1,721,203 research outputs found
Antagonizing the adhesion of type 1 fimbriae - mediated Escherichia coli - a novel therapy for urinary tract infections
Full text linkUrinary tract infections (UTIs), primarily caused by uropathogenic E. coli (UPEC), affect millions of people and account for significant morbidity and high medical costs. The key step in the pathogenesis of UTIs is the bacterial adhesion to urothelial cells, which is mediated by the virulence factor FimH located on type 1 pili. Blocking FimH and therefore the adhesion with FimH antagonists offers a new therapeutic approach for the prevention and treatment of UTIs. However, the antagonists developed so far have hardly met the requirements for clinical applications due to poor pharmacokinetic (PK) properties. In vivo studies indicated that with biphenyl α-D-mannosides as FimH antagonists, high doses were necessary to achieve the minimal concentrations required for anti-adhesive effects in the bladder. Additionally, the binding mode of an antagonist to the carbohydrate recognition domain of FimH can switch from an “in-docking mode” to an “out-docking mode”, depending on the structure of the antagonist. Further studies indicated that the existence of the high- and low-affinity state of FimH could complicate the binding affinity.
To achieve oral bioavailability, to improve binding affinity, and to explore the binding mode, we chemically modified the biphenyl FimH antagonists with diverse strategies. To establish the designed compound libraries, traditional synthesis and dynamic combinatorial techniques were applied. The binding affinity and the thermodynamic profile of the antagonists were evaluated by a cell-free competitive binding assay, a competitive fluorescence polarization assay, a cell-based flow cytometry assay, and isothermal titration calorimetry (ITC). Furthermore, the PK properties were determined by in vitro and in vivo assays. As results, structure-activity and structure-property relationships were established for structurally diversified FimH antagonists. The reported strategies led to FimH antagonists with significantly improved PD/PK profile regarding effectiveness of the anti-adhesive treatment
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Synthesis and in vitro pharmacology of arpromidine and related Phenylpyridylalkylguanidines, a potential new class of positive inotropic drugs
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