Human Cysteine Cathepsins Are Not Reliable Markers of Infection by Pseudomonas aeruginosa in Cystic Fibrosis

Cysteine cathepsins have emerged as new players in inflammatory lung disorders. Their activities are dramatically increased in the sputum of cystic fibrosis (CF) patients, suggesting that they are involved in the pathophysiology of CF. We have characterized the cathepsins in CF expectorations and evaluated their use as markers of colonization by Pseudomonas aeruginosa. The concentrations of active cathepsins B, H, K, L and S were the same in P. aeruginosa-positive (19 Ps+) and P. aeruginosa-negative (6 Ps−) samples, unlike those of human neutrophil elastase. Also the cathepsin inhibitory potential and the cathepsins/cathepsin inhibitors imbalance remained unchanged and similar (∼2-fold) in the Ps+ and Ps− groups (p<0.001), which correlated with the breakdown of their circulating cystatin-like inhibitors (kininogens). Procathepsins, which may be activated autocatalytically, are a potential proteolytic reservoir. Immunoblotting and active-site labeling identified the double-chain cathepsin B, the major cathepsin in CF sputum, as the main molecular form in both Ps+ and Ps− samples, despite the possible release of the ∼31 kDa single-chain form from procathepsin B by sputum elastase. Thus, the hydrolytic activity of cysteine cathepsins was not correlated with bacterial colonization, indicating that cathepsins, unlike human neutrophil elastase, are not suitable markers of P. aeruginosa infection

Deposition of Ni

The soft deposition of Ni13 and Cu13 clusters on Ni(111) and Cu(111) surfaces is studied by means of constant-energy molecular-dynamics simulations. The atomic interactions are described by the Embedded Atom Method. It is shown that the shape of the nickel clusters deposited on Cu(111) surfaces remains rather intact, while the copper clusters impacting on Ni(111) surfaces collapse forming double and triple layered products. Furthermore, it is found that for an impact energy of 0.5 eV/atom the structures of all investigated clusters show the lowest similarity to the original structures, except for the case of nickel clusters deposited on a Cu(111) surface. Finally, it is demonstrated that when cluster and substrate are of different materials, it is possible to control whether the deposition results in largely intact clusters on the substrate or in a spreading of the clusters. This separation into hard and soft clusters can be related to the relative cohesive energy of the crystalline materials

Theoretical Studies of Structural, Energetic, and Electronic Properties of Clusters.

International audienceSize in combination with low symmetry makes theoretical studies of the properties of clusters a challenge. This is in particular the case when the studies also shall identify the structures of the lowest total energy. We discuss here various methods for calculating the structural, energetic, and electronic properties of nanoparticles, emphasizing that the computational method always should be chosen carefully according to the scientific questions that shall be addressed. Therefore, different approximate methods for calculating the total energy of a given structure are discussed, including the embedded-atom method and a parameterized density-functional method. Moreover, different approaches for choosing/determining the structures are presented, including an Aufbau/Abbau method and genetic algorithms. In order to illustrate the approaches we present results from calculations on metallic and semiconducting nanoparticles as well as on nanostructured HAlO

Sign and Language in Anton Marty: Before and after Brentano

On the basis of Anton Marty’s 1867 Preisschrift, this article offers a reconstruction of the semiotic and linguistic investigations the Swiss philosopher develops just before becoming a student of Brentano. The paper then compares this account with the view on signs that will be given in Marty’s later work, as well as within the Austro-German tradition

Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion

Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3$^{+}$ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT$^{hi}$, CT$^{lo}$) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT$^{hi}$ conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT$^{lo}$- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3$^{+}$ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT$^{lo}$- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3$^{+}$ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae