu studieren wurde die Analyse auf 3 Monate alte PrPmtA Mäuse ausgeweitet. Diese ergab, Expressionsveränderungen für Homer1, cFos, NOR1, Nurr1 und Nur77.
In einem weiteren Versuchsansatz wurde die Auswirkung des SNCA Funktionsgewinns auf das Verhalten sowie auf molekulare Parameter nach Apomorphin Behandlung analysiert. Die Analyse ergab ein erhöhtes Niveau an unwillkürlichen Bewegungsmustern mit stereotypen und dystonischen Eigenschaften in PrPmtA im Vergleich zu Wildtypen (wt). Die molekulare Analyse von striatalem Gewebe wurde zu zwei Zeitpunkten durchgeführt, 30 min nach Apomorphin Injektion und 100 min nach Injektion. Die Analyse von striatalem Gewebe welches zum Zeitpunkt 30 min nach Injektion entnommen wurde ergab eine erhöhte Apomorphin abhängige Phosphorylierung von ERK1/2, sowie eine erhöhte Apomorphin abhängige Expression von Dusp1, Dusp6 und cFos in transgenen und wt Tieren. Genotyp abhängige Unterschiede ergaben sich für cFos, welches signifikant höher in PrPmtA induziert wurde. 100 min nach Apomorphin Injektion ergab die gleiche Analyse eine erhöhte Apomorphin abhängige Phosphorylierung von ERK1 und eine erhöhte Apomorphin abhängige Expression von Dusp1, Dusp6, cFos und Nur77 in PrPmtA im Vergleich zu wt. Die Daten unterstreichen die fundamentale Rolle von SNCA auf die Neurotransmission und synaptische Plastizität und zeigen auf, dass PrPmtA ein zuverlässiges Modell für die Analyse von präsynaptischer Dysfunktion in Frühstadien der Parkinson Erkrankung darstellt.
Der letzte Versuchsansatz stellt die Charakterisierung des DM-Mausmodells welches sich durch einen starken Phänotyp auszeichnet, sowie die Analyse des Pink1 Effektes auf die SNCA induzierte Neurotoxizität dar. DM-Tiere zeigen deutlich reduzierte Spontanmotorik im Alter von 3 Monaten sowie einer progressiven Lähmung der Hinterläufe, was Anlass zu einer immunhistologischen Charakterisierung mittels Schnitten des Gehirns und Rückenmarks gab. Die histologische Analyse zeigte pSer129-SNCA, p62/SQSTM1 und Ubiquitin positive Aggregate innerhalb der grauen Substanz des Rückenmarks sowie innerhalb einer neuronalen Zellpopulation welche dorsal der Substantia nigra angeordnet ist. Das histologische Erscheinungsbild wurde spezifisch in gelähmten DM-Tieren gefunden und nicht in Einzelmutanten oder DM-Tieren ohne Lähmung. Dieses Modell stellt ein wertvolles Instrument für die Identifizierung von pathologischen Mechanismen und Signalkaskaden welche beiden Parkinson relevanten Genen gemeinsam sind, dar.
This work deals with so-called wh-determination. The notion of D-linking (Discourse-linking) is used to uncover and explain properties of constructions involving wh-determiners. The central claim is that there are two types of wh-determination: Token-whs and Kind-whs. These two forms of wh-determination trigger different syntactic effects. Three structural triggers for the syntactic effects exhibited by D-linked wh-phrases (DWH) are discussed. DWH are argued to be instances of Token-whs since triggers for the syntactic effects of D-linking are identical to the once for the token-reading of a wh-phrase.
In chapter 2, which-phrases are shown to be canonical DWH with a special syntax labelled DL-S(yntax). The five most prominent and frequent DL-S effects are the absence of superiority-effects with DWH, the ability of DWH to be extracted out of weak islands, the fact that DWH licence resumptive elements, the obviation of WCO effects by DWH, and the possibility for DWH to stay in-situ. The syntax of Token-whs and Kind-whs are compared. It is demonstrated that regardless of the actual form of the wh-determiner, there are only these two types of wh-determination. These data support the idea that the DL-S effects observable with DWH are triggered by structural properties of the wh-determiners heading DWH.
In chapter 3, it is demonstrated that although presuppositions projected by the Nominal Restrictor are important for triggering DL-I(nterpretation), they do not directly influence DL-S. The ambiguity of Amount-whs is also examined and the conclusion reached is that there are two #P projections: A NumP and a CardP. The dissertation proceeds with the structurally represented notions of definiteness and specificity and examines how these can help capturing the wh-determiner typology proposed. The idea that D-linking can be explained by recourse to topicality is discussed in detail. Empirical evidence is provided for the existence of wh-topics in general and for the claim that many DWH can be construed as wh-topics.
In chapter 4, the general pattern on which wh-pronouns are built are examined, and it is argued that the results bear directly on the topic of this thesis since wh-determiners are universally derived from pronouns. Wh-pronouns are diachronically built out of an element indicating the function of the proform (wh-morpheme), and an element denoting the range of the proform (Range Restrictor). Among other things, it is argued that the wh-morpheme does not mark interrogativity, leading to the adoption of a version of Q-theory. It is also briefly discussed whether the results are compatible with the hypothesis that wh-determiner phrases are Small Clauses. One claim is that all wh-pronouns are fossilized interrogative sentences, lending further support to the parallelism between sentential and nominal structures. It is then argued that Morphological Restrictors can be subdivided into Formal Features and Functional Nouns (and that elements which can become Functional Nouns are taken from the pool of Basic Ontological Categories). The question answered is how these elements synchronically contribute to the meaning of the wh-determiners. After examining the role of the Nominal Restrictor to the syntax of wh-determiners, the thesis continues investigating how Nominal Restrictor are related to Functional Nouns. Finally, the discussion expands to the structural correlates for DL-S effects. It is demonstrated how the results can formally be applied to wh-split constructions in order to explain differences between empty categories. Then, the results of the section on partitivity support the idea that the occurrences of most of the DL-S effects seem to strongly depend on the presence of a second nominal constituent in the structure of wh-phrases. This second nominal can be either a Functional Noun inside the wh-item used as wh-pronoun or an overt second noun as in wh-partitive phrases.
The contribution of this thesis to linguistic theorizing is not a full-fledged technical analysis of every single DL-S effect, but rather the systemisation proposed. Although a lot of terminology is introduced, the outcome of this proliferation of terms is a sharper picture of the intricate relations between the constituents of the wh-items used as wh-determiners and the Nominal Restrictor. Another main conclusion is that the concept of D-linking is not a basic notion. It is comprised of four components (of which DL-Syntax and Morphological-DL have been scrutinized in this thesis). This assumption explains why DWH do not constitute a homogeneous class. The gradual character of D-linking (i.e. the fact that certain wh-determiner constructions show only a subset of DL-S effects even if they are headed by what could faithfully be classified as a/the Token-wh determiner of the respective language) is argued to be related to the fact that the Token-reading itself can have several triggers.
Die Sulfonyl-Gruppe (-SO2-) ist ein weit verbreitetes Strukturmotiv in der organischen Chemie und Bestandteil vieler biologisch aktiver Moleküle, insbesondere Arzneistoffen. Zwei der am häufigsten auftretenden Gruppen sind Sulfone und Sulfonamide, die in über 100 zugelassenen Medikamenten und 10% der meistverkauften Medikamente sind. Insofern kommt der Entwicklung neuer Synthesemethoden eine große Bedeutung zu. Dabei stehen besonders einfache, wirtschaftliche und zeitsparende Vorgehensweisen im Vordergrund, die eine große Bandbreite an neuen Substanzen generieren können. Ein Ansatz hierfür sind Multikomponenten- oder Eintopfreaktionen.
Aufgrund der Wichtigkeit dieser zwei Strukturklassen, sollen im Rahmen der hier vorliegenden Doktorarbeit neue Syntheserouten für Sulfone und Sulfonamide entwickelt werden. Besonderes Augenmerk wird auf die die Einführung der SO2-Einheit während der Reaktionsführung gelegt. Im Vergleich zu bereits existierenden Verfahren ist dies ein enormer Fortschritt, da die Mehrheit der bekannten Routen auf Schwefel- oder Schwefeldioxid-haltige Startmaterialien zurückgreift.
In der vorliegenden Arbeit gelang es, einen synthetischen Zugang zu Arylsulfonen basierend auf von Natrium-, Lithium-, Magnesium- und Zinksulfinaten zu finden. Diese Reaktion besitzt eine sehr große Anwendungsbandbreite und setzt sowohl Aryl- als auch Alkylsulfinate effizient um. Außerdem weisen Reaktionen mit unsymmetrischen Diaryliodoniumsalzen hohe Chemoselektivitäten auf.
Auf der Grundlage auf der Reaktion zwischen Natriumsulfinaten und Iodoniumsalzen wurde eine simple Route zur Synthese von Diarylsulfonen abgeleitet, jedoch war hierbei die Sulfonylgruppe noch Bestandteil eines der Edukte. Um die SO2-Einheit während der Reaktion einführen zu können, wurde ein praktisches Eintopf-Protokoll entwickelt, welches die direkte Umsetzung von (hetero)aromatischen und alkylischen Halogeniden zu Arylsulfonen gestattet. Diese innovative Methode besteht aus folgenden vier Schritten: (1) Generierung des Organometallreagenzes via Halogen-Metall-Austausch, direkte Metallinsertion oder Deprotonierung; (2) Reaktion des Organometallreagenzes mit SO2 zum Sulfinat; (3) Entfernen des SO2-Überschusses und flüchtiger Komponenten und (4) Umsetzung des nicht aufgereinigten Sulfinates mit einem Iodoniumsalz.
Desweiteren wird in dieser Arbeit ein neuartiger Übergangsmetall-katalysierter Ansatz zur Darstellung von Diarylsulfonen ausgehend von Arylhalogeniden und Sulfinaten diskutiert. Erste Experimente deuten auf Nickel-Katalysatoren als gute Wahl für die Reaktion. Optimierungsreaktionen zeigten eine starke Abhängigkeit der Ausbeute in Hinsicht auf die Bisswinkel der an das zentrale Nickelatom koordinierten Liganden. Da die bis dato besten Ergebnisse mit dem Komplex [o-tol-Ni(PPh2Me)2Cl] erzielt wurden, wird der [o-tol-Ni(PMe3)2Cl]-Komplex momentan in unserem Labor weiteren Studien unterzogen. Bislang ist davon auszugehen, dass dieser Katalysator hervorragende Ergebnisse liefert und zu einer allgemein gültigen Methode führt.
In weiteren Kapiteln wird die Anwendbarkeit von SO2-Surrogaten, Metabisulfiten „S2O52-„ oder DABSO; untersucht; mit dem Ziel eine Eintopf- oder Multikomponentenreaktion zu entwickeln.
