Migration – Kommunikation – Transfer (Volume 1, Edition 1)

Der Band behandelt Fragen des gegenseitigen Austauschs sowie ethnischer, kultureller und religiöser Verflechtungen der mitteleuropäischen Länder und ihrer Bevölkerung. In zwölf Beiträgen von Archäologen und Historikern der Nikolaus-Kopernikus-Universität Torun spiegelt sich die Komplexität und Vielschichtigkeit dieser Problematik. Damit bilden sie den Auftakt einer neuen Schriftenreihe, die als ein Forum für den Austausch über die neueste wissenschaftliche Forschung zur Geschichte Polens im weit verstandenen mitteleuropäischen Kontext dient. In den jährlich erscheinenden Bänden werden komplexe Themen der Geschichte untersucht. This volume not only focusses on issues on mutual exchange but also on ethnic, cultural and religious ties of the Middle European countries and their citizens. The twelve contributions of archaeologists and historians from the Nicolaus Copernicus University in Toruń reflect the complexity of this issue. The authors therefore kick off a new series of journals which serve as a forum for the exchange on recent research on the history of Poland in the wider sense of the Middle European context. The annually published volume will analyse complex subjects of history

Migration – Kommunikation – Transfer (Volume 1, Edition 1)

Der Band behandelt Fragen des gegenseitigen Austauschs sowie ethnischer, kultureller und religiöser Verflechtungen der mitteleuropäischen Länder und ihrer Bevölkerung. In zwölf Beiträgen von Archäologen und Historikern der Nikolaus-Kopernikus-Universität Torun spiegelt sich die Komplexität und Vielschichtigkeit dieser Problematik. Damit bilden sie den Auftakt einer neuen Schriftenreihe, die als ein Forum für den Austausch über die neueste wissenschaftliche Forschung zur Geschichte Polens im weit verstandenen mitteleuropäischen Kontext dient. In den jährlich erscheinenden Bänden werden komplexe Themen der Geschichte untersucht. This volume not only focusses on issues on mutual exchange but also on ethnic, cultural and religious ties of the Middle European countries and their citizens. The twelve contributions of archaeologists and historians from the Nicolaus Copernicus University in Toruń reflect the complexity of this issue. The authors therefore kick off a new series of journals which serve as a forum for the exchange on recent research on the history of Poland in the wider sense of the Middle European context. The annually published volume will analyse complex subjects of history

Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice

International audienceMutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th aminoacid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftr tm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl −) conductance in F508del Cftr tm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis

Rattlesnake Phospholipase A2 Increases CFTR-Chloride Channel Current and Corrects ∆F508CFTR Dysfunction: Impact in Cystic Fibrosis

International audienceDeletion of Phe508 in the nucleotide binding domain (∆F508-NBD1) of the cystic fibrosis transmembrane regulator (CFTR; a cyclic AMP-regulated chloride channel) is the most frequent mutation associated with cystic fibrosis. This mutation affects the maturation and gating of CFTR protein. The search for new high-affinity ligands of CFTR acting as dual modulators (correctors/activators) presents a major challenge in the pharmacology of cystic fibrosis. Snake venoms are a rich source of natural multifunctional proteins, potential binders of ion channels. In this study, we identified the CB subunit of crotoxin from Crotalus durissus terrificus as a new ligand and allosteric modulator of CFTR. We showed that CB interacts with NBD1 of both wild type and ∆F508CFTR and increases their chloride channel currents. The potentiating effect of CB on CFTR activity was demonstrated using electrophysiological techniques in Xenopus laevis oocytes, in CFTR-HeLa cells, and ex vivo in mouse colon tissue. The correcting effect of CB was shown by functional rescue of CFTR activity after 24-h ΔF508CFTR treatments with CB. Moreover, the presence of fully glycosylated CFTR was observed. Molecular docking allowed us to propose a model of the complex involving of the ABCβ and F1-like ATP-binding subdomains of ΔF508-NBD1. Hydrogen-deuterium exchange analysis confirmed stabilization in these regions, also showing allosteric stabilization in two other distal regions. Surface plasmon resonance competition studies showed that CB disrupts the ∆F508CFTR-cytokeratin 8 complex, allowing for the escape of ∆F508CFTR from degradation. Therefore CB, as a dual modulator of ΔF508CFTR, constitutes a template for the development of new anti-CF agents