Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers

In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.

Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

La duchesse d'Enville à Genève, une aristocrate chez les Républicains

Admiratrice de Tronchin, la duchesse d'Enville se rend plusieurs fois à Genève pour de longs séjours. Elle y fréquente toute la bonne société. Et manifestement, elle y apprend à s'intéresser à la politique, à cause des troubles de la cité, qu'elle observe en personne en 1765-1766 et, par l'intermédiaire de ses amis genevois, au début des années 1780. Cette expérience lui a-t-elle servi au début de la révolution française, à l'époque où son salon sert de lieu de rivalité aux Jacobins ?

Ms.Ff.F.Stoltze 3. 583 - Brief von Friedrich Stoltze an Friedrich Stoltze und Marie Stoltze

Zürich, Zürichsee, Bibliothek

Marie Dillon

G. Syrkin

Marie Dillon [Illustration] : (Porträt)

Scan von Monochrom-Mikroform

Marie Cohen [Illustration] : (Porträt)

Scan von Monochrom-Mikroform

Nature and community in Western culture: Wendell Berry's alternative tradition

This dissertation is an examination of the ideals and practices that have characterized Western culture's relationship to the natural world. The conventional approach, depicted by some of the most prominent ecological publications of recent years, criticizes the Western tradition for both its ideals and practices. The ideals are assumed to be best represented in Western philosophy and religion and both of these sources have been indicted. These ideals are coupled with the Western way of life that is equally indicted as exploitive and destructive. Author, professor and farmer, Wendell Berry, offers an alternative to these indictments. Berry insists that a theme, advocating ecological accountability, runs through some of the West's most significant literature and that Western tradition contains a practice that can support these ecological principles. ^

Ein ungedruckter Brief von Caroline Herder an Garlieb Merkel

Paul Michaelis

Marie : aus einem neuen Roman des Dichters, der voraussichtlich im Frühjahr bei S. Fischer erscheinen wird

Jakob Wassermann

Der Duft der Erde ; Die Magd Marie : (Gedichte)

Ernst Waldinger

Die Frage nach dem Sinn des Judentums : dem Andenken meiner Mutter Caroline Schlesinger geb. Fränkel

Abraham Schlesinger