Zum einen wird die Entwicklung einer Ein-Topf-Reaktion von Alkylhalogeniden mit Metabisulfiten und Organozinkreagenzien zur Darstellung von Alkylarylsulfonen vorgestellt. Darüber hinaus wird eine Übergangsmetall-katalysierte Multikomponenten Reaktion zur Synthese von Sulfonsäureamiden vorgestellt. Eine Reaktion zwischen Aminen, Arylhalogeniden und DABSO als SO2-Quelle wurde in Form einer Palladium-katalysierten Aminosulfonylierung entwickelt.
Die vorliegende Dissertation mit dem Titel: Ecophysiological monitoring of Oaks in Central Europe, introduced in the framework of proactive climate change mitigation beschäftigt sich mit der Anwendung zerstörungsfreier, radiometrischer Methoden zur Bestimmung von Pigment- und Stickstoffkonzentrationen und der photosynthetischen Funktionalität in Blättern von heimischen und gebietsfremden Eichen und ihre Beeinflussung durch Trocken-, Hitze- und Kältestress.
Die Eichenarten Quercus robur L. (Stieleiche), Q. pubescens Willd. (Flaumeiche), Q. frainetto Ten. (Ungarische Eiche), Q. ilex L. (immergrüne Steineiche) und Q. rubra L. (amerikanische Roteiche) wurden im Frühjahr 2011 auf einer Versuchsfläche im Frankfurter Stadtwald gepflanzt, um ihre Nutzung als potentielle Waldbäume in einem sich ändernden Klima zu untersuchen. Über eine Dauer von zwei Jahren wurden diese Arten mit einem hohen Maß an blattspezifischer Merkmalsvariabilität beobachtet und beprobt. Ziel war es, die interspezifischen Unterschiede und die jahreszeitliche Dynamik von morphologischen und chemischen Blattmerkmalen sowie die Beeinflussung der radiometrischen Bestimmung des Chlorophyllgehaltes (und damit assoziierten Komponenten wie z.B. Blattstickstoffgehalt und Karotinoiden) und der photosynthetischen Funktionalität durch klimatische Umweltbelastungen in Eichen zu untersuchen. Die Analyse der Blattproben zielte neben der Bestimmung der Beziehung zwischen absoluten und optisch ermittelten Pigmentgehalten auf die Ermittlung des Einflusses der Blattstruktur auf die Lichttransmission im roten und infrarotem Bereich des Elektromagnetischen Spektrums ab, sowie auf die artspezifische Korrelation von Blattstickstoff zu Blattchlorophyll zu dessen indirekte Quantifizierung. Des Weiteren wurden Versuche zur Trocken- und Hitzestressanpassung durchgeführt, um eine potentiell artspezifische Stressantwort, sowie eine mögliche Beeinflussung der aufgenommenen radiometrischen Messwerte zu ermitteln. Ein zusätzliches Monitoringprogramm im Winter 2012/2013 mit einer Dauer von sechs Monaten ermöglichte die Überprüfung der Anpassungsfähigkeit der immergrünen Steineiche (Q. ilex) an mitteleuropäische Winterbedingungen und die Veränderung der photosynthetischen Funktionalität unter Kältestress. Messungen im Zusammenhang mit der praktischen Anwendbarkeit der zerstörungsfreien, optischen Methode und zur Bereitstellung von Referenzdaten für zukünftige Evaluierungen komplementieren die Untersuchungen.
Signifikante, artspezifische Unterschiede wurden in den blattmorphologischen Schlüsselmerkmalen in den Quercus-Arten ermittelt. Die artspezifischen Unterschiede in den morphologischen Blattmerkmalen beeinflussten auf signifikante Weise die Beziehung zwischen absoluten, massebasierten Pigment- und Stickstoffgehalten und deren radiometrischen Bestimmung. Wurden die Pigmentgehalte hingegen auf die Blattfläche bezogen und die Stickstoffgehalte mittels des Verhältnisses von Blattfläche zu Trockenmasse korrigiert, zeichnete sich eine Beziehung zwischen absoluten und optisch ermittelten Werten ab, der jegliche jahreszeitliche oder artspezifisch morphologische Variabilität fehlte und die somit für alle Quercus-taxa anwendbar ist. Koeffizienten für die Berechnung von flächenbezogenen Gehalten von Gesamtchlorophyll, Chl a, Chl b und Carotinoiden für die jeweiligen Quercus-taxa, wie auch für ein artübergreifendes Modell wurden ermittelt, um die Bestimmung dieser Gehalte während aller Entwicklungsstufen zu ermöglich. Aus der jahreszeitlichen Entwicklung der Pigmentgehalte konnten drei deutliche Phasen abgeleitet werden: Die Phase der Blattentwicklung im Frühling, einer Plateauphase mit geringen Veränderungen (“core vegetation time”) und die Phase des Pigmentabbaus während der Herbstlaubfärbung. Die Übergänge zwischen diesen Phasen variierten zum Teil erheblich zwischen einzelnen Individuen einer Art sowie zwischen den Arten, was Unterschiede in der potentiellen, jährlichen Kohlenstoffaufnahme nach sich zieht. Stressbedingungen, wie Hitze- Kälte- oder Trockenstress, können zu Veränderung von Fluoreszenzparametern ohne gleichzeitige Änderung des Pigmentgehaltes führen, wie auch die indirekte Bestimmung von mit Chl assoziierten Komponenten (Carotinoide, Chl a, Chl b) mittels optischer Bestimmung (durch die Veränderungen von Pigmentverhältnissen) beeinflussen.
Im Rahmen des Forschungsprojektes konnten, Modelle zur Berechnung von Blattpigmenten und Blattstickstoff aus optischem Messdaten, Veränderungen der photosynthetischen Funktionalität, sowie Referenzdaten für die zukünftig nutzbaren Eichenarten hinsichtlich artspezifischer und jahreszeitlicher Variabilität unter mitteleuropäischen Umweltbedingungen ermittelt werden, die eine Nutzung und Einordnung von zerstörungsfreien, optischen Messwerten zur Ermittlung von Vitalitätsunterschieden in Eichen ermöglichen.
ISOE Policy Briefs – Neue Reihe zu Ergebnissen der Nachhaltigkeitsforschung +++ Autonome Fahrzeuge: eine Chance für den ÖPNV +++ Trotz Hitzewelle: Noch verzichtet die Mehrheit der Deutschen auf Klimaanlagen +++ ISOE-Mobilitätsforschung: Sharing-Konzepte in der Rhein-Main-Region +++ Neues Forschungsprojekt zur sozial-ökologischen Transformation im Bereich Wohnen und Mobilität +++ Aus dem ISOE: Nachhaltigkeitspreis für ISOE-Forscherin +++ Termine +++ Publikationen
Blaue Zukunft – Die kostbare Ressource Wasser und wie wir damit umgehen (müssen) +++ Leseempfehlung: Nachhaltige Wissenschaft im Anthropozän +++ Wegweiser Hauskauf: Neueigentümer für die energetische Sanierung motivieren +++ Klima- und Umweltschutz im Alltag: Leitfaden für die Zielgruppen MigrantInnen und Geringverdienende +++ Nachhaltiges Wasserressourcen-Management für das Einzugsgebiet der Nidda +++ ISOE-Forschungsschwerpunkt Biodiversität und Bevölkerung +++ Gesellschaftliche Trends und Mobilität im urbanen Raum +++ GreenTec Award 2015 für Forschungsprojekt Semizentral +++ Thomas Jahn im Wissenschaftlichen Beirat der Zeitschrift Sustainability +++ Aus dem ISOE +++ Termine +++ Publikationen
Die Debatte, wie die Organisation des universitären Lehrbetriebs an deutschen Hochschulen verbessert werden kann, wurde in den vergangenen Monaten intensiv medial begleitet. Eine ehrliche Diskussion über realistisch umsetzbare Reformen ist notwendig. Ich plädiere vor allem für eine Diversifizierung der Prüfungsleistungen, wodurch sich gleichzeitig die Vorbereitung auf Seminare verbessern könnte. Darüber hinaus wäre ein konsensorientierteres Verhältnis zwischen Dozenten_innen, Administration und Studentenschaft wünschenswert.
Kaisers neue Kleider: Anmerkungen zur Kritik der Hochschullehre im "akademischen Kapitalismus"
(2015)
An dieser Stelle beschrieb Stefan Müller kürzlich Drei Vorschläge für eine Verbesserung der Lehre an deutschen Universitäten. Er reagierte damit auf Vorwürfe des finnischen Studenten Juuso Nisula, der unter dem Titel Acht Gründe, nie wieder in Deutschland zu studieren seinem Unmut über das intransparente und austauschhinderliche Studienklima an der Universität Köln massenmedientauglich Luft verschafft hatte – einer Universität übrigens, die ihrerseits auf Nisula reagierte, wenngleich so allgemein, wie man es auch von den standardisierten PR-Abteilungen größerer Unternehmen gewohnt ist: Mit herablassender Freundlichkeit pusten sie berechtige Verbraucherbeschwerden in den Wind und flaggen lieber ihre austauschbaren Imagesätzchen aus.
Photosynthesis is one of the most vital processes that takes place on Earth. Due to its global significance related to food, energy and material production, photosynthesis research is one of the leading scientific fields in the contemporary world. Particular interest in photosynthesis research is focused on diatoms and as one of the major players of marine phytoplankton, diatoms have a huge impact on global photosynthesis.
Diatoms originated from a secondary endosymbiosis that took place between a putative photosynthetic red algal ancestor and a heterotrophic eukaryote. Secondary endosymbiosis resulted in the formation of chloroplasts with four membranes. Centric diatoms (e.g. Thalassiosira pseudonana or Cyclotella meneghiniana) usually possess many small chloroplasts, while pennates (e.g. Phaeodactylum tricornutum) have several larger ones, or even only one which can occupy half of the cell volume...
Innovative Wasserinfrastrukturen, wie sie etwa mit den Neuartigen Sanitärsystemen entwickelt worden sind, versprechen Effizienzgewinne. Ihre Anwendung bedeutet nicht nur, den Einsatz neuer Techniken, sondern auch, dass sich die im konventionellen System erprobten Arbeitsteilungen zwischen verschiedenen Akteuren verändern. Ebenso können sich Beweggründe und Motivationen der beteiligten Akteure wandeln. Die Innovations- und Umsetzungsschritte werden dabei komplexer. Die Konstellationen der verschiedenen (heterogenen) Akteure und ihre Zusammenarbeit haben dabei hohe Relevanz für die Umsetzung innovativer Infrastrukturkonzepte.
