1,720,976 research outputs found
Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage
No full text: The tropism of the Human Immunodeficiency Virus type 1 (HIV-1) is determined by the use of either or both chemokine coreceptors CCR5 (R5) and CXCR4 (X4) for entry into the target cell. The ability of HIV-1 to bind R5 or X4 is determined primarily by the third variable loop (V3) of the viral envelope glycoprotein gp120. HIV-1 strains of pandemic group M contain an antisense gene termed asp, which overlaps env outside the region encoding the V3 loop. We previously showed that the ASP protein localizes on the envelope of infectious HIV-1 virions, suggesting that it may play a role in viral entry. In this study, we first developed a statistical method to predict coreceptor tropism based on Fisher's linear discriminant analysis. We obtained three linear discriminant functions able to predict coreceptor tropism with high accuracy (94.4%) when applied to a training dataset of V3 sequences of known tropism. Using these functions, we predicted the tropism in a dataset of HIV-1 strains containing a full-length asp gene. In the amino acid sequence of ASP proteins expressed from these asp genes, we identified five positions with substitutions significantly associated with viral tropism. Interestingly, we found that these substitutions correlate significantly with substitutions at six amino acid positions of the V3 loop domain associated with tropism. Altogether, our computational analyses identify ASP amino acid signatures coevolving with V3 and potentially affecting HIV-1 tropism, which can be validated through in vitro and in vivo experiments
IFN-alpha2b increases interleukin-10 expression in primary activated human CD8+ T cells
No full textInterleukin-10 (IL-10) is a multifunctional cytokine with diverse effects on most hematopoietic cell types. It appears the principal function of IL-10 is to limit and ultimately terminate inflammatory response. We demonstrate here that interferon-alpha2b (IFN-alpha) increases the expression of IL-10 in activated primary CD8(+) T cells. Optimal induction of mRNA expression and protein synthesis was observed when IFN-alpha was added to cells activated by the combination of anti-CD3 monoclonal antibody (mAb) and IL-2. Maximal stimulation of IL-10 protein production was observed after prolonged incubation periods (48-72 h). No effects were observed on the production of IL-4, whereas IFN-gamma was produced with a faster kinetics than an untreated control. Our data indicate that IFN-alpha promotes the development of a CD8(+) T cell population with enhanced anti-inflammatory activity, which may play a critical role in the regulation of a proper immune response
IFN-α2b reduces IL-2 production and IL-2 receptor function in primary CD4+ T cells
No full textInitially described as an antiviral cytokine, IFN-alpha has been subsequently shown to affect several cellular functions, including cellular differentiation and proliferation. For these reasons, IFN-alpha is currently used in clinical practice for the treatment of viral infections and malignancies. In this manuscript, we show two novel mechanisms concomitantly responsible for the antiproliferative effect of IFN-alpha. First, long-term treatment with IFN-alpha of primary CD4+ T cells reduced surface expression of CD3 and CD28. These events resulted in decreased phosphorylation of the mitogen-activated extracellular signal-regulated activating kinase and its substrate extracellular signal-regulated kinase, leading to diminished production of IL-2. Second, IFN-alpha treatment of primary CD4+ T cells reduced proliferative response to stimulation in the presence of exogenous IL-2 by markedly decreasing mRNA synthesis and surface expression of CD25 (alpha-chain), a critical component of the IL-2R complex. These results may be relevant for the antitumor effects of IFN-alpha and may help us to better understand its detrimental role in the inhibition of proliferation of the bulk of CD4+ T cells (uninfected cells) in HIV-infected persons, who are known to overproduce IFN-alpha
Human primary CD4 + T cells activated in the presence of IFN-alpha 2b express functional indoleamine 2,3-dioxygenase
No full textIndoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the catabolism
of tryptophan. By creating a local microenvironment in which levels of tryptophan
are low, IDO-expressing antigen-presenting cells (APC) could regulate T cell
activation. This may be relevant to control both viral and bacterial replication
as well as neoplastic cell growth. Interferon-alpha (IFN-alpha) is an antiviral
cytokine affecting cellular differentiation. In addition, it reduces
proliferation of CD4(+) T cells by several molecular mechanisms. To dissect the
molecular steps responsible for the INF-mediated antiproliferative activity, we
sought to determine whether activated primary CD4(+) T cells in the presence of
IFN-alpha would produce IDO. We demonstrate here that IDO mRNA is not present in
resting CD4(+) T cells. Stimulation with anti-CD3 plus interleukin-2 (IL-2)
induces expression of IDO mRNA (about 2000 copies/150,000 cells), as determined
by semiquantitative RT-PCR. When cells were stimulated in the presence of
IFN-alpha, expression of IDO mRNA was significantly increased (more than 12,000
copies/150,000 cells). Functional analysis of IDO activity paralleled the results
obtained with RT-PCR, demonstrating increased production of active enzyme in
CD4(+) T cells stimulated in the presence of IFN-alpha. Our results indicate that
IFN-alpha modulates levels of IDO produced by activated CD4(+) T cells. This
would likely affect bystander cells by modifying levels of tryptophan in the
local microenvironment
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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