1,721,044 research outputs found
Computational studies of mutations associated to resistance in HIV-1 macromolecular targets and implications in rational design of novel antiviral agents
Full text linkAl fine di identificare nuovi farmaci anti-HIV capaci di superare i problemi legati alla resistenza, è stato condotto uno studio teorico combinando l’analisi strutturale sui modelli cristallografici della trascrittasi inversa (RT), i dati clinici relativi ai residui conservati dell’RT ed un’innovativa metodica computazionale basata sulle mappe di GRID.
Tale analisi ha permesso di riprodurre i risultati clinici e di evidenziare le conseguenze delle mutazioni nella fase di ricognizione. Inoltre l’approccio computazionale ha portato all’identificazione di un modello farmacoforico utile per la progettazione di nuovi inibitori dell’RT.
E’ stato riscontrato che la presenza del polimorfismo I135T nei pazienti NNRTI-naïve correlasse in modo significativo con la mutazione K103N nei casi di fallimento agli NNRTI, suggerendo così che la sostituzione I135T rappresenti un punto cruciale per l’evoluzione della resistenza agli NNRTI. Le simulazioni di dinamica molecolare (MD) hanno mostrato che la mutazione I135T contribuisce alla stabilizzazione della chiusura della tasca di legame degli NNRTI indotta dalla K103N in seguito alla riduzione della distanza ed all’aumento del numero di legami idrogeno tra l’Asn103 e la Tyr188.
Inoltre è stata valutata l’influenza di due mutazioni associate a resistenza, L33F e L76V, presenti a livello della proteasi (PR) di HIV-1 rispetto alla ricognizione molecolare del Lopinavir (LPV) e dell’Atazanavir (ATV). L’analisi delle energie di interazione ottenute in seguito alla MD ha rivelato che la mutazione L33F determina una riduzione delle interazioni tra il ligando ed il recettore, dell’affinità di legame e della stabilità del dimero per entrambi gli inibitori della PR. In presenza della mutazione L76V, il LPV ha mostrato una minore affinità di legame ed un ridotto network di legami idrogeno, mentre i complessi con l’ATV hanno rivelato una migliore affinità, un effetto stabilizzante a livello dell’interfaccia del dimero e più efficaci interazioni ligando-recettore, in accordo con i dati di ipersuscettibilità.
Al fine di valutare la stabilità del 6-helix bundle, sono state studiate le proprietà conformazionali della glicoproteina gp41 in presenza delle mutazioni associate a resistenza all’enfuvirtide V38A ed N140I. Le simulazioni di MD hanno mostrato che la copresenza delle mutazioni V38A+N140I è in grado di abolire l’interazione stabilita tra i residui 38 e 145, che risulta fondamentale per la stabilizzazione del 6-helix bundle.In order to discover novel selective anti-HIV resistance-evading drugs, a theoretical study was carried out combining structural analysis of RT crystallographic models, clinical data about RT conserved residues and an innovative computational method based on GRID maps. Such analysis allowed to reproduce clinical results and to highlight the consequences of the mutations in the recognition step. Moreover the computational approach generated a pharmacophore model useful for the design of novel RT inhibitors.
The presence of the I135T polymorphism in NNRTI-naive patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular Dynamics simulations (MD) showed that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y.
In addition the influence of two drug resistance-associated mutations, L33F and L76V, of HIV-1 PR has been evaluated with respect to lopinavir (LPV) and atazanavir (ATV) molecular recognition. The evaluation of the interaction energies after the MD revealed that L33F substitution is related to reduced host/guest interactions, decreased affinity and to a dimer destabilizing effect for both PR inhibitors. In presence of L76V mutation, LPV showed a lowered binding affinity and a reduced hydrogen bonding network, while ATV complexes revealed a more productive binding affinity, increased host/guest interactions and dimer stabilizing effects, in agreement with hyper susceptibility data.
With the aim to estimate the stability of its 6-helix bundle, the gp41 conformational properties were investigated in presence of V38A and N140I, known enfuvirtide resistance-associated mutations. MD showed that the co-presence of V38A+N140I abolished the interaction between residue 38 and 145 important for the 6-helix-bundle stabilization
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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
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