Das vorliegende Diskussionspapier zeigt – aufbauend auf Ergebnisse aus zwei BMBFForschungsvorhaben – welcher Koordinationsbedarf bei einer Umsetzung auf der Quartiersebene zu erwarten ist. Zudem werden Hinweise gegeben, wie sich die Koordination zwischen den beteiligten Akteuren optimieren lässt.
In dem vorliegenden Text wird die „Kritik des ökologischen Diskurses“ analysiert, die von Thomas Gehrig in einem monumentalen zweibändigen Werk vorgetragen wird. Darin kritisiert er fundamental die wissenschaftliche Bearbeitung des Themas in der Sozialen Ökologie. In seiner Studie zieht er 107 Texte von Autorinnen und Autoren aus dem ISOE heran, die in einem Zeitraum von 35 Jahren entstanden sind. Anhand dieser Texte versucht er seine zentralen Thesen zu beweisen: Der ökologische Diskurs lenke von der notwendigen radikalen Kapitalismuskritik ab und treibe die Modernisierung des kapitalistischen Systems voran; eine kritische Theorie der gesellschaftlichen Naturverhältnisse lasse sich philosophisch nicht begründen und sie sei wissenschaftlich unmöglich. Den Maßstab seiner Kritik entnimmt Gehrig der frühen Kritischen Theorie sowie einem von der marxistischen Interpretationsgeschichte gereinigten Marx. In der vorliegenden Analyse wird die aus einer soziologischen Dissertation hervorgegangene Studie als Dokumentation eines politischen Prozesses und eines pseudowissenschaftlichen Tribunals über die Soziale Ökologie detailliert rekonstruiert und dabei gezeigt, wie das von dem Autor beanspruchte Verfahren einer radikalen Kritik funktioniert. Diskutiert wird auch, was aus dem Gehrig’schen Werk dennoch für die Weiterarbeit am theoretischen Programm der Sozialen Ökologie zu lernen ist.
Since few decades there is a broad debate about the so called ecological crisis. The debate had its highlight at the Rio-Conference in 1992. This conference was also the starting point for a wide range of political efforts concerned with a broad spectrum of biodiversity issues. Insofar, the term ‘biodiversity’ is not one of the natural sciences, but one which is inherently connected with questions of good human life. This article argues that the question for the good life predominantly fulfills a heuristic function and is to be answered in light of certain societal relations to nature. Furthermore, in light of these societal relations to nature it is argued for a virtue ethical approach with respect to the individual good life, whereas concerning the scale of societal aspects transdisciplinarity is identified as the appropriate research mode, which addresses both societal and scientific issues.
Increasing bike traffic in many European countries is a sign of a shift in planning paradigms towards more sustainable mobility cultures. It is also the result of 20 to 30 years of evolution and refinement in the training of urban and transport planners. Capacity development is therefore key when it comes to changing mobility cultures. Nevertheless, the day-to-day work of transport planners still focuses mostly on motorised traffic and the tasks of creating a smooth traffic flow, improving accessibility, and maintaining infrastructure. Cycling plays only a minor role, with efforts often still concentrated on the building of cycle lanes. The broader strategic goal of how to make urban mobility culture more sustainable – and within this the need to focus on cycling as an everyday mode of transport – is often neglected. Direct regulation is not possible when it comes to mobility cultures. Instead they represent a community-wide (communication) process that calls for a new planning paradigm: Besides the political will to establish a sustainable urban mobility culture, emphasis must also be placed on skills and training for urban and transport planners.
Debates about climate-induced migratory movements – and their possible links to instability and conflict – along with the discussion on migration flows across the Mediterranean Sea frequently highlight the West African Sahel as a region of concern. However, findings from recent empirical research on Sahelian regions in Mali and Senegal suggest no evidence for increasing population movements towards Europe as a direct result of environmental stress and climate change. It is the patterns of migration that are changing and not so much the volume. A closer look at the social-ecological conditions of migration in the Sahel allows for an alternative characterization of the problem dynamics. It reveals a rich and comprehensive picture of mobility and the importance of climate and environment in this respect, and identifies starting points for policy options.
Rain- and floodwater harvesting (RFWH) technologies and water reuse are ideal and generalpurpose technologies to improve water security and to contribute to climate adaptation – in particular for semi-arid regions. These technologies are part of a multi-resources mix within an integrated water resources management (IWRM). They create capacities to buffer water fluctuations and alleviate water scarcity. In this way, they reduce the pressure on existing resources, and can stimulate local economies. However, in order to be sustainable, these technologies need to be adapted to the local context – through suitable design, adapted operation requirements, and a back-up by training users and operators accordingly.
Nach der Landtagswahl in Bremen 2007 haben sich, nach langjähriger SPD/CDU-Partnerschaft (1995-2007), zwei Parteien zu einer Koalition entschlossen, die in ihren Wahlprogrammen eine „Schule für alle“ (Grüne) bzw. eine „Gemeinsame Schule“ (SPD) von 5 bis 10 angekündigt haben. Die Befürworter einer solchen Schule erwarteten, dass den Ankündigungen im Wahlkampf nun auch Taten folgen. So forderte die GEW von SPD und Grünen die als ersten Schritt versprochenen Maßnahmen: Alle Schulen werden verpflichtet, „die aufgenommenen Schülerinnen und Schüler in ihrer Schule zu einem Abschluss zu führen“ (SPD) und alle Abschlüsse der Sekundarstufe I können „an jeder Schule erworben werden“ (Grüne), womit alle Bildungsgänge, das Gymnasium eingeschlossen, bei der Entwicklung eines integrativen Schulsystems einbezogen waren...
Es geht um eine spezielle Auseinandersetzung mit dem Sachunterricht der hessischen Grundschule. Ziel eines Projektes („IGEL“ - Individuelle Förderung und adaptive Lern-Gelegenheiten in der Grundschule) des Frankfurter IDeA-Zentrums war es, das pädagogische Handeln von Lehrkräften zu verändern. Wir folgen diesem Versuch anhand dreier Lehrerinnen, die von Projektseite in der Methode der „Kognitiven Strukturierung“ fortgebildet wurden und die diese Methode im Rahmen einer standardisierten Unterrichtseinheit zum „Schwimmen und Sinken“ erproben sollen. Zu diesem Zweck führen wir Fallanalysen von Sachunterrichtsstunden vor und nach der Fortbildung derselben Lehrkräfte durch, sowie detaillierte didaktische Analysen des jeweils eingesetzten Materials. Wir kommen zu differenzierten kritischen Schlüssen. Das pädagogische und insbesondere das didaktische Handeln der Lehrerinnen wird in Folge der Fortbildungen stark perturbiert; zu der beabsichtigten und in Form von Handreichungen vorgegebenen „Kognitiven Strukturierung“ auf Schülerseite kommt es indes nicht. Stattdessen studieren wir intensiv die Überforderung der Lehrerinnen, die aus einer Kombination von a. den fachwissenschaftlichen Hintergründen, b. der freiwilligen Verpflichtung zur Manualumsetzung und c. den artikulierten Bedürfnissen der Schüler resultiert. Wir können anhand des Versuchs, die Lehrpersonen in „Kognitiver Strukturierung“ fortzubilden, einen Blick auf deren eigene kognitive und pädagogische Strukturen werfen; eine kontrollierte Eingriffnahme in diese Strukturen jedoch findet im Rahmen der „Implementationen“ nicht statt. Die Interventionsform der randomisierten Nachmittagsfortbildung wird zwar verworfen, lediglich angerissen aber die Frage, wie das erlangte Wissen zu nutzen wäre.
Im Rahmen des FRANZ-Projektes wurde nach einer Ionenquelle verlangt welche in der Lage ist einen intensiven hochbrillanten Protonenstrahl von 200 mA bei 120 keV im Dauerstrichbetrieb zur Verfügung zu stellen, bei gleichzeitig niedriger Strahlemittanz. Der recht hohe Protonenstrom von 200 mA stellt dabei eine Herausforderung an den Experimentator dar.
Die grundsätzliche Problematik bei der Entwicklung einer solchen Ionenquelle besteht im Wesentlichen darin, ein geeignetes Extraktionssystem zu designen, welches in der Lage ist den geforderten hohen Protonenstrom zu extrahieren und transportieren. In diesem Zusammenhang wurden Abschätzungen bezüglich des notwendigen Emissionsradius, der elektrischen Feldstärke im Extraktionsspalt sowie des Protonenanteils für den verlangten Protonenstrom von 200 mA durchgeführt. Für die praktische Umsetzung wurden Lösungsstrategien erarbeitet. Ziel war es die elektrische Feldstärke im Gap so hoch wie möglich und den Radius der Emissionsöffnung so klein wie möglich zu wählen, bei gleichzeitig möglichst hohem Protonenanteil. Basierend auf diesen Erkenntnissen wurde ein Prototyp der Bogenentladungs-Volumenionenquelle entwickelt und erfolgreich in Betrieb genommen.
Zur Steigerung des Protonenanteils im Wasserstoffplasma wurden diverse Parameter der Ionenquelle optimiert wie bspw. Bogenleistung, Gasdruck sowie insbesondere die Feldverteilung und die magnetische Flussdichte des magnetischen Filters. Diese Ergebnisse wurden mit dem verbesserten theoretischen Modell zur Erzeugung von atomaren Wasserstoffionenstrahlen verglichen. Um die elektrische Feldstärke im Extraktionsspalt zu steigern wurden die Elektroden aus einem thermisch belastbaren Material hergestellt und einer speziellen Oberflächenbehandlung unterzogen. Des Weiteren wurden theoretische und experimentelle Untersuchungen bezüglich der Emissionsstromdichte und der Strahlqualität durchgeführt. Weiterhin wurde die Emittanz des Ionenstrahls berechnet sowie mit einer eigens am Institut für Angewandte Physik entwickelten Pepperpot-Emittanzmessanlage experimentell bestimmt. Die vorliegende Dissertation präsentiert die Ergebnisse der Entwicklung dieser hocheffizienten Bogenentladungs-Volumenionenquelle.
Der Bundesgerichtshof hat mit Urteil vom 28. Januar 2015 entschieden, dass Kinder, die durch künstliche Befruchtung im Wege einer Samenspende gezeugt worden sind, gegen Reproduktionsmediziner und -kliniken einen Anspruch auf Auskunft über die Identität des Samenspenders haben können. Die Geltendmachung des Auskunftsanspruchs setzte kein bestimmtes Mindestalter der „Spenderkinder“ voraus. Der nachfolgende Beitrag analysiert die Konstruktion dieses Anspruchs vor dem Hintergrund eines durch neue Reproduktionstechnologien und gewandelte gesellschaftliche Vorstellungen veränderten Abstammungsrechts. Nach Methodenkritik und Rekonstruktion aus einer gesellschaftlich-institutionellen Perspektive eröffnen sich weitere Aussichten auf zukünftige Formen von Vaterschaft und ein entsprechend zu verwirklichendes Recht auf Kenntnis der eigenen Abstammung.
