Veterinary Microbiology
Prostaglandin A1 inhibits the replication of bovine viral diarrhea virus
Lúcio Ayres Caldasa,
, Tânia Rosária Pereira Freitasb, Renata Campos Azevedoc, Wanderley de Souzad
Corresponding author
lucio@biof.ufrj.br
Corresponding author at: Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Ultraestrutura Celular Hertha Meyer, Rio de Janeiro, RJ, Brazil.
Corresponding author at: Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Ultraestrutura Celular Hertha Meyer, Rio de Janeiro, RJ, Brazil.
a Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Rio de Janeiro, RJ, Brazil
b Ministério da Agricultura, Pecuária e Abastecimento, Laboratório Nacional Agropecuário – LANAGRO – MG, Pedro Leopoldo, MG, Brazil
c Universidade Federal do Rio de Janeiro, Instituto de Microbiologia Professor Paulo de Góes, Rio de Janeiro, RJ, Brazil
d Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil
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Infected and non-infected MDBK cells were treated with PGA<span class="elsevierStyleInf">1</span> for 36<span class="elsevierStyleHsp" style=""></span>h, and then processed for routine TEM. Vacuoles (v) were rare or absent in the majority of sections from non-infected cells (A), but were abundant in BVDV-infected cells not treated with PGA<span class="elsevierStyleInf">1</span> (B). Many of these structures exhibited extracellular content, as shown by ruthenium red labeling (arrows) in traditional (C) and <span class="elsevierStyleItalic">en face</span> (D) sections. Treatment with 1<span class="elsevierStyleHsp" style=""></span>μg/mL (E) or 2.5<span class="elsevierStyleHsp" style=""></span>μg/mL (F) PGA<span class="elsevierStyleInf">1</span> could not prevent BVDV-induced vacuolization in infected cells, which had large vacuoles (arrows) with multilamellar structures (arrowheads), and often surrounded by smaller vesicles-containing vacuoles (thin arrows). (G) Treatment with 10<span class="elsevierStyleHsp" style=""></span>g/mL PGA<span class="elsevierStyleInf">1</span>, however, dramatically reduced virus-induced vacuolization. n, nucleus. Scale bars: (A) 5<span class="elsevierStyleHsp" style=""></span>μm; (B, G) 2<span class="elsevierStyleHsp" style=""></span>μm; (C, E) 500<span class="elsevierStyleHsp" style=""></span>nm; (D, F) 1<span class="elsevierStyleHsp" style=""></span>μm.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Bovine viral diarrhea virus (BVDV) is an insidious, complex and ubiquitous pathogen that can affect cattle of all breeds and all ages, as well as others domestic and wild ruminants.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> The disease caused by BVDV ranges in severity from asymptomatic to acute infection and fatal mucosal disease, with a mortality index of approximately 5%, which leads to an economic impact of BVDV infections of up to £993 per cow per year.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In pregnant cows, BVDV can reach the fetus and cause abortion, stillbirth or teratogenic defects, depending on the gestational period when infection was established.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> When the infection is established in the final period of gestation, calves can give birth to immunotolerant and persistently infected calves that are considered reservoirs of the virus.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> Also, the serum of infected animals may contain active BVDV viral particles, which may result in permanent infection in primary cultures and established cell lines that are routinely cultivated using bovine serum, in the laboratory.</p><p id="par0015" class="elsevierStylePara elsevierViewall">BVDV is the type-species of the <span class="elsevierStyleItalic">Pestivirus</span> genus (from the <span class="elsevierStyleItalic">Flaviviridae</span> family) that also includes the border disease virus (BDV) and the classical swine fever virus (CSFV), responsible for significant economic losses worldwide.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> The pestivirus capsid has an icosahedral symmetry formed by a single protein (capsid protein C), and is enveloped by a lipoprotein membrane. Its genome consists of a positive sense, single-stranded RNA of about 12,000 nucleotides, containing a large open reading frame coding for a single polyprotein with about 4000 amino acids. This large polypeptide is cleaved (by host and viral proteases) to generate the capsid protein (C), the glycoproteins Erns, E1 and E2, a non-structural protease (Npro) and a number of other non-structural proteins (p7, NS2/NS3, NS4A, NS4B, NS5A and NS5B). The E2 protein appears to be of major importance for pestivirus neutralization.