The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia

Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF

Data mapping as search

In this paper, we describe and situate the system for data mapping in relational databases. Automating the discovery of mappings between structured data sources is a long standing and important problem in data management. Starting from user provided example instances of the source and target schemas, approaches mapping discovery as search within the transformation space of these instances based on a set of mapping operators. mapping expressions incorporate not only data-metadata transformations, but also simple and complex semantic transformations, resulting in significantly wider applicability than previous systems. Extensive empirical validation of , both on synthetic and real world datasets, indicates that the approach is both viable and effective

Inductive Types in the Calculus of Algebraic Constructions

International audienceIn a previous work, we proved that almost all of the Calculus of Inductive Constructions (CIC), which is the basis of the proof assistant Coq, can be seen as a Calculus of Algebraic Constructions (CAC), an extension of the Calculus of Constructions with functions and predicates defined by higher-order rewrite rules. In this paper, we not only prove that CIC as a whole can be seen as a CAC, but also that it can be extended with non-free constructors, pattern-matching on defined symbols, non-strictly positive types and inductive-recursive types

Organisation-oriented super-peer networks for digital libraries

Abstract. The transition from traditional paper libraries to digital libraries enables new strategies for the use and maintenance of artifact collections. We present an organisation-oriented super-peer network which represents the organisational structures of distributed digital libraries in a natural way and is able to integrate distributed resources as well as local devices. Organisational structures can be considered in searching and accessing distributed services and documents. The approach leads to a generalized support for the self-organisation of widely distributed, loosely coupled, and autonomous digital library systems which can be structured by arbitrary inter- and intra-organisational relationships.