Device-related infections in recipients of left ventricular assist devices (LVAD) have been recognized as a major source of morbidity and mortality. They require a high level of diagnostic effort as part of the overall burden resulting from infectious complications in LVAD recipients. We present a multi-allergic patient who was treated for persistent sterile intrathoracic abscess formation and pericardial empyema following minimally invasive LVAD implantation including use of a sheet of e-polytetrafluoroethylene (ePTFE) membrane to restore pericardial integrity. Sterile abscess formation and pericardial empyema recurred after surgical removal until the ePTFE membrane was removed, suggesting that in disposed patients, ePTFE may be related to sterile abscess formation or sterile empyema.
Background: Lithium has proven suicide preventing effects in the long-term treatment of patients with affective disorders. Clinical evidence from case reports indicate that this effect may occur early on at the beginning of lithium treatment. The impact of lithium treatment on acute suicidal thoughts and/or behavior has not been systematically studied in a controlled trial. The primary objective of this confirmatory study is to determine the association between lithium therapy and acute suicidal ideation and/or suicidal behavior in inpatients with a major depressive episode (MDE, unipolar and bipolar disorder according to DSM IV criteria). The specific aim is to test the hypothesis that lithium plus treatment as usual (TAU), compared to placebo plus TAU, results in a significantly greater decrease in suicidal ideation and/or behavior over 5 weeks in inpatients with MDE.
Methods/Design: We initiated a randomized, placebo-controlled multicenter trial. Patients with the diagnosis of a moderate to severe depressive episode and suicidal thoughts and/or suicidal behavior measured with the Sheehan-Suicidality-Tracking Scale (S-STS) will be randomly allocated to add lithium or placebo to their treatment as usual. Change in the clinician administered S-STS from the initial to the final visit will be the primary outcome.
Discussion: There is an urgent need to identify treatments that will acutely decrease suicidal ideation and/or suicidal behavior. The results of this study will demonstrate whether lithium reduces suicidal ideation and behavior within the first 5 weeks of treatment.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
Background: Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic properties. Here, we analyze the influence of DMF on TNF-α-induced expression of the important pro-inflammatory and pro-atherogenic chemokine MCP-1 and investigate the underlying mechanisms of this expression.
Findings: We analyzed constitutive and TNF-α-induced expression of MCP-1 in human umbilical vascular endothelial cells (HUVEC) +/− DMF treatment via enzyme-linkes immunosorbent assay (ELISA). DMF significantly inhibited the protein expression levels in a time- and concentration-dependent manner. Furthermore, MCP-1 mRNA expression was also reduced in response to DMF, as demonstrated by RT-PCR. Thus, the regulation occurs at the transcriptional level. Interestingly, DMF prolonged the TNF-α-induced p38 and JNK phosphorylation in HUVEC, as demonstrated by Western blot analysis; however, the p38 and JNK inhibitor SB203580 did not affect the DMF-conveyed suppression of TNF-α-induced MCP-1 expression. DMF suppressed the TNF-α-induced nuclear translocation and phosphorylation (Serine 536) of p65 in these cells. These results were additionally approved by p65 luciferase promoter assays. Furthermore, we found that DMF slightly inhibited the early degradation of IκBα. In addition, we verified our results using other important inflammatory cytokines such as CCL-5, PDGF-BB, GM-CSF and IL-6.
Conclusion: DMF suppresses various TNF-α-induced pro-inflammatory and pro-atherogenic cytokines/chemokines in human endothelial cells. This action is regulated by reduced p65 activity and nuclear translocation, which can be explained in part by the reduced early degradation of IκBα and more important the reduced phosphorylation of p65 at Serine 536. These effects were independent of the p38, PI3K and p42/44 signaling pathways. As a result, DMF might be suitable for treating patients with vascular diseases.
In honeybees, reproductive females usually mate early in their life with more than 10 males in free flight, often within 10 minutes, and then store male gametes for up to five years. Because of the extreme polyandry and mating in free flight special adaptations in males are most likely. We present here the results of an investigation of the protein content of four types of male reproductive glands from the Western honeybee (Apis mellifera) drone, namely seminal vesicles (secretion in ejaculate), as well as bulbus, cornua and mucus glands (secretions for the mating plug). Using high resolution and accuracy mass spectrometry and a combination of database searching and de novo sequencing techniques it was possible to identify 50 different proteins in total, inside all mentioned glands, except in the mucus gland. Most of the proteins are unique for a specific gland type, only one of them (H9KEY1/ATP synthase subunit O) was found in three glands, and 7 proteins were found in two types of glands. The identified proteins represent a wide variety of biological functions and can be assigned to several physiological classes, such as protection, energy generation, maintaining optimal conditions, associated mainly with vesicula seminalis; signaling, cuticle proteins, icarpin and apolipoproteins located mainly in the bulbus and cornua glands; and some other classes. Most of the discovered proteins were not found earlier during investigation of semen, seminal fluid and tissue of reproductive glands of the bee drone. Moreover, we provide here the origin of each protein. Thus, the presented data might shed light on the role of each reproductive gland.
Sparse coding is a popular approach to model natural images but has faced two main challenges: modelling low-level image components (such as edge-like structures and their occlusions) and modelling varying pixel intensities. Traditionally, images are modelled as a sparse linear superposition of dictionary elements, where the probabilistic view of this problem is that the coefficients follow a Laplace or Cauchy prior distribution. We propose a novel model that instead uses a spike-and-slab prior and nonlinear combination of components. With the prior, our model can easily represent exact zeros for e.g. the absence of an image component, such as an edge, and a distribution over non-zero pixel intensities. With the nonlinearity (the nonlinear max combination rule), the idea is to target occlusions; dictionary elements correspond to image components that can occlude each other. There are major consequences of the model assumptions made by both (non)linear approaches, thus the main goal of this paper is to isolate and highlight differences between them. Parameter optimization is analytically and computationally intractable in our model, thus as a main contribution we design an exact Gibbs sampler for efficient inference which we can apply to higher dimensional data using latent variable preselection. Results on natural and artificial occlusion-rich data with controlled forms of sparse structure show that our model can extract a sparse set of edge-like components that closely match the generating process, which we refer to as interpretable components. Furthermore, the sparseness of the solution closely follows the ground-truth number of components/edges in the images. The linear model did not learn such edge-like components with any level of sparsity. This suggests that our model can adaptively well-approximate and characterize the meaningful generation process.
Background: It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.
Methods: Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit.
Results: CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively.
Conclusions: The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.
The assignment of functions to genes in the carotenoid biosynthesis pathway is necessary to understand how the pathway is regulated and to obtain the basic information required for metabolic engineering. Few carotenoid ε-hydroxylases have been functionally characterized in plants although this would provide insight into the hydroxylation steps in the pathway. We therefore isolated mRNA from the endosperm of maize (Zea mays L., inbred line B73) and cloned a full-length cDNA encoding CYP97C19, a putative heme-containing carotenoid ε hydroxylase and member of the cytochrome P450 family. The corresponding CYP97C19 genomic locus on chromosome 1 was found to comprise a single-copy gene with nine introns. We expressed CYP97C19 cDNA under the control of the constitutive CaMV 35S promoter in the Arabidopsis thaliana lut1 knockout mutant, which lacks a functional CYP97C1 (LUT1) gene. The analysis of carotenoid levels and composition showed that lutein accumulated to high levels in the rosette leaves of the transgenic lines but not in the untransformed lut1 mutants. These results allowed the unambiguous functional annotation of maize CYP97C19 as an enzyme with strong zeinoxanthin ε-ring hydroxylation activity.
Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients’ interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self-referential and semantic processing of threat words in SAD.
Computed ABC analysis for rational selection of most informative variables in multivariate data
(2015)
Objective: Multivariate data sets often differ in several factors or derived statistical parameters, which have to be selected for a valid interpretation. Basing this selection on traditional statistical limits leads occasionally to the perception of losing information from a data set. This paper proposes a novel method for calculating precise limits for the selection of parameter sets.
Methods: The algorithm is based on an ABC analysis and calculates these limits on the basis of the mathematical properties of the distribution of the analyzed items. The limits implement the aim of any ABC analysis, i.e., comparing the increase in yield to the required additional effort. In particular, the limit for set A, the "important few", is optimized in a way that both, the effort and the yield for the other sets (B and C), are minimized and the additional gain is optimized.
Results: As a typical example from biomedical research, the feasibility of the ABC analysis as an objective replacement for classical subjective limits to select highly relevant variance components of pain thresholds is presented. The proposed method improved the biological interpretation of the results and increased the fraction of valid information that was obtained from the experimental data.
Conclusions: The method is applicable to many further biomedical problems including the creation of diagnostic complex biomarkers or short screening tests from comprehensive test batteries. Thus, the ABC analysis can be proposed as a mathematically valid replacement for traditional limits to maximize the information obtained from multivariate research data.
Introduction: By producing H2O2, the NADPH oxidase Nox4 is involved in differentiation of mesenchymal cells. Exercise alters the composition of slow and fast twitch fibres in skeletal. Here we hypothesized that Nox4 contributes to exercise-induced adaptation such as changes in muscle metabolism or muscle fibre specification and studied this in wildtype and Nox4-/- mice.
Results: Exercise, as induced by voluntary running in a running wheel or forced running on a treadmill induced a switch from fast twitch to intermediate fibres. However the induced muscle fibre switch was similar between Nox4-/- and wildtype mice. The same held true for exercise-induced expression of PGC1α or AMPK activation. Both are increased in response to exercise, but with no difference was observed between wildtype and Nox4-/- mice.
Conclusion: Thus, exercise-induced muscle fibre switch is Nox4-independent.
Background: The pathomechanisms of atherosclerosis and vascular remodelling are under intense research. Only a few in vivo tools to study these processes longitudinally in animal experiments are available. Here, we evaluated the potential of micro-CT technology.
Methods: Lumen areas of the common carotid arteries (CCA) in the ApoE-/- partial carotid artery ligation mouse model were compared between in vivo and ex vivo micro-CT technique and serial histology in a total of 28 animals. AuroVist-15 nm nanoparticles were used as in vivo blood pool contrast agent in a Skyscan 1176 micro-CT at resolution of 18 μmeter voxel size and a mean x-ray dose of 0.5 Gy. For ex vivo imaging, animals were perfused with MicroFil and imaged at 9 μmeter voxel size. Lumen area was evaluated at postoperative days 7, 14, and 28 first by micro-CT followed by histology.
Results: In vivo micro-CT and histology revealed lumen loss starting at day 14. The lumen profile highly correlated (r = 0.79, P<0.0001) between this two methods but absolute lumen values obtained by histology were lower than those obtained by micro-CT. Comparison of in vivo and ex vivo micro-CT imaging revealed excellent correlation (r = 0.83, P<0.01). Post mortem micro-CT yielded a higher resolution than in vivo micro-CT but there was no statistical difference of lumen measurements in the partial carotid artery ligation model.
Conclusion: These data demonstrate that in vivo micro-CT is a feasible and accurate technique with low animal stress to image remodeling processes in the murine carotid artery.
DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV-1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C) efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C-induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection.
Background & aims: Vitamin D, best known to regulate bone mineralization, has numerous additional roles including regulation inflammatory pathways. Recently, an increased incidence of 25-hydroxyvitamin D3 (25(OH)D3) deficiency has been found in subjects suffering from liver diseases. We here investigated if low vitamin D levels might be associated with prognosis, inflammation and infectious complications in patients with cirrhosis.
Methods: We performed a prospective cohort study investigating the relation between 25(OH)D3 levels and stages of cirrhosis, mortality and complications of cirrhosis, including infections.
Results: 251 patients with cirrhosis were enrolled into the present prospective cohort study. 25(OH)D3 levels were quantified by radioimmunoassay from serum samples obtained at study inclusion. The mean follow-up time was 411 ± 397 days with a range of 1-1382 days. 30 (12.0%) patients underwent liver transplantation and 85 (33.8%) individuals died within the study. The mean serum 25(OH)D3 concentration was 8.93 ± 7.1 ng/ml with a range of 1.0 to 46.0 ng/ml. 25(OH)D3 levels differed significantly between Child Pugh scores and showed a negative correlation with the model of end stage liver disease (MELD) score. Patients with decompensated cirrhosis and infectious complications, had significantly lower 25(OH)D3 levels compared to subjects without complications. Low 25(OH)D3 was associated with mortality in uni- as well as multivariate Cox regression models.
Conclusions: 25(OH)D3 deficiency is associated with advanced liver disease and low 25(OH)D3 levels are an indicator for a poor outcome and are associated with infectious complications.
Background: Despite its largely mountainous terrain for which this Himalayan country is a popular tourist destination, Nepal is now endemic for five major vector-borne diseases (VBDs), namely malaria, lymphatic filariasis, Japanese encephalitis, visceral leishmaniasis and dengue fever. There is increasing evidence about the impacts of climate change on VBDs especially in tropical highlands and temperate regions. Our aim is to explore whether the observed spatiotemporal distributions of VBDs in Nepal can be related to climate change.
Methodology: A systematic literature search was performed and summarized information on climate change and the spatiotemporal distribution of VBDs in Nepal from the published literature until December 2014 following providing items for systematic review and meta-analysis (PRISMA) guidelines.
Principal findings: We found 12 studies that analysed the trend of climatic data and are relevant for the study of VBDs, 38 studies that dealt with the spatial and temporal distribution of disease vectors and disease transmission. Among 38 studies, only eight studies assessed the association of VBDs with climatic variables. Our review highlights a pronounced warming in the mountains and an expansion of autochthonous cases of VBDs to non-endemic areas including mountain regions (i.e., at least 2,000 m above sea level). Furthermore, significant relationships between climatic variables and VBDs and their vectors are found in short-term studies.
Conclusion: Taking into account the weak health care systems and difficult geographic terrain of Nepal, increasing trade and movements of people, a lack of vector control interventions, observed relationships between climatic variables and VBDs and their vectors and the establishment of relevant disease vectors already at least 2,000 m above sea level, we conclude that climate change can intensify the risk of VBD epidemics in the mountain regions of Nepal if other non-climatic drivers of VBDs remain constant.
Australia has experienced dramatic declines and extinctions of its native rodent species over the last 200 years, particularly in southern Australia. In the tropical savanna of northern Australia significant declines have occurred only in recent decades. The later onset of these declines suggests that the causes may differ from earlier declines in the south. We examine potential regional effects (northern versus southern Australia) on biological and ecological correlates of range decline in Australian rodents. We demonstrate that rodent declines have been greater in the south than in the tropical north, are strongly influenced by phylogeny, and are consistently greater for species inhabiting relatively open or sparsely vegetated habitat. Unlike in marsupials, where some species have much larger body size than rodents, body mass was not an important predictor of decline in rodents. All Australian rodent species are within the prey-size range of cats (throughout the continent) and red foxes (in the south). Contrary to the hypothesis that mammal declines are related directly to ecosystem productivity (annual rainfall), our results are consistent with the hypothesis that disturbances such as fire and grazing, which occur in non-rainforest habitats and remove cover used by rodents for shelter, nesting and foraging, increase predation risk. We agree with calls to introduce conservation management that limits the size and intensity of fires, increases fire patchiness and reduces grazing impacts at ecological scales appropriate for rodents. Controlling feral predators, even creating predator-free reserves in relatively sparsely-vegetated habitats, is urgently required to ensure the survival of rodent species, particularly in northern Australia where declines are not yet as severe as those in the south.
AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor δ (PPARδ) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.
Augmenting LTP-like plasticity in human motor cortex by spaced paired associative stimulation
(2015)
Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60min and 180min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60min and 180min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.
Background: The peroneal muscles are the most effective lateral stabilisers whose tension braces the ankle joint complex against excessive supination. The purpose of this study was to identify the morphological and biomechanical effects of two machine-based shank muscle training methods.
Methods: Twenty-two healthy male recreationally active sports students performed ten weeks of single-set high resistance strength training with 3 training sessions per week. The subjects conducted subtalar pronator/supinator muscle training (ST) with the right leg by using a custom-made apparatus; the left foot muscles were exercised with machine-based talocrural plantar and dorsiflexor training (TT). Muscle strength (MVIC), muscle volume and foot biomechanics (rearfoot motion, ground reaction forces, muscle reaction times) during a sudden ankle supination were recorded before and after the intervention.
Results: Compared to TT, ST resulted in significantly higher pronator (14% vs. 8%, P<0.01) and supinator MVIC (25% vs. 12%, P<0.01). During sudden foot inversions, both ST and TT resulted in reduced supination velocity (-12%; P<0.01). The muscle reaction onset time was faster after the training in peroneus longus (PL) (P<0.01). Muscle volume of PL (P<0.01) and TA (P<0.01) increased significantly after both ST and TT.
Conclusion: After both ST and TT, the ankle joint complex is mechanically more stabilised against sudden supinations due to the muscle volume increase of PL and TA. As the reduced supination velocities indicate, the strength training effects are already present during free-fall. According to a sudden ankle supination in standing position, both machine-based dorsiflexor and pronator strength training is recommended for enhancing the mechanical stability of the ankle.
Cognitive stability and flexibility are core functions in the successful pursuit of behavioral goals. While there is evidence for a common frontoparietal network underlying both functions and for a key role of dopamine in the modulation of flexible versus stable behavior, the exact neurocomputational mechanisms underlying those executive functions and their adaptation to environmental demands are still unclear. In this work we study the neurocomputational mechanisms underlying cue based task switching (flexibility) and distractor inhibition (stability) in a paradigm specifically designed to probe both functions. We develop a physiologically plausible, explicit model of neural networks that maintain the currently active task rule in working memory and implement the decision process. We simplify the four-choice decision network to a nonlinear drift-diffusion process that we canonically derive from a generic winner-take-all network model. By fitting our model to the behavioral data of individual subjects, we can reproduce their full behavior in terms of decisions and reaction time distributions in baseline as well as distractor inhibition and switch conditions. Furthermore, we predict the individual hemodynamic response timecourse of the rule-representing network and localize it to a frontoparietal network including the inferior frontal junction area and the intraparietal sulcus, using functional magnetic resonance imaging. This refines the understanding of task-switch-related frontoparietal brain activity as reflecting attractor-like working memory representations of task rules. Finally, we estimate the subject-specific stability of the rule-representing attractor states in terms of the minimal action associated with a transition between different rule states in the phase-space of the fitted models. This stability measure correlates with switching-specific thalamocorticostriatal activation, i.e., with a system associated with flexible working memory updating and dopaminergic modulation of cognitive flexibility. These results show that stochastic dynamical systems can implement the basic computations underlying cognitive stability and flexibility and explain neurobiological bases of individual differences.
El artículo, después de haber tratado la cuestión del tiranicidio en Tomás de Aquino y en Bartolo de Sassoferrato, muestra cómo Francisco de Vitoria, consciente de las soluciones que ofrecen los autores anteriores a él, afronta el argumento de forma innovadora, aunque en línea con la tradición anterior. En la base de la solución que propone Vitoria, se encuentra, en efecto, la afirmación de un derecho a la auto-defensa, entendido como derecho natural inalienable que reside en los individuos y en las comunidades; un derecho que siempre lo pueden ejercer los súbditos en relación con un gobernante que se convierte en tirano. Vitoria expresa de este modo el principio de resistencia a la autoridad injusta e ilegal en los términos de un derecho subjetivo, el de la auto-defensa, pero, al mismo tiempo, señala los límites afirmando la necesidad de cada individuo de respetar y someterse a un orden de justicia objetivo. De aquí su prohibición a un particular de matar a un hombre, aunque sea un tirano, sin un justo procedimiento jurídico. Así pues, el artículo muestra, a través del debate sobre la licitud del tiranicidio cómo en la obra de Vitoria se encuentra una teoría sólida de la soberanía juntamente con la afirmación tenaz de derechos naturales individuales. En efecto, Vitoria retoma, por una parte, una tradición de pensamiento para la que la formación de las sociedades políticas era la consecuencia de la sociabilidad natural de los hombres; y por otra, desarrollaba una teoría coherente de los derechos subjetivos a partir de la necesidad misma de los individuos de asociarse los unos con los otros para los fines de una vida éticamente justa y gratificante.
kurz und kn@pp news : Nr. 34
(2015)
Die Frage was ein Fach ausmacht ist keinesfalls leicht zu beantworten. Dennoch haben sich in den letzten Wochen auf FAZ.net Kolleginnen und Kollegen verschiedenster Fächer daran versucht. Für Schülerinnen und Schülern dürfte dies bei der Studienfachwahl hilfreich sein. Doch der Versuch von Prof. Korte zur Politikwissenschaft stellt das Fach zu eingeschränkt dar.
Es gibt Neuigkeiten von Chinas bekanntestem Dissidenten und Künstler Ai Weiwei. Aber dieses Mal ist es nicht die chinesische Regierung, die sich Fragen stellen lassen muss, sondern die britische. Denn Ai erhielt kein 6-Monatsvisum, weil er „straffällig“ sei. Doch der Künstler wurde niemals angeklagt. Was steckt hinter der Verweigerung? Ein Kommentar.
