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Glucocorticoid modulation of the innate antiviral immune response in bronchial epithelial cells
No full textInhaled corticosteroids (ICS), alone or in combination with long acting β2 adrenergic agonists (LABA) are widely prescribed medications for the treatment of chronic pulmonary disorders such as asthma and COPD. Rhinovirus (RV) is the most frequently detected virus during exacerbations. The effect of the standard glucocorticoid (GC) Fluticasone propionate (FP) and selective glucocorticoid receptor (GR) agonists (GRT10) and modulators (GRT7 and GRT8) on pro-inflammatory and antiviral immune responses was investigated in an in vitro model of bronchial epithelial cells (BEAS2B) infected with human rhinovirus 1B (HRV-1B).
The suppression of pro-inflammatory cytokines IL-6 [FP (IC50=0.4nM); GRT7 (IC50=0.3nM); GRT8 (IC50=106nM); GRT10 (IC50=1nM)] and IL-8 [FP (IC50=0.2nM); GRT7 (IC50=0.2nM); GRT8 (IC50=29nM); GRT10 (IC50=0.5nM)] and antiviral cytokine IL-29/IFNλ1 [FP (IC50=0.6nM); GRT7 (IC50=0.4nM); GRT10 (IC50=1nM)] release was assessed by ELISA. Compound GRT8 did not affect IFNλ1 production, showing a different pharmacological profile relative to FP, GRT7 and GRT10. Dose-responsive interferon stimulated gene (ISG) expression was quantified by qRT-PCR. At a concentration of 15nM all tested compounds suppressed viperin [FP (75%); GRT7 (62%); GRT8 (40%); GRT10 (58%)] and OAS [FP (54%); GRT7 (34%); GRT8 (53%); GRT10 (41%)] relative to DMSO. FP, GR7 and GRT10 also increased viral genome replication in a dose-dependent way (~2-fold each at 62nM) by qRT-PCR, whereas no effect was observed with GRT8. In addition, RV replication was measured by endpoint titre determination (TCID50). The viral titre was increased by FP (2.5-fold) and GRT7 (1.7-fold) but unaffected by GRT8 and GRT10 at a concentration of 250nM. Thus, the expected anti-inflammatory effect of FP and also of selective GR ligands was demonstrated, together with a total or partial impairment of RV-induced innate antiviral immune response, which results in an increased viral replication, except with GRT8.
The type I IFN signalling pathway was also explored. Uninfected BEAS2B cells were stimulated with recombinant IFN-β and qRT-PCR and WB analyses performed to assess ISG expression and JAK/STAT activation, respectively. At a concentration of 50nM all tested compounds suppressed viperin [FP (46%); GRT7 (42%); GRT8 (53%); GRT10 (41%)] and OAS [FP (51%); GRT7 (38%); GRT8 (42%); GRT10 (34%)] gene expression relative to control. Specific phosphorylations of STAT1 (pSTAT1 Y701) and STAT2 (pSTAT2 Y690) at tyrosine (Y) residues were also detected. The rapid (within 30 or 60 minutes) inhibition of pSTAT1 Y701 and pSTAT2 Y690, starting from low doses (0.1-1nM) and even without pre-treatment, suggests the standard glucocorticoid FP and selective compounds GRT7, GRT8 and GRT10 interfere with the activated JAK/STAT pathway. No IFN-β induction and no GC inhibition of pSTAT1 serine S727 was observed with FP.
The effect of Budesonide (Bud) and Dexamethasone (Dex), other two standard steroids, clinically administered as ICS and oral corticosteroid (OCS), respectively, in addition to the β2 adrenergic agonist Formoterol (Form), was assessed in RV-infected BEAS2B cells by qRT-PCR. At 1nM concentration, Bud suppressed viperin (92%) similarly to Dex (75%), while Form suppressed viperin to a lesser extent (60%) and at a higher dose (10nM). Bud also suppressed OAS (82%) similarly to Dex (45%) at 1nM concentration, while Form suppressed OAS to a weaker magnitude (45%) at 10nM. Form had no effect on viral genome replication, whereas an increase of HRV-1B RNA was demonstrated with Bud (1.5-fold) at 10nM and Dex (1.9-fold) at 100nM. The combinations (Bud0.1nM/Form10nM) or (Bud0.5nM/Form10nM) were also tested. A potentiated effect on viperin and OAS suppression with (Bud0.1nM/Form10nM) but not with (Bud0.5nM/Form10nM), compared to Bud and Form alone, was observed, suggesting that a reduction of ICS doses in ICS/LABA combinatorial therapy may be beneficial.I corticosteroidi inalatori (ICS), da soli o in combinazione con agonisti β2 adrenergici a lunga durata (LABA) sono farmaci in uso per il trattamento di disordini polmonari cronici quali asma e BPCO. Il rinovirus (RV) è il virus più frequentemente rilevato durante le esacerbazioni. L’effetto del glucocorticoide (GC) standard Fluticasone propionato (FP) e degli agonisti (GRT10) e modulatori (GRT7 and GRT8) selettivi del recettore dei glucocorticoidi (GR) sulle risposte pro-infiammatoria e immunitaria antivirale è stato indagato su cellule epiteliali bronchiali (BEAS2B) infettate in vitro con rinovirus umano 1B (HRV-1B).
