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The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.
Dies ist der achte Artikel unseres Blogfokus „Salafismus in Deutschland“.
Die salafistische Propaganda kultiviert ein dichotomisches Weltbild, in dem den Muslimen die Rolle des kollektiven Opfers westlicher Expansionsgelüste zufällt. Die historischen Fakten, die dies untermauern sollen, werden jedoch arg strapaziert und sehr einseitig interpretiert. Die Realität ist sehr viel komplexer, als die salafistische Schwarz-Weiß-Malerei der Öffentlichkeit weismachen will...
Little attention so-far has been paid to the influence of chronobiology on the processes of nanoparticle uptake and transport into the brain, even though this transport appears to be chronobiologically controlled to a significant degree. Nanoparticles with specific surface properties enable the transport across the blood–brain barrier of many drugs that normally cannot cross this barrier. A clear dependence of the central antinociceptive (analgesic) effects of a nanoparticle-bound model drug, i.e., the hexapeptide dalargin, on the time of day was observable after intravenous injection in mice. In addition to the strongly enhanced antinociceptive effect due to the binding to the nanoparticles, the minima and maxima of the pain reaction with the nanoparticle-bound drug were shifted by almost half a day compared to the normal circadian nociception: The maximum in the pain reaction after i.v. injection of the nanoparticle-bound dalargin occurred during the later rest phase of the animals whereas the normal pain reaction and that of a dalargin solution was highest during the active phase of the mice in the night. This important shift could be caused by an enhanced endo- and exocytotic particulates transport activity of the brain capillary endothelial cells or within the brain during the rest phase.
Data-parallel programming is more important than ever since serial performance is stagnating. All mainstream computing architectures have been and are still enhancing their support for general purpose computing with explicitly data-parallel execution. For CPUs, data-parallel execution is implemented via SIMD instructions and registers. GPU hardware works very similar allowing very efficient parallel processing of wide data streams with a common instruction stream.
These advances in parallel hardware have not been accompanied by the necessary advances in established programming languages. Developers have thus not been enabled to explicitly state the data-parallelism inherent in their algorithms. Some approaches of GPU and CPU vendors have introduced new programming languages, language extensions, or dialects enabling explicit data-parallel programming. However, it is arguable whether the programming models introduced by these approaches deliver the best solution. In addition, some of these approaches have shortcomings from a hardware-specific focus of the language design. There are several programming problems for which the aforementioned language approaches are not expressive and flexible enough.
This thesis presents a solution tailored to the C++ programming language. The concepts and interfaces are presented specifically for C++ but as abstract as possible facilitating adoption by other programming languages as well. The approach builds upon the observation that C++ is very expressive in terms of types. Types communicate intention and semantics to developers as well as compilers. It allows developers to clearly state their intentions and allows compilers to optimize via explicitly defined semantics of the type system.
Since data-parallelism affects data structures and algorithms, it is not sufficient to enhance the language's expressivity in only one area. The definition of types whose operators express data-parallel execution automatically enhances the possibilities for building data structures. This thesis therefore defines low-level, but fully portable, arithmetic and mask types required to build a flexible and portable abstraction for data-parallel programming. On top of these, it presents higher-level abstractions such as fixed-width vectors and masks, abstractions for interfacing with containers of scalar types, and an approach for automated vectorization of structured types.
The Vc library is an implementation of these types. I developed the Vc library for researching data-parallel types and as a solution for explicitly data-parallel programming. This thesis discusses a few example applications using the Vc library showing the real-world relevance of the library. The Vc types enable parallelization of search algorithms and data structures in a way unique to this solution. It shows the importance of using the type system for expressing data-parallelism. Vc has also become an important building block in the high energy physics community. Their reliance on Vc shows that the library and its interfaces were developed to production quality.
Zu Beginn dieser Arbeit stand die Vermutung, dass die Klangsprache von Arnold Schönbergs Werk Pierrot lunaire stark durch Albert Girauds gleichnamigen, von Otto Erich Hartleben ins Deutsche übertragenen Gedichtzyklus beeinflusst worden ist.
Um genauer herauszuarbeiten, wie ein Gedichtzyklus die Klangsprache eines Komponisten beeinflussen kann, wurde zuerst Girauds Originaltext mithilfe der symbolistischen Ästhetik sowie der ästhetischen Kategorien des Capriccio und der Groteske analysiert. In einem zweiten Schritt wurde - mithilfe von Walter Benjamins Überlegungen zur Aufgabe des Übersetzers - Otto Erich Hartlebens Übertragung von Girauds Zyklus untersucht. Im Laufe dieser jeweiligen Analysen kristallisierte sich die Rolle des Ephemeren sowohl in der Gestaltung des Originaltextes als auch innerhalb des Vorgangs der Übersetzung heraus.
Das Wirken des Ephemeren im Kunstwerk wurde mithilfe von Theodor W. Adornos Ästhetische Theorie genauer dargestellt und mündete in der Hauptfrage der vorliegenden Untersuchung: Wie gestaltet das Ephemere den Pierrot lunaire bei Albert Giraud, Otto Erich Hartleben und Arnold Schönberg? In Bezug auf Schönbergs Werk wurden dabei in erster Linie der Sprechgesang, die Wechselwirkung von Instrumentation und Klangfarbe sowie einzelne Elemente der Klangsprache behandelt.
