Identification of Polymerase and Processivity Inhibitors of Vaccinia DNA Synthesis Using a Stepwise Screening Approach

Nearly all DNA polymerases require processivity factors to ensure continuous incorporation of nucleotides. Processivity factors are specific for their cognate DNA polymerases. For this reason, the vaccinia DNA polymerase (E9) and the proteins associated with processivity (A20 and D4) are excellent therapeutic targets. In this study, we show the utility of stepwise rapid plate assays that i) screen for compounds that block vaccinia DNA synthesis, ii) eliminate trivial inhibitors, e.g. DNA intercalators, and iii) distinguish whether inhibitors are specific for blocking DNA polymerase activity or processivity. The sequential plate screening of 2,222 compounds from the NCI Diversity Set library yielded a DNA polymerase inhibitor (NSC 55636) and a processivity inhibitor (NSC 123526) that were capable of reducing vaccinia viral plaques with minimal cellular cytotoxicity. These compounds are predicted to block cellular infection by the smallpox virus, variola, based on the very high sequence identity between A20, D4 and E9 of vaccinia and the corresponding proteins of variola

A geographical population analysis of dental trauma in school-children aged 12 and 15 in the city of Curitiba-Brazil

<p>Abstract</p> <p>Background</p> <p>The study presents a geographical analysis of dental trauma in a population of 12 and 15 year-old school-children, in the city of Curitiba, Brazil (n = 1581), using a database obtained in the period 2005-2006. The main focus is to analyze dental trauma using a geographic information system as a tool for integrating social, environmental and epidemiological data.</p> <p>Methods</p> <p>Geostatistical analysis of the database and thematic maps were generated showing the distribution of dental trauma cases according to Curitiba's Health Districts and other variables of interest. Dental trauma spatial variation was assessed using a generalized additive model in order to identify and control the individual risk-factors and thus determine whether spatial variation is constant or not throughout the Health Districts and the place of residence of individuals. In addition, an analysis was made of the coverage of dental trauma cases taking the spatial distribution of Curitiba's primary healthcare centres.</p> <p>Results</p> <p>The overall prevalence of dental trauma was 37.1%, with 53.1% in males and 46.7% in females. The spatial analysis confirms the hypothesis that there is significant variation in the occurrence of dental trauma, considering the place of residence in the population studied (Monte Carlo test, p = 0,006). Furthermore, 28.7% of cases had no coverage by the primary healthcare centres.</p> <p>Conclusions</p> <p>The effect of the place of residence was highly significant in relation to the response variable. The delimitation of areas, as a basis for case density, enables the qualification of geographical territories where actions can be planned based on priority criteria. Promotion, control and rehabilitation actions, applied in regions of higher prevalence of dental trauma, can be more effective and efficient, thus providing healthcare refinement.</p

Institutionalisation of Social Movements: Co-option And Democratic Policy-making

Over the past 30 years, urban policy in Brazil has undergone a major transformation, both in terms of regulatory frameworks and the involvement of citizens in the process of policy-making. As an intense process of institutional innovation and mobilisation for decent publicservices took place, academics started to consider the impact of institutionalisation on the autonomy of social movements. Using empirical evidence from a city in the northeast of Brazil, this article addresses the wider literature on citizen participation and social movements to examine specifically the problem with co-optation. I examine the risks linked to co-optation, risks that can undermine the credibility of social movements as agents of change, and explore the tensions that go beyond the ‘co-optation versus autonomy’ divide, an issue frequently found in the practices of social movements, in their dealings with those in power. In particular, this article explores the learning processes and contentious relationships between mainly institutionally oriented urban movements and local government. This study found that the learning of deliberative skills not only led to changes in the objectives and repertoires of housing movements, but also to the inclusion of new components in their objectives that provide room for creative agency and which, in some cases, might allow them to maintain their autonomy from the state