Delivery of antisense oligonucleotide to the cornea by iontophoresis.

We wished to evaluate the potential of iontophoresis to promote the delivery of antisense oligonucleotides (ODN) directed at the vascular endothelial growth factor (VEGF)-R2 receptor (KDR/Flk) to the cornea of the rat eye. Fluorescence (CY5)-labeled ODNs in phosphate-buffered saline (PBS) (20 microM) were locally administered to rat eyes, and their fate within the anterior segment was studied. Thirty-four male, 5-week-old Wistar rats were used for all experiments. The rats were divided in four groups. In group I (12 rats, 12 eyes), the ODNs (20 microM) were delivered by iontophoresis (300 microA for 5 minutes) using a specially designed corneal applicator. In group II (12 rats, 12 eyes), the ODNs (20 microM) were delivered using the same applicator, but no electrical current was applied. In group III (6 rats, 6 eyes), a corneal neovascular reaction was induced prior to the application of ODNs (20 microM), and iontophoresis electrical current was delivered as for group I rats. Group IV (4 rats, 4 eyes) received ODN (60 microM) iontophoresis application (300 microA for 5 minutes) and were used for ODN integrity studies. The animals were killed 5 minutes, 90 minutes, and 24 hours after a single ODN application and studied. Topically applied ODNs using the same iontophoresis applicator but without current do not penetrate the cornea and remain confined to the superficial epithelial layer. ODNs delivered with transcorneoscleral iontophoresis penetrate into all corneal layers and are also detected in the iris. In corneas with neovascularization, ODNs were particularly localized within the vascular endothelial cells of the stroma. ODNs extracted from eye tissues 24 hours after iontophoresis remained unaltered. The iontophoresis current did not cause any detectable ocular damage under these conditions. Iontophoresis promotes the delivery of ODNs to the anterior segment of the eye, including all corneal layers. Iontophoresis of ODNs directed at VEGF-R2 may be used for the design of specific antiangiogenic strategy in diseases of the cornea.

Can the administration be trusted? An analysis of the concept of trust, applied to the public sector

In the first part of this paper, we present the various academic debates and, where applicable, questions that remain open in the literature, particularly regarding the nature of trust, the distinction between trust and trustworthiness, its role in specific relationships and its relationship to control. We then propose a way of demarcating and operationalizing the concepts of trust and trustworthiness. In the second part, on the basis of the conceptual clarifications we present, we put forward a number of "anchor points" regarding how trust is apprehended in the public sector with regard to the various relations hips that can be studied. Schematically, we distinguish between two types of relations hips in the conceptual approach to trust: on one hand, the trust that citizens, or third parties, place in the State or in various public sector authorities or entities, and on the other hand, trust within the State or the public sector, between its various authorities, entities, and actors. While studies have traditionally focused on citizens' trust in their institutions, the findings, limitations and problems observed in public - sector coordination following the reforms associated with New Public Management have also elicited growing interest in the study of trust in the relationships between the various actors within the public sector. Both the theoretical debates we present and our propositions have been extracted and adapted from an empirical comparative study of coordination between various Swiss public - service organizations and their politico - administrative authority. Using the analysis model developed for this specific relationship, between various actors within the public service, and in the light of theoretical elements on which development of this model was based, we propose some avenues for further study - questions that remain open - regarding the consideration and understanding of citizens' trust in the public sector.

The β-sliding clamp directs the localization of HdaA to the replisome in Caulobacter crescentus.

The initiation of chromosome replication is tightly regulated in bacteria to ensure that it takes place only once per cell cycle. In many proteobacteria, this process requires the ATP-bound form of the DnaA protein. The regulatory inactivation of DnaA (RIDA) facilitates the conversion of DnaA-ATP into replication-inactive DnaA-ADP, thereby preventing overinitiation. Homologues of the HdaA protein, together with the β-clamp of the DNA polymerase (DnaN), are required for this process. Here, we used fluorescence resonance energy transfer experiments to demonstrate that HdaA interacts with DnaN in live Caulobacter crescentus cells. We show that a QFKLPL motif in the N-terminal region of HdaA is required for this interaction and that this motif is also needed to recruit HdaA to the subcellular location occupied by the replisome during DNA replication. An HdaA mutant protein that cannot colocalize or interact with DnaN can also not support the essential function of HdaA. These results suggest that the recruitment of HdaA to the replisome is needed during RIDA in C. crescentus, probably as a means to sense whether chromosome replication has initiated before DnaA becomes inactivated. In addition, we show that a conserved R145 residue located in the AAA+ domain of HdaA is also needed for the function of HdaA, although it does not affect the interaction of HdaA with DnaN in vivo. The AAA+ domain of HdaA may therefore be required during RIDA after the initial recruitment of HdaA to the replisome by DnaN.

Improved predictive mapping of indoor radon concentrations using ensemble regression trees based on automatic clustering of geological units.

PURPOSE: According to estimations around 230 people die as a result of radon exposure in Switzerland. This public health concern makes reliable indoor radon prediction and mapping methods necessary in order to improve risk communication to the public. The aim of this study was to develop an automated method to classify lithological units according to their radon characteristics and to develop mapping and predictive tools in order to improve local radon prediction. METHOD: About 240 000 indoor radon concentration (IRC) measurements in about 150 000 buildings were available for our analysis. The automated classification of lithological units was based on k-medoids clustering via pair-wise Kolmogorov distances between IRC distributions of lithological units. For IRC mapping and prediction we used random forests and Bayesian additive regression trees (BART). RESULTS: The automated classification groups lithological units well in terms of their IRC characteristics. Especially the IRC differences in metamorphic rocks like gneiss are well revealed by this method. The maps produced by random forests soundly represent the regional difference of IRCs in Switzerland and improve the spatial detail compared to existing approaches. We could explain 33% of the variations in IRC data with random forests. Additionally, the influence of a variable evaluated by random forests shows that building characteristics are less important predictors for IRCs than spatial/geological influences. BART could explain 29% of IRC variability and produced maps that indicate the prediction uncertainty. CONCLUSION: Ensemble regression trees are a powerful tool to model and understand the multidimensional influences on IRCs. Automatic clustering of lithological units complements this method by facilitating the interpretation of radon properties of rock types. This study provides an important element for radon risk communication. Future approaches should consider taking into account further variables like soil gas radon measurements as well as more detailed geological information.