This master thesis will consider the question how far American history influenced, and is mirrored in, (American) science fiction literature. The main work of reference for this endeavor will be the award-winning Mars Trilogy by the aforementioned, renowned science fiction author Kim Stanley Robinson.
Chapter one will deal specifically with the topic of how certain events of American history – especially the War of Independence, its origins and its aftermath – are more or less mirrored in the Mars novels, often with only minor changes (and adapted into a sci-fi setting, of course). The historic concepts of ‘the Frontier’ and ‘Manifest Destiny’ will find some minor mention here.
The second chapter of this paper will be exclusively about one of the early main characters of the trilogy, one with a lasting influence even though he dies early. The leading thesis will be that this ‘all-American hero’ is, more or less, a fusion of two major figures of early American history, specifically Captain John Smith and legendary ‘frontiersman’ Daniel Boone. The name of this character alone – John Boone – should serve easily as an indicator for the truth of this thesis.
The final chapter of this thesis then leaves the Mars Trilogy behind in order to look at the whole wide field of science fiction literature. Selected works will serve to illustrate the pervasive presence of American history in this genre. The concept of the ‘frontier’ will be of considerable importance to this endeavor, and will feature significantly in this section.
Concluding the paper will be a short overview of the paper’s major points and a few final thoughts will then round out this thesis and mark its end.
Challenging voluntary CSR-initiatives – a case study on the effectiveness of the Equator Principles
(2015)
The Equator Principles (EPs) are a voluntary and self-regulatory Corporate Social Responsibility (CSR) initiative in the field of project finance. The EPs provide a number of principles to businesses to reduce the negative impacts of lending practices linked to environment-damaging projects. The paper argues that the actual impact of the EPs even now as revised version is still limited. This is due to their voluntary nature and their lack of adequate governance mechanisms, that is, enforcement, monitoring and sanctioning. With the help of RepRisk, which provides a database capturing third-party criticism as well as a company’s or project’s exposure to controversial socio-environmental issues, the paper evaluates the on-the-ground performances of the two ‘Equator banks’ Barclays and JPMorgan Chase and compares their performance with the one of the two non-Equator banks Deutsche Bank and UBS. The paper shows that the EPs do not have a substantial influence on the broader CSR-performance of multinational banks due to the EPs’ limited scope – focusing mainly on project finance – and the (still) existing various loopholes, grey areas and discretionary leeway. The paper also gives an overview of the main institutional shortcomings of the EPs and their association and discusses some potential reform steps which should be taken to further strengthen and ‘harden’ this ‘soft law’ EP-framework. The paper thus argues in favor of (more) mandatory and legally binding rules and standards at the transnational level to overcome the EPs’ ‘voluntariness bias’.
Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Defects in flow-induced NO formation go along with endothelial dysfunction, initiation and progression of atherosclerosis as well as with arterial hypertension. Previous work has identified several mechanotransducing signaling processes involved in fluid shear stress-induced endothelial effects. But how fluid shear stress initiates the response is poorly understood. Here, I show in human and bovine endothelial cells that the G-protein Gq/G11 and the purinergic receptor P2Y2 mediate fluid shear stress-induced endothelial responses such as Ca2+ release, nitric oxide (NO) formation and the phosphorylation of platelet-endothelial-cell-adhesion-molecule-1 (PECAM-1), vascular endothelial growth factor-2 (VEGFR-2) and Akt kinase as well as activation of the endothelial NO synthase (eNOS). P2Y2 receptor is activated by adenosine triphosphate (ATP) which is released from endothelial cells under the influence of fluid shear stress. Arteries with P2Y2 or Gαq/Gα11 deficiency have impaired flow-induced dilatation. Mice with induced endothelium-specific deficiency of P2Y2 or Gαq/Gα11 develop hypertension which is accompanied by reduced eNOS activation. My data identify P2Y2 and Gq/G11 as a critical endothelial mechano-signaling pathway located upstream of mechanotransducing processes described so far. Moreover, I demonstrate that P2Y2 and Gq/G11 are required for basal endothelial NO formation, vascular tone and blood pressure.
Die vorliegende Arbeit beschäftigt sich mit den Arbeitsgedächtnisleistungen zweier sprachlicher Sondergruppen und der Möglichkeit über die Leistung des Arbeitsgedächtnisses validere Prognosen des weiteren sprachlichen bzw. schriftsprachlichen Entwicklungsverlaufs zu erreichen, als dies über eine ausschließliche Erhebung der Sprachleistung möglich ist. Die Basis dieser Untersuchungen bilden zwei Längsschnittstudien. Die Daten der sprachlichen Sondergruppe der Late Talker (kognitive Aspekte) wurden in Heidelberg an der Universität und dem Frühinterventionszentrum (FRIZ) zwischen dem zweiten und dem neunten Lebensjahr der Kinder (N=93 mit n1=59 Late Talkers und n2=34 Kontrollkindern) in bestimmten Abständen erhoben. Neben den sprachlichen und kognitiven Leistungstests wurde zum letzten Messzeitpunkt zusätzlich die Arbeitsgedächtnisleistung erfasst. Dabei sollte untersucht werden, ob die Leistungen im Arbeitsgedächtnis valide unterscheiden können zwischen Kindern mit persistierenden Sprachentwicklungsproblemen und Kindern, die das Defizit im weiteren Entwicklungsverlauf aufholen (Late Bloomer). Die Ergebnisse zeigen, dass mithilfe der Leistungen in der Phonologischen Schleife eine sehr gute Trennung der Late Bloomer von den Kindern, die weiter eine Sprachproblematik aufweisen, vorgenommen werden kann. Ein Hinzuziehen der zentral-exekutiven Leistungen bringt hingegen keine Verbesserung in der Vorhersagegenauigkeit.
Der zweiten Untersuchung liegen zum einen die Daten der Normierung der Arbeitsgedächtnistestbatterie für Kinder von fünf bis zwölf Jahren (AGTB 5-12 {Hasselhorn et al., 2012}) zugrunde (N=1.669 davon 243 Kinder mit Migrationshintergrund), anhand derer überprüft wurde, ob Kinder mit Migrationshintergrund in irgendeiner Weise durch die Nutzung der Testbatterie benachteiligt werden, sei es 1. Durch die ungeprüfte Übernahme des Arbeitsgedächtnismodells (nach dem Vorbild von Baddeley (1986)), dass für Muttersprachler bereits bestätigt werden konnte, 2. Durch Benachteiligungen in bestimmten Untertests und 3. Durch die Testbatterie im Allgemeinen, die Art der Testung und die Wahl bestimmter Items. Zur Überprüfung, inwieweit Prädiktoren, die bei Muttersprachlern valide Prognosen der späteren schriftsprachlichen Leistungen erlauben, auch bei Kindern mit Migrationshintergrund genutzt werden können, wird ein weiterer längsschnittlicher Datensatz herangezogen. Von den 127 Kindern der Längsschnittstudie des Projekts ANNA „Gedächtnis und Schulfähigkeit“ (Individual Development and Adaptive Education of Children at Risk am Deutschen Institut für internationale pädagogische Forschung - DIPF) weisen 60 Kinder einen Migrationshintergrund auf. Auf Basis beider Datensätze konnte nachgewiesen werden, dass das Modell des Arbeitsgedächtnisses auch bei Kindern mit Migrationshintergrund Anwendung findet und die Benachteiligungen bei der Testung besonders gering ausfallen, je früher die Kinder untersucht werden. Es zeigt sich aber auch, dass die AGTB 5-12 an manchen Stellen überarbeitet werden sollte, um mögliche Benachteiligungen noch weiter zu verringern. Außerdem konnte gezeigt werden, dass sich auch bei Kindern mit Migrationshintergrund valide Prognosen späterer schriftsprachlicher Leistungen anhand ihrer Arbeitsgedächtnisleistungen treffen lassen und hier hauptsächlich auf Basis der phonologischen Gesamtleistungen (alle Untertests).
Background: Cardiovascular magnetic resonance (CMR) offers quantification of phasic atrial functions based on volumetric assessment and more recently, on CMR feature tracking (CMR-FT) quantitative strain and strain rate (SR) deformation imaging. Inter-study reproducibility is a key requirement for longitudinal studies but has not been defined for CMR-based quantification of left atrial (LA) and right atrial (RA) dynamics.
Methods: Long-axis 2- and 4-chamber cine images were acquired at 9:00 (Exam A), 9:30 (Exam B) and 14:00 (Exam C) in 16 healthy volunteers. LA and RA reservoir, conduit and contractile booster pump functions were quantified by volumetric indexes as derived from fractional volume changes and by strain and SR as derived from CMR-FT. Exam A and B were compared to assess the inter-study reproducibility. Morning and afternoon scans were compared to address possible diurnal variation of atrial function.
Results: Inter-study reproducibility was within acceptable limits for all LA and RA volumetric, strain and SR parameters. Inter-study reproducibility was better for volumetric indexes and strain than for SR parameters and better for LA than for RA dynamics. For the LA, reservoir function showed the best reproducibility (intraclass correlation coefficient (ICC) 0.94–0.97, coefficient of variation (CoV) 4.5–8.2 %), followed by conduit (ICC 0.78–0.97, CoV 8.2–18.5 %) and booster pump function (ICC 0.71–0.95, CoV 18.3–22.7). Similarly, for the RA, reproducibility was best for reservoir function (ICC 0.76–0.96, CoV 7.5–24.0 %) followed by conduit (ICC 0.67–0.91, CoV 13.9–35.9) and booster pump function (ICC 0.73–0.90, CoV 19.4–32.3). Atrial dynamics were not measurably affected by diurnal variation between morning and afternoon scans.
Conclusions: Inter-study reproducibility for CMR-based derivation of LA and RA functions is acceptable using either volumetric, strain or SR parameters with LA function showing higher reproducibility than RA function assessment. Amongst the different functional components, reservoir function is most reproducibly assessed by either technique followed by conduit and booster pump function, which needs to be considered in future longitudinal research studies.
Immunohistochemical assessment of phosphorylated mTORC1-pathway proteins in human brain tumors
(2015)
Background: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.
Methods and findings: Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0–230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.
Conclusion: Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
Objectives: Previous studies investigating speech perception in noise have typically been conducted with static masker positions. The aim of this study was to investigate the effect of spatial separation of source and masker (spatial release from masking, SRM) in a moving masker setup and to evaluate the impact of adaptive beamforming in comparison with fixed directional microphones in cochlear implant (CI) users.
Design: Speech reception thresholds (SRT) were measured in S0N0 and in a moving masker setup (S0Nmove) in 12 normal hearing participants and 14 CI users (7 subjects bilateral, 7 bimodal with a hearing aid in the contralateral ear). Speech processor settings were a moderately directional microphone, a fixed beamformer, or an adaptive beamformer. The moving noise source was generated by means of wave field synthesis and was smoothly moved in a shape of a half-circle from one ear to the contralateral ear. Noise was presented in either of two conditions: continuous or modulated.