Dies ist der vierte Artikel unseres Blogfokus zu Flucht und Migration. Seit einigen Jahren ist ein Anstieg von Feldforschungsprojekten in den Sozialwissenschaften in Deutschland zu verzeichnen. Doch wie finden solche Projekte statt? Werden Flüchtlinge zu reinen Gegenständen der Untersuchungen oder können sie in der Forschung involviert werden?
Viele auf allgemeinen Graphen NP-schwere Probleme (z.B. Hamiltonkreis, k-Färbbarkeit) sind auf Bäumen einfach effizient zu lösen. Baumzerlegungen, Zerlegungen von Graphen in kleine Teilgraphen entlang von Bäumen, erlauben, dies zu effizienten Algorithmen auf baumähnlichen Graphen zu verallgemeinern. Die Baumähnlichkeit wird dabei durch die Baumweite abgebildet: Je kleiner die Baumweite, desto baumähnlicher der Graph.
Die Bedeutung der Baumzerlegungen wurde seit ihrer Verwendung in einer Reihe von 23 Veröffentlichungen von Robertson und Seymour zur Graphminorentheorie allgemein erkannt. Das Hauptresultat der Reihe war der Beweis des Graphminorensatzes, der aussagt, dass die Minorenrelation auf den Graphen Wohlquasiordnung ist. Baumzerlegungen wurden in verschiedenen Bereichen angewandt. So bei probabilistischen Netzen, in der Biologie, bei kombinatorischen Problemen und im Übersetzerbau. Außerdem gibt es algorithmische Metatheoreme, die zeigen, dass sie für weite Problemklassen nützlich sind. Baumzerlegungen sind in dieser Arbeit von zentraler Bedeutung. Die mittels Baumzerlegungen erzielten Erfolge auf baumähnlichen Graphen motivieren Versuche, diese auf größere Graphklassen zu verallgemeinern. Ein erfolgreicher Ansatz beruht auf irrelevanten Knoten und reduziert damit die Probleme auf der größeren Graphklasse auf Probleme auf einer Graphklasse kleiner Baumweite: Wenn der Eingabegraph zu einem Problem kleine Baumweite hat, wird das Problem mittels Baumzerlegungen gelöst. Andernfalls gibt es einen irrelevanten Knoten, so dass das Problem genau dann eine Lösung auf dem ursprünglichen Graphen hat, wenn es auch im Graphen ohne diesen irrelevanten Knoten eine Lösung hat. Es werden solange irrelevante Knoten gefunden und entfernt, bis ein Graph kleiner Baumweite verbleibt.
Ein wichtiges Hilfsmittel zum Finden irrelevanter Knoten ist der Gitterminorensatz: Nach diesem Satz enthalten Graphen großer Baumweite auch große Gitter als Minoren. Die Gitter Baumweite-Dualität ist auch in der Bidimensionalitätstheorie, einem weiteren erfolgreichen Ansatz, um auf größeren Graphklassen, als nur denen kleiner Baumweite, Probleme effizient zu lösen, von zentraler Bedeutung.
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.
Mit Blick auf die gescheiterten Verhandlungen mit Griechenland, argumentiert Jan Krahnen im vorliegenden Policy Beitrag, dass eine zielführende Reformagenda nur von der gewählten Regierung Griechenlands formuliert werden kann. Die Euro-Staaten müssten Griechenland für die Zeitdauer einer Restrukturierungszeit eine Grundsicherung zusagen. Die EU-Staaten fordert Krahnen dazu auf, aus der Griechenlandkrise die notwendigen Konsequenzen zu ziehen. Auch die Eurozone brauche eine effektive Reformagenda. Die Verschuldungsdynamik innerhalb der Währungsunion, deren Auswüchse am Beispiel Griechenlands besonders deutlich werden, könne bei fehlendem guten Willen nur durch eine politische Union und eine in sie eingebettete Fiskalunion aufgelöst werden. Krahnen argumentiert, dass ein Weiterverhandeln über Restrukturierungsauflagen aus der derzeitigen verfahrenen Situation nicht herausführen wird. Entscheidend sei, ein mehr oder weniger umfassendes Paket zu schnüren, das Elemente eines teilweisen internationalen Haftungsverbunds mit Elementen eines partiellen nationalen Souveränitätsverzichts verbindet.
In light of the failed negotiations with Greece, Jan Krahnen argues that an effective reform agenda for Greece can only be designed by the elected government. Fundamental reforms will take time to take full effect and euro area member states will, in the meantime, have to offer Greece a basic level of economic security.
Krahnen demands that policy makers and the professional public involved view the Greek crisis as an opportunity to take the next necessary steps to formulate a reform agenda for the European Monetary Union. A community of supranational and non-party researchers and intellectuals could take the initiative and in a structured process develop a trustworthy and realistic concept that drafts the next big step towards a political union of Europe, including elements of a fiscal union.