1,720,958 research outputs found
Discovery of quinolinonyl derivatives as anti-HIV-1 inhibitors endowed with an innovative mechanism of action.
No full textHIV integrase (IN) is a pivotal antiretroviral drug target. In this regard, IN strand transfer inhibitors (INSTIs), binding to the IN active site, have proven to be highly effective, becoming a potent first-line therapy to treat infected patients. However, despite their effectiveness as therapeutic options and the high barriers with the second-generation FDA-approved INSTIs, drug therapy selects for drug resistance and mutations responsible for multiple INSTIs resistance, underscoring the need for the development of more effective antiretroviral compounds. The development of small molecule protein-protein interaction inhibitors is a new attractive strategy for discovering anti-HIV agents. In this field of research, allosteric IN inhibitors (ALLINIs), are a promising new class of antiretroviral agents. These inhibitors act differently in respect to INSTIs, in fact, they alter the functional IN multimerization. Recently, it was unraveled that aberrant IN multimerization underlies the inhibition of IN-vRNA interactions by ALLINIs. In doing so, ALLINIs indirectly disrupt the IN-vRNA binding, leading to the formation of defective viral particles with greatly reduced infective potential with mis-localization of the vRNA outside the viral capsid. While the indirect disruption of IN-vRNA binding (caused by the impairment of functional IN multimerization) has been described with the treatment of virus-producing cells with ALLINIs, the direct disruption of this binding (without affecting IN multimerization properties) by small molecules has not been reported so far. We describe a series of compounds identified as inhibitors of the IN-vRNA binding via a direct mechanism. In particular, we deepened the mechanism of action of some compounds previously described by us as INSTIs. Indeed, we speculated that these quinolinonyl derivatives, being endowed with two DKA chains, could also act as protein-nucleic acid interaction inhibitors. To verify our hypothesis, we decided to test a set of derivatives and their analogues endowed with a variable “base-like” functional group. We assessed the capability of our derivatives of inhibiting at low micromolar concentrations both IN 3’-processing and strand transfer reactions in a LEDGF/p75 independent assay. In addition, we performed in vitro binding assays, and we found that our quinolinonyl derivatives are able to disrupt the IN-vRNA interaction, that is vital for a correct generation of a functional infective virion. The data coming from the biological assays will be shown and discussed
Identification of novel aminopyrimidine derivatives as protein kinase inhibitors blocking cell growth.
No full textAminopyrimidine scaffold is typical of some of the most promising anticancer drug recently discovered thanks to their ability to inhibit different types of protein kinases. Kinase deregulation has emerged as a relevant mechanism by which cancer cells evade normal physiological constraints and kinases inhibitors have become one of the most intensively pursued classes of recent antitumoral drugs. Owing to the significance of pyrimidine derivatives as anticancer agents through kinase inhibition and our longstanding expertise in the development of pyrimidine derivatives, we designed and synthesized various classes of anilino and bis-anilinopyrimidines. Most of them were found active in in vitro HTRF inhibition assays in low nanomolar range against one or more kinases, like EGFR, c-KIT, VEGFR, PDGFR, Akt and AURKA, wild type or mutated and double-mutated isoforms. Some compounds were also crystallized in the active site of some kinases, showing a preference for DFG-in or DFG-out conformation. Subsequently, the antitumor activity of selected compounds was evaluated on three different human cancer types chosen on the basis of their unsatisfactory therapeutic strategies and poor prognosis: glioblastoma multiforme, triple-negative breast cancer, colon adenocarcinoma, tongue squamous carcinoma and hypopharyngeal squamous carcinoma. Various pyrimidines demonstrated to also hinder cell proliferation and cell cycle and to induce apoptosis in all the tested cell lines, without exerting cytotoxic effects at the same concentrations. The data coming from the biological assays will be shown and discussed
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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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