1,721,068 research outputs found
Unveiling SARS-CoV-2's heart: role, structure and inhibition of SARS-CoV-2 RNA-dependent RNA polymerase
Full text linkSARS-CoV-2 emergence in late 2019 represented an incredible challenge for virological research and the development of novel as well as repurposed antiviral agents. Among the targeted viral proteins, one is nsp12 that carries the RNA-dependent RNA polymerase (RdRp) activity, essential for the viral replication. Together with nsp7 and nsp8 cofactors, having an essential role in aiding processivity and associated with several other nonstructural proteins such as helicase, methyltransferase, endo- and exonuclease, nsp12 forms the large viral replication and transcription complex (RTC). Within such RTC, nsp12 catalyzes the synthesis of one of the longest RNA genomes in the viral world, requiring exceptional speed, processivity and fidelity compared to other viral RdRps. Moreover, the peculiar replication cycle of coronaviruses requires nsp12 to perform less conventional functions in backtracking on the viral genome for proof-reading activity and "jumping" during discontinuous synthesis of subgenomic mRNAs. The structure of the minimal RTC was resolved with a resolution <3 Å by cryo-electron microscopy in complex with RNA and with inhibitors, opening the doors to structural studies on its functions and drug development. Given its essential role in viral replication, extensive research was carried out over the last years to identify both nucleoside (NI) and non-nucleoside (NNI) inhibitors, resulting in two NIs reaching clinical use, although their efficacy in vivo is still under evaluation. This review aims at summarizing the currently known structural and functional aspects and the state-of-the art in drug discovery for SARS-CoV-2 RdRp
The emerging field of human endogenous retroviruses: Understanding their physiological role and contribution to diseases
Full text linkIntegration of SARS-CoV-2 RNA in infected human cells by retrotransposons: an unlikely hypothesis and old viral relationships
Full text linkZhang et al. (Proc Natl Acad Sci 118:e2105968118, 2021) recently reported that SARS-CoV-2 RNA can be retrotranscribed and integrated into the DNA of human cells by the L1 retrotransposon machinery. This phenomenon could cause persistence of viral sequences in patients and may explain the prolonged PCR-positivity of SARS-CoV-2 infected patients, even long after the phase of active virus replication has ended. This commentary does critically review the available data on this topic and discusses them in the context of findings made for other exogenous viruses and ancestral endogenous retroviral elements
Prolonged activity of HERV-K(HML2) in Old World Monkeys accounts for recent integrations and novel recombinant variants
Full text linkAround 8% of the human genome comprises Human Endogenous Retroviruses (HERVs) acquired over primate evolution. Some are specific to primates such as HERV-K, consisting of 10 HML subtypes and including the most recently acquired elements. Particularly, HML2 is the youngest clade, having some human-specific integrations, and while it has been widely described in humans its presence and distribution in non-human primates remain poorly characterized. To investigate HML2 distribution in non-human primates, the present study focused on the characterization of HML2 integrations in Macaca fascicularis and Macaca mulatta which are the most evolutionarily distant species related to humans in the Catarrhini parvorder. We identified overall 208 HML2 proviruses for M. fascicularis (77) and M. mulatta (131). Among them, 46 proviruses are shared by the two species while the others are species specific. Only 12 proviruses were shared with humans, confirming that the major wave of HML2 diffusion in humans occurred after macaques’ divergence. Phylogenetic analysis confirmed structural variations between HML2 macaques’ species-specific proviruses, and the ones shared between macaques and humans. The HML2 loci were characterized in terms of structure, focusing on potential residual open reading frames (ORFs) for gag, pol, and env genes for the latter being reported to be expressed in human pathological conditions. The analysis identified highly conserved gag and pol genes, while the env genes had a very divergent nature. Of the 208 HML2 proviral sequences present in Macaca species, 81 sequences form a cluster having a MER11A, a characteristic HML8 LTR sequence, insertion in the env region indicating a recombination event that occurred between the HML2 env gene and the HML8 LTR. This recombination event, which was shown to be present only in a subset of macaques’ shared sequences and species-specific sequences, highlights a recent viral activity leading to the emergence of an env variant specific to the Old World Monkeys (OWMs). We performed an exhaustive analysis of HML2 in two species of OWMs, in terms of its evolutionary history, structural features, and potential residual coding capacity highlighting recent activity of HML2 in macaques that occurred after its split from the Catarrhini parvorder, leading to the emergence of viral variants, hence providing a better understanding of the endogenization and diffusion of HML2 along primate evolution
Human endogenous retroviruses (HERVs) and mammalian apparent Ltrs retrotransposons (MALRs) are dynamically modulated in different stages of immunity
Full text linkHuman Endogenous retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) are remnants of ancient retroviral infections that represent a large fraction of our genome. The HERV and MaLR transcriptional activity is regulated in developmental stages, adult tissues, and pathological conditions. In this work, we used a bioinformatics approach based on RNA-sequencing (RNA-seq) to study the expression and modulation of HERVs and MaLR in a scenario of activation of the immune response. We analyzed transcriptome data from subjects before and after the administration of an inactivated vaccine against the Hantaan orthohantavirus, the causative agent of Korean hemorrhagic fever, to investigate the HERV and MaLR expression and differential expression in response to the administration of the vaccine. Specifically, we described the HERV transcriptome in PBMCs and identified HERV and MaLR loci differentially expressed after the 2nd, 3rd, and 4th inactivated vaccine administrations. We found that the expression of 545 HERV and MaLR elements increased in response to the vaccine and that the activation of several individual HERV and MaLR loci is specific for each vaccine administration and correlated to different genes and immune-related pathways
Unlocking STING as a Therapeutic Antiviral Strategy
Full text linkInvading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality
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
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