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">BVDV isolates are divided into the genetic groups BVDV 1 and 2, which are genetically related to a separate species, the BVDV-3 or Hobi group,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> which was initially identified in fetal bovine serum from Brazil.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a> BVDV isolates are also classified into cytopathogenic (cpBVDV) or non-cytopathogenic (ncpBVDV) depending on their ability to cause cytopathic effect in cell culture.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> Birk et al.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> showed that cpBVDV induced extensive vacuolization in Madin-Darby bovine kidney (MDBK) cells; however, this phenomenon appeared morphologically different from that observed in apoptosis and necrosis.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Prostaglandins are natural eicosanoids secreted by a variety of human tissues and capable of causing profound and diverse physiological effects at very low concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways. Prostaglandin A<span class="elsevierStyleInf">1</span> (PGA<span class="elsevierStyleInf">1</span>) is capable of blocking the replication of a wide variety of RNA and DNA viruses, including CSFV.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">9–11</span></a> Despite the importance of BVDV for animal health, the effect of PGA<span class="elsevierStyleInf">1</span> on BVDV replication has not been examined. Therefore, we evaluate the effect of PGA<span class="elsevierStyleInf">1</span> on the replication of cpBVDV in MDBK cells, focusing on changes in BVDV-induced vacuolization.</p><p id="par0035" class="elsevierStylePara elsevierViewall">MDBK cells were cultured <span class="elsevierStyleItalic">in vitro</span> in Dulbecco Modified Eagle Medium (DMEM), supplemented with 10% BVDV-free fetal bovine serum (FBS, Gibco), penicillin (500<span class="elsevierStyleHsp" style=""></span>U/mL), streptomycin (100<span class="elsevierStyleHsp" style=""></span>μg/mL) and amphotericin B (fungizone, at 2.5<span class="elsevierStyleHsp" style=""></span>μg/mL).</p><p id="par0040" class="elsevierStylePara elsevierViewall">Monolayers of MDBK cells were infected with cpBVDV-1 (NADL strain) at a multiplicity of infection of 0.1. Viral particles were allowed to interact with host cells for 1<span class="elsevierStyleHsp" style=""></span>h in the absence of FBS, and then the supernatant was replaced with complete growth medium containing 0.1, 1, 2.5, 5 or 10<span class="elsevierStyleHsp" style=""></span>μg/mL Prostaglandin A<span class="elsevierStyleInf">1</span> (PGA<span class="elsevierStyleInf">1</span>, Sigma Chemical Co.; stored as a 1<span class="elsevierStyleHsp" style=""></span>mg/mL solution in 100% ethanol). After treatment of monolayers with PGA<span class="elsevierStyleInf">1</span> for 36<span class="elsevierStyleHsp" style=""></span>h, culture supernatants were tested for the presence of virus by 50% tissue culture infective dose (TCID50) titration, and cell monolayers were fixed and stained with the Panoptic Solution Kit<span class="elsevierStyleSup">®</span> (Laborclin Ltda. Pinhais/PR, Brazil). Panoptic-stained monolayers were observed in a Zeiss-Observer D1 light microscope equipped with a Nomarski differential interferential contrast system.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Cell viability was determined by incubating monolayers in a solution containing 5<span class="elsevierStyleHsp" style=""></span>μg/mL Neutral red (diluted in PBS) for 3<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>°C, in wells of 96-well plates. Then, the solution was discarded, and cells were incubated with 4% formaldehyde (in PBS) for 1<span class="elsevierStyleHsp" style=""></span>min, and 100% methanol for 20<span class="elsevierStyleHsp" style=""></span>min. Samples were analyzed by absorbance at 490<span class="elsevierStyleHsp" style=""></span>nm, in an ELISA plate reader (SpectraMax M2).</p><p id="par0050" class="elsevierStylePara elsevierViewall">For transmission electron microscopy (TEM) analysis, treated and untreated monolayers in 25<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> plastic culture flasks were fixed in 2.5% glutaraldehyde in 0.1<span class="elsevierStyleHsp" style=""></span>M cacodylate buffer (pH 7.2), post-fixed for 1<span class="elsevierStyleHsp" style=""></span>h in 1% OsO<span class="elsevierStyleInf">4</span>/0.8% potassium ferrocyanide in the same buffer, dehydrated in ethanol and ‘flat-embedded’ in Polybed resin (Polysciences1), to preserve the cell architecture. Ultrathin sections (both routine, and <span class="elsevierStyleItalic">en face</span>) were stained with uranyl acetate and lead citrate and observed in a FEI Tecnai T20 transmission electron microscope.