Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models

LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1 beta. Furthermore, inhibition of LasBmediated IL-1 beta activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen

A coleção fotográfica de Marcel Gautherot

Considering contemporary Anthropologys debate around photography, there is a\ud keen interest in the understanding of one of the most important open to public consultation\ud photographic collections on 20th Century Brazil, that of Frenchman Marcel Gautherot (1910-\ud 1996). The collection comprises around 25,000 photographs, purchased in 1999 by Instituto\ud Moreira Salles and kept in its fund in the city of Rio de Janeiro. The text comments on the\ud photographers work, linked to documentary projects under the patronage of institutions such as\ud the Musée de l´Homme in Paris, at the end of the 1930s, and both the National Historic and\ud Artistic Patrimony Service and the Brazilian Folklore Defence Campaign, in Brazil, between the\ud years of 1940 -1960. Such commitments and interests define important thematic groupings in\ud the production and organisation of his personal photographic archive. A discussion about criteria and technical procedures adopted by the photographer is attempted, detailing series\ud and visual narratives about Brazilian cultures density. With the photographs purchase by the\ud IMS, the oeuvres aesthetic quality, now as an institutional collection, is highlighted. The collections\ud manners of preservation and conservation, reproduction and circulation are redefined

Varieties of Non-ordinary Experiences in Brazil—a Critical Review of the Contribution of Studies of ‘Religious Experience’ to the Study of Religion

According to the latest national census, 64.6% of Brazilians identified themselves as Roman Catholic. However, the census has little or nothing to do with actual practice or belief. Professing to be a Christian (within any confessional specification) is still part of being Brazilian. But the self-identification does not take into account that religiosity is expressed in very diverse ways nor does it prevent people from believing and practising one of the many Brazilian traditions though identifying themselves as Christian in the census. This perception represents the framework of the following discussion of non-ordinary experiences in Brazil, whether they are perceived as religious, spiritual or ‘just’ extraordinary. This article presents an overview of studies about non-ordinary experiences in Brazil. The aim is to show the importance of these experiences for the understanding of the religious landscape of Brazil

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment