1,721,074 research outputs found
Molecular mechanisms of dengue virus infection: cell tropism, antibody-dependent enhancement, and cytokines
Full text linkDengue is the most prevalent mosquito-borne viral disease in humans. Although most infections occur in the (sub)tropical areas, recent outbreaks in Italy and Madeira indicate that the virus is spreading into Europe. Despite its relevance, no vaccine or medications are available against this virus. This is, in part, due to the complex pathogenesis of the virus. Dengue virus has four serotypes, and protection against one serotype can lead to enhanced disease after infection with another serotype. It is known that antibodies play a pivotal role in the enhanced severity, yet the underlying mechanism is unknown since the 1970’s. To unravel this mechanism, the authors followed the virus step-by-step throughout its life cycle. Surprisingly, antibodies were found to facilitate higher penetration of the virus into the cell yet combined with unaltered binding to the cell. The latter prevents that the cell is alarmed, and thus facilitates higher efficiency of infection. At last, the cells perceive the infection and give a disproportional response, culminating into severe disease. Besides the mechanism, the authors also describe the relevance of the cell type that is infected: dendritic cells give high virus production yet the produced virus particles are low-infectious, suggesting that these struggle to continue the infectious process. Macrophages, however, produce less virus particles yet these are more infectious. The results in this thesis provide insights for future treatments
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
Dengue virus cell entry : unraveling the role of antibodies, maturation status, and antiviral drugs
Full text linkMeer inzicht in rol antistoffen tijdens dengue-infectie
Antistoffen bepalen hoe dengue-virusdeeltjes een cel binnendringen. Dat concludeert Vanesa Ayala Núñez in haar promotieonderzoek. Antistoffen binden aan virusdeeltjes waarna ze worden opgenomen door cellen om te worden afgebroken. Dengue ontsnapt echter aan afbraak waardoor infectie van de cel plaatsvindt.
Dengue, ook wel bekend als knokkelkoorts, is de meest voorkomende tropische, virale infectieziekte. De ziekte wordt overgebracht door muggen. Meestal gaat dengue vanzelf over, maar soms ontwikkelt een patiënt een ernstige vorm van de ziekte met mogelijk fataal verloop. Ayala Núñez stelt voorop dat al ruime tijd bekend is dat zuigelingen (via de moedermelk) en mensen die opnieuw geïnfecteerd worden, de grootste risico’s lopen om die ernstige vorm van de ziekte te ontwikkelen. Dit komt omdat deze mensen pre-existerende antistoffen hebben tegen dengue. Toch is nog onduidelijk hoe antistoffen de effectiviteit van dengue-virusdeeltje kunnen beïnvloeden.
De promovenda bestudeerde daarom op celniveau wat er precies gebeurt wanneer een virusdeeltje een menselijke cel infecteert. Zij deed dat met behulp van lasermicroscopie in twee scenario’s: in af- en aanwezigheid van antistoffen. Ook testte Ayala Núñez twee nieuwe geneesmiddelen tegen dengue (de antibiotica LTA-949 en SA-17). Ze heeft een volledig nieuw virusopnamemechanisme ontdekt waardoor we nu beter begrijpen hoe antistof-gebonden dengue kan ontsnappen aan afbraak. Ook stelt ze dat beide geneesmiddelen goede resultaten laten zien, zowel bij een eerste infectie als bij een herinfectie, dus in aanwezigheid van antistoffen. Deze inzichten brengen de behandeling en preventie van dengue weer een stap dichterbij.
Antibody-dependent enhancement (ADE) is thought to play a critical role in the exacerbation of dengue virus-induced disease during a heterologous re-infection. Pre-existing cross-reactive anti-dengue antibodies are generally believed to bind to the newly infecting DENV and target the antibody-virus complexes to Fc-receptor expressing cells, cells that are highly permissive to DENV infection. Intriguingly, instead of neutralizing viral infection, these cross-reactive antibodies have been shown to facilitate successful viral entry at sub-neutralizing antibody concentrations, thereby promoting viral infection and consequently disease. The mechanism by which antibodies influence viral infection is poorly understood. The work presented in this thesis provides a detailed insight into the internalisation route and endocytic trafficking of DENV in macrophages in the absence and presence of enhancing concentrations of antibody. Also, we analysed which antibodies stimulate the infectivity of immature DENV particles. Furthermore, given the clinical importance of ADE, we also aimed to identify anti-dengue compounds that interfere with DENV infection in the presence of antibodies.
Role of autophagy-related proteins and cellular microRNAs in chikungunya and dengue virus infection
Full text linkDengue virus (DENV) and chikungunya virus (CHIKV) are the causative agents of febrile diseases with a wide range of clinical manifestations worldwide, for which there are no specific treatments or fully efficacious vaccines available. Research on the cellular host factors involved in the control of the replication of these viruses is urgently needed in order to better understand their pathogenesis and to provide potential therapeutic targets. Autophagy is a cellular mechanism that aids in the degradation of cellular components in vesicles known as autophagosomes during stress conditions, such as viral infection. First, we investigated the role of proteins involved in autophagy (ATG proteins) in the replication of DENV and CHIKV in human cell lines. We found that ATG proteins differentially modulate the replication of these viruses. Even more, we identified a protein, e.g., BNIP3, which regulates CHIKV infection via mechanisms independent of the functions that have been described in the literature so far. We showed that depletion of BNIP3 favours CHIKV at an early stage in the replication cycle, resulting in higher infectivity and viral production. Next we also investigated the changes that occur in the expression of small non-coding RNAs, microRNAs (miRNAs), in macrophages infected with DENV. We found the virus to change the expression of several miRNAs. Furthermore, we found miR-3614-5p to have antiviral activity against DENV, possibly through the regulation of the expression of the cellular protein ADAR1. In conclusion, this thesis provides evidence of the role of cellular host factors in the control of viral infection
Cell entry mechanisms of dengue virus
Full text linkDengue virus (DENV) currently causes the most common mosquito-borne viral infection worldwide. According to the estimates of the World Health Organization, 50 to 100 million infections occur annually leading to 500,000 hospitalizations and 20,000 deaths. Despite this high impact, there are neither vaccines nor antiviral drugs available to prevent or treat DENV infections. DENV can cause disease in humans ranging from dengue fever, an illness with flu-like symptoms, to the more severe dengue hemorrhagic fever, characterized by potentially life-threatening bleeding manifestions. Antibodies are believed to play an important role in controlling disease severity by directly influencing the infectious properties of the virus. The studies presented in this thesis elucidate the mechanisms that DENV uses to enter and infect the host cell. First, we have followed individual fluorescently labeled virus particles in real-time as they enter a cell, in which different compartments are illuminated by fluorescent marker proteins. Thus, we have visualized the cell entry pathway of DENV and identified the organelle in which the virus undergoes membrane fusion to deliver its genome into the cell. Additionally, we have investigated the infectious properties of a subpopulation of DENV particles, called immature particles, that are considered to be non-infectious. Remarkably, with the help of antibodies, immature DENV particles are able to productively infect cells and therefore might participate in the pathogenesis of severe disease. Collectively, our findings have enriched our knowledge on the critical determinants in DENV infection and may contribute to the development of antiviral drugs and safe dengue vaccines.
A fight against viral infections: host factors and antiviral therapies against positive-strand RNA viruses
Full text linkViral outbreaks can have devastating impacts on both human health and society. To develop effective antiviral treatments, it is important to understand the interactions between the host and the virus at the molecular level. In the first part of the thesis, we investigated the relationship between mosquito-borne viruses like chikungunya virus (CHIKV), dengue (DENV), Zika virus (ZIKV) and West Nile virus (WNV), and autophagy, a cellular degradative pathway. We discovered that the role of autophagy and autophagy-related proteins (ATG) can vary depending on the virus. For example, depletion of BNIP3 showed a marked increase in CHIKV replication, suggesting that BNIP3 is a new host factor that inhibits CHIKV early in its replication cycle. Moreover, knockout of ATG7 and ATG16L1 reduced DENV-2 viral particle production, suggesting the pro-viral role of these proteins in post-replicative stages of DENV-2 replication cycle. In the second part of this thesis, we examined the effectiveness of some antiviral agents against SARS-CoV-2. We found that boceprevir can inhibit β-coronaviruses by binding to the SARS-CoV-2 3CLpro protease's catalytic pocket. Resveratrol and pterostilbene also showed promise in inhibiting SARS-CoV-2 production by acting on post-entry stages of the replication cycle. Overall, this thesis provides new insights into the molecular mechanisms of mosquito-borne viruses and highlights potential avenues for developing antiviral therapies against SARS-CoV-2
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