Results: SRTs in the S0Nmove setup were significantly improved compared to the S0N0 setup for both the normal hearing control group and the bilateral group in continuous noise, and for the control group in modulated noise. There was no effect of subject group. A significant effect of directional sensitivity was found in the S0Nmove setup. In the bilateral group, the adaptive beamformer achieved lower SRTs than the fixed beamformer setting. Adaptive beamforming improved SRT in both CI user groups substantially by about 3 dB (bimodal group) and 8 dB (bilateral group) depending on masker type.
Conclusions: CI users showed SRM that was comparable to normal hearing subjects. In listening situations of everyday life with spatial separation of source and masker, directional microphones significantly improved speech perception with individual improvements of up to 15 dB SNR. Users of bilateral speech processors with both directional microphones obtained the highest benefit.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Species recognition in lichen-forming fungi has been a challenge because of unsettled species concepts, few taxonomically relevant traits, and limitations of traditionally used morphological and chemical characters for identifying closely related species. Here we analyze species diversity in the cosmopolitan genus Protoparmelia s.l. The ~25 described species in this group occur across diverse habitats from the boreal -arctic/alpine to the tropics, but their relationship to each other remains unexplored. In this study, we inferred the phylogeny of 18 species currently assigned to this genus based on 160 specimens and six markers: mtSSU, nuLSU, ITS, RPB1, MCM7, and TSR1. We assessed the circumscription of species-level lineages in Protoparmelia s. str. using two coalescent-based species delimitation methods – BP&P and spedeSTEM. Our results suggest the presence of a tropical and an extra-tropical lineage, and eleven previously unrecognized distinct species-level lineages in Protoparmelia s. str. Several cryptic lineages were discovered as compared to phenotype-based species delimitation. Many of the putative species are supported by geographic evidence.
The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL.
Little work has been done on large-scale patterns of stream insect richness in China. We explored the influence of climatic and catchment-scale factors on stream insect (Ephemeroptera, Plecoptera, Trichoptera; EPT) richness across mid-latitude China. We assessed the predictive ability of climatic, catchment land cover and physical structure variables on genus richness of EPT, both individually and combined, in 80 mid-latitude Chinese streams, spanning a 3899-m altitudinal gradient. We performed analyses using boosted regression trees and explored the nature of their influence on richness patterns. The relative importance of climate, land cover, and physical factors on stream insect richness varied considerably between the three orders, and while important for Ephemeroptera and Plecoptera, latitude did not improve model fit for any of the groups. EPT richness was linked with areas comprising high forest cover, elevation and slope, large catchments and low temperatures. Ephemeroptera favoured areas with high forest cover, medium-to-large catchment sizes, high temperature seasonality, and low potential evapotranspiration. Plecoptera richness was linked with low temperature seasonality and annual mean, and high slope, elevation and warm-season rainfall. Finally, Trichoptera favoured high elevation areas, with high forest cover, and low mean annual temperature, seasonality and aridity. Our findings highlight the variable role that catchment land cover, physical properties and climatic influences have on stream insect richness. This is one of the first studies of its kind in Chinese streams, thus we set the scene for more in-depth assessments of stream insect richness across broader spatial scales in China, but stress the importance of improving data availability and consistency through time.
Is postoperative imaging mandatory after meningioma removal? : results of a prospective study
(2015)
Background: Routine postoperative imaging (PI) following surgery for intracranial meningiomas is common practice in most neurosurgical departments. The purpose of this study was to determine the role of routine PI and its impact on clinical decision making after resection of meningioma.
Methods: Patient and tumor characteristics, details of radiographic scans, symptoms and alteration of treatment courses were prospectively collected for patients undergoing removal of a supratentorial meningioma of the convexity, falx, tentorium, or lateral sphenoid wing at the authors’ institution between January 1st, 2010 and March 31st, 2012. Patients with infratentorial manifestations or meningiomas of the skull base known to be surgically difficult (e.g. olfactory groove, petroclival, medial sphenoid wing) were not included. Maximum tumor diameter was divided into groups of < 3cm (small), 3 to 6 cm (medium), and > 6 cm (large).
Results: 206 patients with meningiomas were operated between January 2010 and March 2012. Of these, 113 patients met the inclusion criteria and were analyzed in this study. 83 patients (73.5%) did not present new neurological deficits, whereas 30 patients (26.5%) became clinically symptomatic. Symptomatic patients had a change in treatment after PI in 21 cases (70%), while PI was without consequence in 9 patients (30%). PI did not result in a change of treatment in all asymptomatic patients (p<0.001) irrespective of tumor size (p<0.001) or localization (p<0.001).
Conclusions: PI is mandatory for clinically symptomatic patients but it is safe to waive it in clinically asymptomatic patients, even if the meningioma was large in size.
Background and aims: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions.
Methods: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated.
Results: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%.
Conclusion: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.
The α-defensins, human neutrophil peptides (HNPs) are the predominant antimicrobial peptides of neutrophil granules. They are synthesized in promyelocytes and myelocytes as proHNPs, but only processed in promyelocytes and stored as mature HNPs in azurophil granules. Despite decades of search, the mechanisms underlying the posttranslational processing of neutrophil defensins remain unidentified. Thus, neither the enzyme that processes proHNPs nor the localization of processing has been identified. It has been hypothesized that proHNPs are processed by the serine proteases highly expressed in promyelocytes: Neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3), all of which are able to process recombinant proHNP into HNP in vitro. We investigated whether serine proteases are in fact responsible for processing of proHNP in human bone marrow cells and in human and murine myeloid cell lines. Subcellular fractionation of the human promyelocytic cell line PLB-985 demonstrated proHNP processing to commence in fractions containing endoplasmic reticulum. Processing of 35S-proHNP was insensitive to serine protease inhibitors. Simultaneous knockdown of NE, CG, and PR3 did not decrease proHNP processing in primary human bone marrow cells. Furthermore, introduction of NE, CG, and PR3 into murine promyelocytic cells did not enhance the proHNP processing capability. Finally, two patients suffering from Papillon–Lefèvre syndrome, who lack active neutrophil serine proteases, demonstrated normal levels of fully processed HNP in peripheral neutrophils. Contradicting earlier assumptions, our study found serine proteases dispensable for processing of proHNPs in vivo. This calls for study of other protease classes in the search for the proHNP processing protease(s).
Background: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
Methods: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
Results: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
Conclusion: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
Elementar für eine zukunftsfähige Verkehrsplanung ist eine möglichst detaillierte Kenntnis des Mobilitätsverhaltens der Bevölkerung in der Region. Zur Analyse des Mobilitätsverhaltens der Bevölkerung in Deutschland wurden in der Vergangenheit auf verschiedenen räumlichen Ebenen mehrere größtenteils voneinander unabhängige Datenerhebungen durchgeführt. Für die Region Frankfurt Rhein-Main besonders relevant sind dabei zum einen die Längsschnitt- bzw. Panelerhebungen des „Rhein-Main-Panels“ (RMP) und des „Deutschen Mobilitätspanels“ (MOP), zum anderen die Querschnittserhebungen der Befragung „Mobilität in Deutschland“ (MiD) und speziell für Frankfurt auch „Mobilität in Städten – SrV“ (SrV).
Ziel dieser Publikation ist es, diese vier unterschiedlichen Erhebungen in einem kurzen Vergleich vorzustellen. Dabei sollen die jeweiligen spezifischen Potentiale, aber auch Einschränkungen aufgezeigt werden, die diese Mobilitätsdatensätze bezüglich der Auswertung und weiteren Nutzung aufweisen. Danach werden in knapper Form mögliche Kombinationsmöglichkeiten dieser Datensätze untereinander, aber auch mit ergänzenden Datenbeständen dargestellt. Anschließend werden die aus den verschiedenen Mobilitätsdatensätzen ermittelten zentralen regionalen Mobilitätskennziffern in einem Vergleich veranschaulicht. Als Abschluss soll schließlich ein kurzer Blick auf mögliche Anwendungsfelder der Mobilitätsdaten in Politik und Planung geworfen werden.
Since the domestication of the urus, 10.000 years ago, mankind utilizes bovine milk for different purposes. Besides usage as a nutrient also the external application of milk on skin has a long tradition going back to at least the ancient Aegypt with Cleopatra VII as a great exponent. In order to test whether milk has impact on skin physiology, cultures of human skin fibroblasts were exposed to commercial bovine milk. Our data show significant induction of proliferation by milk (max. 2,3-fold, EC50: 2,5% milk) without toxic effects. Surprisingly, bovine milk was identified as strong inducer of collagen 1A1 synthesis at both, the protein (4-fold, EC50: 0,09% milk) and promoter level. Regarding the underlying molecular pathways, we show functional activation of STAT6 in a p44/42 and p38-dependent manner. More upstream, we identified IGF-1 and insulin as key factors responsible for milk-induced collagen synthesis. These findings show that bovine milk contains bioactive molecules that act on human skin cells. Therefore, it is tempting to test the herein introduced concept in treatment of atrophic skin conditions induced e.g. by UV light or corticosteroids.
Thrombopoietin (Thpo) signals via its receptor Mpl and regulates megakaryopoiesis, hematopoietic stem cell (HSC) maintenance and post-transplant expansion. Mpl expression is tightly controlled and deregulation of Thpo/Mpl-signaling is linked to hematological disorders. Here, we constructed an intracellular-truncated, signaling-deficient Mpl protein which is presented on the cell surface (dnMpl). The transplantation of bone marrow cells retrovirally transduced to express dnMpl into wildtype mice induced thrombocytopenia, and a progressive loss of HSC. The aplastic BM allowed the engraftment of a second BM transplant without further conditioning. Functional analysis of the truncated Mpl in vitro and in vivo demonstrated no internalization after Thpo binding and the inhibition of Thpo/Mpl-signaling in wildtype cells due to dominant-negative (dn) effects by receptor competition with wildtype Mpl for Thpo binding. Intracellular inhibition of Mpl could be excluded as the major mechanism by the use of a constitutive-dimerized dnMpl. To further elucidate the molecular changes induced by Thpo/Mpl-inhibition on the HSC-enriched cell population in the BM, we performed gene expression analysis of Lin-Sca1+cKit+ (LSK) cells isolated from mice transplanted with dnMpl transduced BM cells. The gene expression profile supported the exhaustion of HSC due to increased cell cycle progression and identified new and known downstream effectors of Thpo/Mpl-signaling in HSC (namely TIE2, ESAM1 and EPCR detected on the HSC-enriched LSK cell population). We further compared gene expression profiles in LSK cells of dnMpl mice with human CD34+ cells of aplastic anemia patients and identified similar deregulations of important stemness genes in both cell populations. In summary, we established a novel way of Thpo/Mpl inhibition in the adult mouse and performed in depth analysis of the phenotype including gene expression profiling.
