1,720,992 research outputs found
Structural and functional characterization of new human thymidylate synthase interface variants
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Exploring acyclic boronic derivatives as potent beta-lactamases inhibitors with broad spectrum activity
No full textBackground: Bacterial resistance has become a worldwide concern after the emergence of pan-resistant clinical isolates. beta-lactamases enzymes (BLs) represent one of the major mechanisms of bacterial resistance. Among them, the metallo depedent subclass (MBLs) are particularly worrisome, given their capability of hydrolysing beta-lactam antibiotics as well as any inhibitors currently in use. In particular, New Delhi metallo-BL-1 (NDM-1), the most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. While for serine-beta-lactamases (SBLs) inhibitors are available in therapy, for MBLs no inhibitor have been at the present approved, compromising the efficacy of treatments of bacterial infections.
Objectives: Our study aimed to characterize promising β-lactamases inhibitors with broad spectrum activity toward both serine and metallo BLs. We focused our attention on boron based benzothiophene derivatives and used a small library, based on such scaffold, to develop non-beta-lactam-like compounds able to bind BLs active site and inhibit their activity. Our choice has been encouraged by the recently approved serine BLs inhibitor vaborbactam and promising studies on cyclic boronic inhibitors.
Methods: We performed an in depth structural and mechanicistic study of a small library of acyclic boronic benzothiophene derivatives with broad spectrum (both SBLs and MBLs) activity.
Results: In solution kinetic characterization as well as extensive X-Ray crystallographic analysis of our best candidates have been performed and will be presented here
Structural comparison between Enterococcus faecalis and human thymidylate synthase provides hints about enzyme conformational variabilities
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Conveying a newly designed hydrophilic anti-human thymidylate synthase peptide to cisplatin resistant cancer cells: are pH-sensitive liposomes more effective than conventional ones?
No full textLR-peptide, a novel hydrophilic peptide synthetized and characterized in previous work, is able to reduce the multi-drug resistance response in cisplatin (cDPP) resistant cancer cells by inhibiting human thymidylate synthase (hTS) overexpressed in several tumors, including ovarian and colon-rectal cancers, but it is unable to enter the cells spontaneously. Objective: The aim of this work was to design and characterize liposomal vesicles as drug delivery systems for the LR peptide, evaluating the possible benefits of the pH-responsive feature in improving intracellular delivery. Materials and methods: For this purpose, conventional and pH-sensitive liposomes were formulated, compared regarding their physical-chemical properties (size, PDI, morphology, in vitro stability and drug release) and studied for in vitro cytotoxicity against a cDDP-resistant cancer cells. Results and discussion: Results indicated that LR peptide was successfully encapsulated in both liposomal formulations but at short incubation time only LR loaded pH-sensitive liposomes showed cell inhibition activity while for long incubation time the two kinds of liposomes demonstrated the same efficacy. Conclusions: Data provide evidence that acidic pH-triggered liposomal delivery is able to significantly reduce the time required by the systems to deliver the drug to the cells without inducing an enhancement of the efficacy of the drug
Optimizing cell permeation of an antibiotic resistance inhibitor for improved efficacy
No full textBenzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C beta lactamase AmpC and potentiates the activity of beta lactam antibiotics in bacteria that express this and related enzymes. As is often true, the potency of compound 1 against the enzymes is much attenuated in cell culture against Gram negative bacteria, where the minimum inhibitor concentration of compound 1 is in the mid-micromolar range. Here, we modulated the properties of this lead to enhance its ability to cross the membrane, using a combination of X-ray crystallography, structure-based design, and application of physical models of outer membrane crossing. This strategy led us to derivatives with substantially improved permeability. Also, the greater solubility of these compounds allowed us to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of ceftazidime on resistant bacteria.Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C β-lactamase AmpC and potentiates the activity of β-lactam antibiotics in bacteria that express this and related enzymes. As is often true, the potency of compound 1 against the enzymes is much attenuated in cell culture against Gram negative bacteria, where the minimum inhibitor concentration of compound 1 is in the mid-micromolar range. Here, we modulated the properties of this lead to enhance its ability to cross the membrane, using a combination of X-ray crystallography, structure-based design, and application of physical models of outer membrane crossing. This strategy led us to derivatives with substantially improved permeability. Also, the greater solubility of these compounds allowed us to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of ceftazidime on resistant bacteria. © 2007 American Chemical Society
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