1,720,977 research outputs found
Targeting G-quadruplexes to achieve antiviral activity
Full text linkWith the emergence of new viruses in the human population and the fast mutation rates of existing viruses, new antiviral targets and compounds are needed. Most existing antiviral drugs are active against proteins of a handful of viruses. Most of these proteins in the end affect viral nucleic acid processing, but direct nucleic acid targeting is less represented due to the difficulty of selectively acting at the nucleic acid of interest. Recently, nucleic acids have been shown to fold in structures alternative to the classic double helix and Watson and Crick base-pairing. Among these non-canonical structures, G-quadruplexes (G4s) have attracted interest because of their key biological roles that are being discovered. Molecules able to selectively target G4s have been developed and since G4s have been investigated as targets in several human pathologies, including viral infections. Here, after briefly introducing viruses, G4s and the G4-binding molecules with antiviral properties, we comment on the mechanisms at the base of the antiviral activity reported for G4-binding molecules. Understanding how G4-ligands act in infected cells will possibly help designing and developing next-generation antiviral drugs
G-quadruplexes and G-quadruplex ligands: targets and tools in antiviral therapy
Full text linkG-quadruplexes (G4s) are non-canonical nucleic acids secondary structures that form within guanine-rich strands of regulatory genomic regions. G4s have been extensively described in the human genome, especially in telomeres and oncogene promoters; in recent years the presence of G4s in viruses has attracted increasing interest. Indeed, G4s have been reported in several viruses, including those involved in recent epidemics, such as the Zika and Ebola viruses. Viral G4s are usually located in regulatory regions of the genome and implicated in the control of key viral processes; in some cases, they have been involved also in viral latency. In this context, G4 ligands have been developed and tested both as tools to study the complexity of G4-mediated mechanisms in the viral life cycle, and as therapeutic agents. In general, G4 ligands showed promising antiviral activity, with G4-mediated mechanisms of action both at the genome and transcript level. This review aims to provide an updated close-up of the literature on G4s in viruses. The current state of the art of G4 ligands in antiviral research is also reported, with particular focus on the structural and physicochemical requirements for optimal biological activity. The achievements and the to-dos in the field are discussed
]quinoxalines via Addition–Elimination Followed by Cycloacylation
No full textThis paper describes a convenient and efficient synthesis of new fused tricyclic diazepino[3,2,1-ij]
quinolines and substituted pyrido[1,2,3-de]quinoxalines. o-Phenylenediamines are transformed in the
tricycle nucleus in only a few-step synthetic sequence to produce ethyl 2,8-dioxo-1,2,3,4-tetrahydro-8H
[1,4]diazepino[3,2,1-ij]quinoline-7-carboxylate, ethyl 8-oxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]
quinoline-7-carboxylate and ethyl 2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate.
The method is economical and simple to perform
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
Identification of i-motifs in Alphaherpesvirus immediate early promoters and their dynamic folding with G4s during infection
No full textI-motifs (iMs) and G-quadruplexes (G4s) are non-canonical DNA secondary structures formed by C-rich and G-rich sequences, respectively. While G4s have been identified as regulatory elements in both human and viral genomes, iMs remain largely unexplored. This study investigates the presence of iMs in the immediate-early (IE) promoters of human Alphaherpesviruses (αHHVs), namely herpes simplex virus 1 (HSV-1), herpes simplex virus 2 and varicella-zoster virus. αHHVs IE promoters, crucial for initiating an efficient viral cycle, embed G4s, but the potential presence of iMs in these regions is unknown.
We identified highly conserved putative iM-forming sequences in IE promoters of all αHHVs. Biophysical characterization by circular dichroism, thermal difference spectroscopy and bromine footprinting, confirmed the ability of these sequences to form iMs in vitro, with varying conformations and distributions among the three viruses.
Using a CUT&Tag-qPCR assay, we detected and quantified both iM and G4 structures in the HSV-1 genome during active viral infection. Our results show the dynamic formation of iMs and G4s in IE promoters, with enrichment levels changing over time. These structural changes correlated with variations in IE gene expression, indicating a functional role in HSV-1 biology.
This study provides the first evidence of iMs in a viral genome, revealing a novel layer of genome organization through iMs folding alongside G4s in viruses
The iMab antibody selectively binds to intramolecular and intermolecular i-motif structures
Full text linki-Motifs (iMs) are quadruplex nucleic acid conformations that form in cytosine-rich regions. Because of their acidic pH dependence, iMs were thought to form only in vitro. The recent development of an iM-selective antibody, iMab, has allowed iM detection in cells, which revealed their presence at gene promoters and their cell cycle dependence. However, recent evidence emerged which appeared to suggest that iMab recognizes C-rich sequences regardless of their iM conformation. To further investigate the selectivity of iMab, we examined the binding of iMab to C-rich sequences, using a combination of pull-down and western blot assays. Here, we observe that the composition of buffers used during binding and washing steps strongly influences the selectivity of antibody binding. In addition, we demonstrate by nuclear magnetic resonance that several of the previously reported C-rich sequences, which were not expected to form iMs, actually form intermolecular iMs which are selectively recognized by iMab. Our results highlight the specificity of the iMab antibody, emphasize the importance of avoiding in vitro artifacts by optimizing DNA concentrations, blocking and washing conditions, and confirm that iMab is selective not only for intramolecular iMs but also for intermolecular iMs, while not affecting the iM conformation
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
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