Inverted perceptual judgment of nociceptive stimuli at threshold level following inconsistent cues
(2015)
Objective: The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far.
Methods: Nociceptive stimuli (300 ms intranasal gaseous CO2) at the individual pain threshold level were applied after a visual cue announcing the stimulus as either "no pain", merely a "stimulus", or "pain". Among the stimuli at threshold level, other CO2 stimuli that were clearly below or above pain threshold were randomly interspersed. These were announced beforehand in 12 subjects randomly with correct or incorrect cues, i.e., clearly painful or clearly non-painful stimuli were announced equally often as not painful or painful. By contrast, in a subsequent group of another 12 subjects, the stimuli were always announced correctly with respect to the evoked pain.
Results: The random and often incorrect announcement of stimuli clearly below or above pain threshold caused the subjects to rate the stimuli at pain-threshold level in the opposite direction of the cue, i.e., when the stimuli were announced as "pain" significantly more often than as non-painful and vice versa (p < 10-4). By contrast, in the absence of incongruence between announcement and perception of the far-from-threshold stimuli, stimuli at pain threshold were rated in the cued direction.
Conclusions: The present study revealed the induction of associations incongruent with a given message in the perception of pain. We created a context of unreliable cues whereby subjects perceived the stimulus opposite to that suggested by a prior cue, i.e., potentially nociceptive stimuli at pain threshold level that were announced as painful were judged as non-painful and vice versa. These findings are consistent with reported data on the effects of distrust on non-painful cognitive responses.
Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.
Even though the microevolution of plant hosts and pathogens has been intensely studied, knowledge regarding macro-evolutionary patterns is limited. Having the highest species diversity and host-specificity among Oomycetes, downy mildews are a useful a model for investigating long-term host-pathogen coevolution. We show that phylogenies of Bremia and Asteraceae are significantly congruent. The accepted hypothesis is that pathogens have diverged contemporarily with their hosts. But maximum clade age estimation and sequence divergence comparison reveal that congruence is not due to long-term coevolution but rather due to host-shift driven speciation (pseudo-cospeciation). This pattern results from parasite radiation in related hosts, long after radiation and speciation of the hosts. As large host shifts free pathogens from hosts with effector triggered immunity subsequent radiation and diversification in related hosts with similar innate immunity may follow, resulting in a pattern mimicking true co-divergence, which is probably limited to the terminal nodes in many pathogen groups.
Translation elongation factor Tuf of Acinetobacter baumannii is a plasminogen-binding protein
(2015)
Acinetobacter baumannii is an important nosocomial pathogen, causing a variety of opportunistic infections of the skin, soft tissues and wounds, urinary tract infections, secondary meningitis, pneumonia and bacteremia. Over 63% of A. baumannii infections occurring in the United States are caused by multidrug resistant isolates, and pan-resistant isolates have begun to emerge that are resistant to all clinically relevant antibiotics. The complement system represents the first line of defense against invading pathogens. However, many A. baumannii isolates, especially those causing severe bacteremia are resistant to complement-mediated killing, though the underlying mechanisms remain poorly understood. Here we show for the first time that A. baumannii binds host-derived plasminogen and we identify the translation elongation factor Tuf as a moonlighting plasminogen-binding protein that is exposed on the outer surface of A. baumannii. Binding of plasminogen to Tuf is at least partly dependent on lysine residues and ionic interactions. Plasminogen, once bound to Tuf can be converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component C3b. Thus, Tuf acts as a multifunctional protein that may contribute to virulence of A. baumannii by aiding in dissemination and evasion of the complement system.
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Introduction: Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay.
Methods: For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three.
Results: M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4).
Conclusion: The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials.
Die Spinozerebelläre Ataxie Typ 2 (SCA2) ist eine autosomal dominant vererbte neurodegenerative Krankheit, welche durch die Expansion des Trinukleotids Cytosin-Adenin-Guanin von ~22/23 auf >32 im Ataxin-2 Gen (ATXN2) verursacht wird. Dieses Trinukleotid codiert für die Aminosäure Glutamin weshalb SCA2 auch zu den Polyglutaminerkrankungen zählt. Zu dieser Gruppe zählen außerdem fünf weitere SCA-Subtypen sowie drei weitere neurodegenerative Erkrankungen, darunter die Huntington-Krankheit.
SCA2 wurde 1971 zum ersten Mal von Wadia und Swami beschrieben und unterscheidet sich von den anderen SCAs aufgrund der typischen Störung der sakkadischen Augenbewegungen. Weitere klinische Symptome von SCA2 sind Ataxie, Tremor, Dysmetrie, Dysarthrie, Hyporeflexie und Dysdiadochokinese. Die Symptome gehen auf einen neuronalen Verlust insbesondere im Cerebellum, aber auch in anderen Hirnregionen wie zum Beispiel dem Hirnstamm zurück.
Atxn2 wird in weiten Teilen des Zentralnervensystems aber auch in vielen nicht-neuronalen Geweben exprimiert. Es handelt sich um ein überwiegend cytoplasmatisch lokalisiertes Protein, welches im Gegensatz zu vielen anderen SCA-Proteinen cytoplasmatische und nur selten nukleäre Aggregate bildet. Die exakte Funktion von Atxn2 ist bisher unklar, es wurde allerdings mehrfach gezeigt, dass es in die mRNA Translation involviert ist aufgrund seiner Interaktion mit dem PolyA-bindenden Protein PABPC1.
Eine Expansion des Trinukleotids in Ataxin-2 kann nicht nur zu SCA2 führen, sondern stellt bei Wiederholungen zwischen 27 und 32 CAGs auch ein erhöhtes Risiko für eine Erkrankung an Amyotropher Lateralsklerose (ALS) und anderen neurodegenerativen Krankheiten dar. Eine Interaktion zwischen ATXN2 und dem ALS-verursachenden TDP43 (Tardbp) wurde bereits zahlreich beforscht, da Aggregate von ATXN2 in Motoneuronen des Rückenmarks von ALS-Patienten und aggregiertes TDP43 in SCA2-Neuronen beobachtet wurden.
Generell sind die Mechanismen, die zur Pathologie von SCA2 und ALS führen, noch weitgehend unklar. Ziel dieser Arbeit war es daher auf der einen Seite einen Einblick in den Pathomechanismus von SCA2 zu erhalten, indem mögliche oder bereits bekannte Interaktoren in etablierten Atxn2-Mausmodellen untersucht wurden. Auf der anderen Seite wurden zwei neue Mausmodelle charakterisiert, um ihre Eignung für die Erforschung von ALS und SCA2 zu prüfen.
Für den ersten Teil der Arbeit dienten Daten aus mehreren Transkriptomstudien von Atxn2-Knock-Out (KO) und Atxn2-CAG42-Knock-In (KIN) Mäusen als Grundlage. Konnten die Daten mit einer unabhängigen Methode bestätigt werden, folgten weitere Untersuchungen auf mRNA und Proteinebene sowie unter zusätzlicher Verwendung von Zellkultur und Patientenmaterial. Dadurch konnten neue Interaktionspartner von ATXN2 identifiziert und bereits bekannte in diesen Mausmodellen bestätigt werden.
So wurde zum Beispiel eine Interaktion von ATXN2 mit der E3-Ubiquitin-Protein-Ligasekomponente FBXW8 gezeigt und deren Beteiligung am Abbau von expandiertem ATXN2. Außerdem wurde eine Interaktion von FBXW8 mit dem bereits bekannten ATXN2-degradierenden Protein PARK2 gezeigt. Eine Hochregulierung des Fbxw8 Transkripts wurde sowohl im Atxn2-CAG42-KIN-Mausmodell als auch in SCA2-Patientenfibroblasten gefunden, während Park2 in keinem der Modelle signifikant veränderte Transkriptspiegel aufwies. Diese Daten belegen die Relevanz von Fbxw8 für den Abbau von moderat-expandiertem Atxn2 und begründen weitere Studien zur genauen Funktion dieses Proteins im Pathomechanismus von Atxn2.
Des Weiteren wurden diverse Kalziumhomöostasefaktoren untersucht, welche eine konsistente Herunterregulierung der Transkripte in beiden Mausmodellen aufwiesen. Auf Proteinebene zeigten sich jedoch Unterschiede zwischen den Modellen. Diese Daten belegen, dass zwar ähnliche Transkriptveränderungen im KIN- und KO-Modell auftreten, diesen aber vermutlich verschiedene Mechanismen zugrunde liegen. Welche Mechanismen dies genau sind bleibt zu klären, es ist jedoch wahrscheinlich, dass im KIN-Modell die Aggregatbildung sowie in beiden Modellen die Beteiligung von ATXN2 an der Translationregulation eine Rolle spielen. Die Ergebnisse dieser Studie unterstreichen die Relevanz des Ca2+ Signalwegs für die Entwicklung von SCA2.
Der zweite Teil der Arbeit beinhaltet die Charakterisierung einer ATXN2/TDP43 Doppelmutante auf Verhaltensebene sowie die gründliche Evaluierung des Phänotyps einer vollkommen neuen SCA2 Mausmutante. Während in der Doppelmutante trotz doppelter Genmutation nur ein sehr schwacher Phänotyp auf Verhaltensebene festgestellt werden konnte und bis zu einem Alter von 12 Monaten keine Potenzierung der Mutationen zu beobachten war, zeigte die Atxn2-CAG100-KIN Maus signifikante und früh auftretende Pathologie. Neben einer verminderten Überlebensrate, einem Gewichtsverlust und diversen motorischen Störungen, konnten auch Aggregate des mutierten Proteins in diversen Hirnregionen identifiziert werden. Der Atxn2-CAG100-KIN Phänotyp spiegelt die humanen Symptome daher recht gut wider, weshalb diese Mausmutante ein wertvolles Modell für die weitere SCA2-Forschung darstellt.
Zusammengefasst zeigt diese Arbeit die Bedeutung des ATXN2-Interaktors FBXW8 im SCA2-Mausmodell als auch im Patientenmaterial. Sie betont die Relevanz des Atxn2-KO-Modells in Bezug auf Störungen der Kalziumhomöostase und dokumentiert die Alters- und Gewebespezifität dieser Veränderungen. Außerdem beinhaltet sie die vorläufige Beschreibung eines kombinierten Atxn2/TDP43-Mausmodells und schließlich die ausführliche Charakterisierung eines vollkommen neuen und äußerst wertvollen SCA2-Mausmodells.