La soppressione del rilascio delle citochine pro-infiammatorie IL-6 [FP (IC50=0.4nM); GRT7 (IC50=0.3nM); GRT8 (IC50=106nM); GRT10 (IC50=1nM)] e IL-8 [FP (IC50=0.2nM); GRT7 (IC50=0.2nM); GRT8 (IC50=29nM); GRT10 (IC50=0.5nM)] e della citochina antivirale IL-29/IFNλ1 [FP (IC50=0.6nM); GRT7 (IC50=0.4nM); GRT10 (IC50=1nM)] è stata misurata tramite ELISA. Il composto GRT8 non ha influenzato la produzione di IFNλ1, mostrando un profilo farmacologico differente. L’espressione di geni stimolati da interferone (ISG) e la replicazione virale sono state quantificate mediante qRT-PCR. A 15nM tutti i composti testati hanno soppresso viperin [FP (75%); GRT7 (62%); GRT8 (40%); GRT10 (58%)] e OAS [FP (54%); GRT7 (34%); GRT8 (53%); GRT10 (41%)] rispetto a DMSO. FP, GR7 and GRT10 hanno inoltre aumentato il genoma virale in maniera dose dipendente (~2 volte a 62nM), mentre nessun effetto è stato osservato con GRT8. In aggiunta, determinando il titolo finale (TCID50) virale, è stato osservato un incremento dovuto a FP (2.5 volte) e GRT7 (1.7 volte) ma non a GRT8 e GRT10 a 250nM. Pertanto è stato dimostrato l’atteso effetto anti-infiammatorio di FP, oltre che dei composti selettivi per GR, assieme al totale o parziale indebolimento della risposta immunitaria antivirale innata indotta da RV. Il risultato è una accresciuta replicazione virale, ad eccezione di GRT8.
Il segnale attivato da IFN di tipo I è stato inoltre indagato. Cellule BEAS2B non infettate sono state stimolate con IFN-β ricombinante. A 50nM tutti i composti testati hanno soppresso l’espressione genica di viperin [FP (46%); GRT7 (42%); GRT8 (53%); GRT10 (41%)] e OAS [FP (51%); GRT7 (38%); GRT8 (42%); GRT10 (34%)] rispetto al controllo, tramite qRT-PCR. In aggiunta, specifiche fosforilazioni su residui tirosinici (Y) di STAT1 (pSTAT1 Y701) e STAT2 (pSTAT2 Y690) sono state rivelate tramite WB. La rapida (entro 30 o 60 minuti) inibizione di pSTAT1 Y701 e pSTAT2 Y690, a partire da basse dosi (0.1-1nM) e perfino senza pretrattamento, suggerisce che il GC standard FP e i composti selettivi GRT7, GRT8 e GRT10 interferiscono con il segnale JAK/STAT attivato. Nessuna induzione da IFN-β e nessuna inibizione da GC è stata osservata con FP su pSTAT1 S727.
L’effetto degli steroidi standard Budesonide (Bud) e Dexametasone (Dex), rispettivamente somministrati come ICS e OCS, in aggiunta al LABA Formoterol (Form), è stato valutato mediante qRT-PCR in cellule BEAS2B infettate con RV. A 1nM Bud ha soppresso viperin (92%) similmente a Dex (75%), mentre Form ha soppresso viperin con minore entità (60%) e ad una dose più alta (10nM). Bud ha inoltre soppresso OAS (82%) similmente a Dex (45%) a 1nM, mentre Form ha soppresso OAS con minore entità (45%) a 10nM. Form non ha avuto effetto sulla replicazione del genoma virale, mentre un incremento di HRV-1B RNA è stato dimostrato con Bud (1.5 volte) a 10nM e Dex (1.9 volte) a 100nM. Le combinazioni (Bud0.1nM/Form10nM) o (Bud0.5nM/Form10nM) sono state inoltre testate. Un effetto potenziato sulla soppressione di viperin e OAS con (Bud0.1nM/Form10nM) ma non con (Bud0.5nM/Form10nM) è stato osservato rispetto a Bud e Form da soli, suggerendo un potenziale beneficio con la riduzione delle dosi di ICS nella terapia combinata ICS/LABA
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
Phloridzin derivatives inhibiting proinflammatory cytokine expression in human cystic fibrosis IB3-1 cells
No full textCystic Fibrosis (CF) is the most diffuse autosomal recessive genetic disease present in caucasian people. A persistent recruitment of neutrophils in the bronchi of CF patients contributes to exacerbate the airway tissue damage, suggesting the importance of modulating the expression of chemokines during the patient management. The identification of innovative anti-inflammatory drugs is considered a therapeutic target to prevent the progressive tissue deterioration1. Phloridzin, isolated from Malus domestica by a selective Molecular Imprinting extraction, and its structural analogues, Phloridzin eptaproprionate (F1) and Phloridzin tetraproprionate (F2)2, have been firstly investigated to discover their ability in reducing mainly IL-6 and IL-8 expression, released from CF cells under the control of the NF-kB Transcription Factor (TF), in human CF bronchial epithelial cells (IB3-1) stimulated with TNF-α. Among all the derivatives tested, F2 was the most interesting, demonstrating inhibitory effects also on the expression and production of different cytokines involved in CF inflammation processes, including RANTES, VEGF, GM-CSF, IL-12, G-CSF, MIP-1b, IL-17, IL-10 and IP-10, without any correlated anti- proliferative and pro-apoptotic effects
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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