c-di-GMP Turn-Over in Clostridium difficile Is Controlled by a Plethora of Diguanylate Cyclases and Phosphodiesterases

Clostridium difficile infections have become a major healthcare concern in the last decade during which the emergence of new strains has underscored this bacterium's capacity to cause persistent epidemics. c-di-GMP is a bacterial second messenger regulating diverse bacterial phenotypes, notably motility and biofilm formation, in proteobacteria such as Vibrio cholerae, Pseudomonas aeruginosa, and Salmonella. c-di-GMP is synthesized by diguanylate cyclases (DGCs) that contain a conserved GGDEF domain. It is degraded by phosphodiesterases (PDEs) that contain either an EAL or an HD-GYP conserved domain. Very little is known about the role of c-di-GMP in the regulation of phenotypes of Gram-positive or fastidious bacteria. Herein, we exposed the main components of c-di-GMP signalling in 20 genomes of C. difficile, revealed their prevalence, and predicted their enzymatic activity. Ectopic expression of 31 of these conserved genes was carried out in V. cholerae to evaluate their effect on motility and biofilm formation, two well-characterized phenotype alterations associated with intracellular c-di-GMP variation in this bacterium. Most of the predicted DGCs and PDEs were found to be active in the V. cholerae model. Expression of truncated versions of CD0522, a protein with two GGDEF domains and one EAL domain, suggests that it can act alternatively as a DGC or a PDE. The activity of one purified DGC (CD1420) and one purified PDE (CD0757) was confirmed by in vitro enzymatic assays. GTP was shown to be important for the PDE activity of CD0757. Our results indicate that, in contrast to most Gram-positive bacteria including its closest relatives, C. difficile encodes a large assortment of functional DGCs and PDEs, revealing that c-di-GMP signalling is an important and well-conserved signal transduction system in this human pathogen

Bank Leverage Ratios and Financial Stability: A Micro- and Macroprudential Perspective

Bank leverage ratios have made an impressive and largely unopposed return; they are mostly used alongside risk-weighted capital requirements. The reasons for this return are manifold, and they are not limited to the fact that bank equity levels in the wake of the global financial crisis (GFC) were exceptionally thin, necessitating a string of costly bailouts. A number of other factors have been equally important; these include, among others, the world's revulsion with debt following the GFC and the eurozone crisis, and the universal acceptance of Hyman Minsky's insights into the nature of the financial system and its role in the real economy. The best examples of the causal link between excessive debt, asset bubbles, and financial instability are the Spanish and Irish banking crises, which resulted from nothing more sophisticated than straightforward real estate loans. Bank leverage ratios are primarily seen as a microprudential measure that intends to increase bank resilience. Yet in today's environment of excessive liquidity due to very low interest rates and quantitative easing, bank leverage ratios should also be viewed as a key part of the macroprudential framework. In this context, this paper discusses the role of leverage ratios as both microprudential and macroprudential measures. As such, it explains the role of the leverage cycle in causing financial instability and sheds light on the impact of leverage restraints on good bank governance and allocative efficiency

Il dovere di riservatezza

Analisi dei doveri di riservatezza delle organizzazioni sindacali in materia di informazione e consultazione introdotti dal d.lgs n. 25/200

Anti-hcv treatment for opiate addicts: Clinical and immunological issues

HCV infection is a major health concern worldwide, and the main cause of liver failure. A total of 180 million people is infected with HCV, and is the most frequent infection among drug addicts, with a frequency in the range of 50-90% in Europe. Chronic persistence of HCV infection and its progression are linked to a variety of factors, including the current exposure to opiate drugs themselves, because of their direct impact on the immune system. Opiates are believed to be immunosuppressant as a rule, but recent evidence has shown that opiates differ as regards their immunological properties. Methadone, which is commonly used for opiate addiction treatment, is a synthetic compound acting mainly on µ-opioid receptors; methadone happens to be free of immunosuppressant properties, at least when its slow-acting formulation is administered continuously. It is likely that such an action is achieved by its impact on suprarenal activity, as it restores the suprarenal abnormalities of heroin addicts, and the long-lasting tonic activation of µ-receptors in the central nervous system and activates a range of immune cells. The enrolment of methadone-maintained addicts in HCV treatment programmes may help to increase the effectiveness of HCV treatment by systematically impeding the transmission of HCV infection via the reservoir of drug addicts