Design, synthesis and structure of an amphipathic peptide with pH-inducible haemolytic activity

A synthetic, 26-residue peptide having a strong helix forming potential in the protonated state was designed to interact with lipid bilayers in a pH-dependent way. On the basis of this concept a cluster of four glutamk acid residues was inserted in the central region of the amphipathic peptide to promote helix destabilization by mutual charge repulsion at neutral pH. Protonation of these residues might then bring about both a pH-mediated change in hydrophobteity and conformation forming a membrane-active amphiphilk helix. The sequence GLGTLLTLLEFLLEELLEFLKRKRQQamide produced by the design strategy induced pH-triggered lysis of human erythrocytes. A molecular model correlating the lytic activity to the formation of transmembrane pores which were detected by electron microscopy in erythrocyte membranes is discussed. Circular dichroism studies indicated a selfassociation of the monomeric random coil form with increasing peptide concentration leading to the apparent induction of strong a-helix formation (˜ 100% helkity) in the fully aggregated state. However, no pH-dependent helixrandom coil transition was observed, implying that interhelical hydrophobk and ionic interactions not only govern the self-association but also decisively influence the conformational stability of the peptid

Nuclear magnetic resonance studies and molecular dynamics simulations of the solution conformation of a ‘designed', α-helical peptide

The complete three-dimensional structure in methanol of an amphipathic a-helical peptide, that has been designed by taking into account the three-dimensional structures of small haemolytic peptides, secondary structure prediction algorithms and the well documented literature on α-helix stabilizing factors, has been elucidated by two-dimensional NMR spectroscopy. Initially various two-dimensional spectra (COSY, TOCSY, and NOESY) allowed the complete sequence specific assignment of all signals in the 1H spectrum. Consequently trial structures were generated which were then subjected to molecular dynamics simulations using 121 NOE-derived distances and 25 vicinal coupling constant values as structural restraints to give a final set of calculated structures. These structures are in complete agreement with the results of a circular dichroism study and reveal that the peptide adopted a highly ordered a-helical conformation. Details of the structure which throw light on future peptide/protein design are discusse

Democratic and Authoritarian Political Systems in 21st Century World Society

This book is about the radical novelty of modern polities in a functionally differentiated world society. Premodern states were at the apex of a stratified, hierarchical society. They dominated society and all its groups and strata. Modern polities have to be understood through the ecology of relations among different function systems. They have to find and incessantly redefine their place in society. They produce decisions that are collectively binding, but in preparing these decisions experience constraints and knowledge deficiencies that are related to the complexity of a functionally differentiated society. The book concentrates on six analytical perspectives that reflect how modern polities are embedded into 21st century society. These perspectives are: the concept of inclusion and the inclusion revolution constitutive of modern polities; the internal differentiation of polities that endows them with an unprecedented complexity; the fact that polities do not know anything about society and the ways in which they compensate for this; representation and responsiveness as strategies to reconnect with society; the self-restriction of some polities that brings about ever new autonomous expert organizations; the symmetrical rise of autocracies and democracies as the two modern variants of political regimes

Conservation laws in the continuum 1/r21/r^2 systems

We study the conservation laws of both the classical and the quantum mechanical continuum $1/r^2$ type systems. For the classical case, we introduce new integrals of motion along the recent ideas of Shastry and Sutherland (SS), supplementing the usual integrals of motion constructed much earlier by Moser. We show by explicit construction that one set of integrals can be related algebraically to the other. The difference of these two sets of integrals then gives rise to yet another complete set of integrals of motion. For the quantum case, we first need to resum the integrals proposed by Calogero, Marchioro and Ragnisco. We give a diagrammatic construction scheme for these new integrals, which are the quantum analogues of the classical traces. Again we show that there is a relationship between these new integrals and the quantum integrals of SS by explicit construction.Comment: 19 RevTeX 3.0 pages with 2 PS-figures include

"Magisches Vieleck" der Arbeitsmarktpolitik: ein Vorschlag für eine humane und ökonomisch vernünftige Perspektive

Aktive Arbeitsmarktpolitik als ein bedeutendes sozial- und wirtschaftspolitisches Handlungsfeld hat mehrere Ziele und Interessengruppen zu vereinen. In der alltäglichen Debatte sowie auch offiziell im Arbeitsmarktservicegesetz werden meist die Wiedereingliederung von Arbeitslosen in den Arbeitsmarkt und die Senkung von Arbeitslosigkeit als Ziele angegeben. Der Artikel schlägt einen erweiterten Zielkanon im Sinne eines magischen Vieleckes für aktive Arbeitsmarktpolitik vor. Hierbei charakterisiert sich eine humane und ökonomisch vernünftige Arbeitsmarktpolitik durch eine ausgewogene Berücksichtigung der Interessen von ArbeitnehmerInnen und ArbeitgeberInnen. Vor diesem Hintergrund werden zentrale Instrumente der aktiven Arbeitsmarktpolitik in Österreich (Eingliederungsbeihilfe, Qualifizierungsmaßnahmen, sozialökonomische Betriebe und gemeinnützige Beschäftigungsprojekte, Beratungs- und Betreuungseinrichtungen) auf Mikro- und auf Makroebene evaluiert. Es wird gezeigt, dass Qualifizierungsmaßnahmen in der Lage sind, die meisten Ziele zu vereinen.For active labour market policy to succeed as a central social and economic policy field, it must address a diverse array of interest groups. However, the current public debate and the official law of public employment services focuse only on reintegrating unemployed and on reducing the overall unemployment. This article offers a broader target catalog for active labour market policy in the sense of a "magic polygon": A human and economically prudent active labour market policy is characterized by a fair balance between the interests of workers and employers. Through the lens of this target catalogue, this article aims to evaluate central instruments of an active labour market policy (wage subsidies, qualification measures, socioeconomic businesses, non-profit employment projects, consultants and care institutions) on a micro-level and a macro-level. Finally, the article shows that qualification measures are able to combine most of the aims

The Cl--channel TMEM16A is involved in the generation of cochlear Ca2+ waves and promotes the refinement of auditory brainstem networks in mice

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) spontaneously fire action potentials, thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISCs) of Kölliker’s organ through the activity of the Ca2+-activated Cl--channel TMEM16A (ANO1). Here, we show that conditional deletion of Ano1 (Tmem16a) in mice disrupts Ca2+ waves within Kölliker’s organ, reduces the burst-firing activity and the frequency selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the functional refinement of MNTB projections to the lateral superior olive. These results reveal the importance of the activity of Kölliker’s organ for the refinement of central auditory connectivity. In addition, our study suggests the involvement of TMEM16A in the propagation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A