</p><p id="par0055" class="elsevierStylePara elsevierViewall">For the visualization of extracellular lamellae by TEM, 0.5<span class="elsevierStyleHsp" style=""></span>mg/mL ruthenium red was added to the TEM fixation and post-fixation solutions (as well as to the intermediate washes in cacodylate buffer), and cells were processed for TEM as described above. This procedure was also performed during en face sectioning, in order to avoid removal of the cells from the substratum, which could disrupt and disorient their architecture.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Treatment of BVDV-infected MDBK monolayers with PGA<span class="elsevierStyleInf">1</span> at concentrations of 0.1 and 0.5<span class="elsevierStyleHsp" style=""></span>μg/mL reduced the virus yield in culture supernatants by 50%, and treatment with the highest concentration of PGA<span class="elsevierStyleInf">1</span> tested in this assay (5<span class="elsevierStyleHsp" style=""></span>μg/mL) reduced the viral yield by 94% (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Thus, PGA<span class="elsevierStyleInf">1</span> treatment resulted in strong inhibition of BVDV replication in MDBK cells.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In light microscopy images, similar cytoplasmic alterations were observed in untreated and PGA<span class="elsevierStyleInf">1</span>-treated cells (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Although treatment with 5<span class="elsevierStyleHsp" style=""></span>μg/mL decreased by almost 2 logs the virus titration in the supernatant of infected cells (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), vacuolization was not inhibited by PGA<span class="elsevierStyleInf">1</span> at this concentration (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E). A reduction in vacuolization was only detectable when cells were treated with 10<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>F). At this concentration, treatment of MDBK cells with PGA<span class="elsevierStyleInf">1</span> for 36<span class="elsevierStyleHsp" style=""></span>h did not result in cytotoxicity, as determined by microscopic examination or vital dye exclusion (data not shown).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The cytosolic vacuoles induced by BVDV infection were further investigated by transmission electron microscopy analysis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). BVDV infection induced a dramatic increase in vacuolar structures in MDBK cells (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). When viewed in both traditional and <span class="elsevierStyleItalic">en face</span> sections, many of the vesicles in infected cells were positive for ruthenium red and, thus, contained extracellular material (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C and D). One of the main features that we observed in BVDV-infected cells was the presence of multilamellar structures inside vacuoles (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C, E and F), while smaller vacuoles with internal vesicles surrounded those with multilamellar structures (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>E, F). Multilamellar structures were previously reported by Sanz-Sanchez and Risco, where they were linked to a cellular response to detachment from substratum due to bunyavirus infection.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> Despite the strong reduction in BVDV replication achieved by treatment with 5<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), this PGA<span class="elsevierStyleInf">1</span> concentration did not prevent vacuolization in BVDV-infected cells (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E). A strong reduction of virus-induced vacuolization was only achieved after treatment with 10<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>G).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Although prostaglandins (PGs) are capable of inhibiting the replication of a variety of RNA and DNA viruses, their mode of action is not entirely clear.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">9–11</span></a> In some systems, PGAs exert potent antiviral activity by inducing the synthesis of proteins from the heat shock protein 70 (HSP70) family, through cycloheximide-sensitive activation of a heat-shock trigger factor.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The reduction of virus-induced vacuolization after PGA<span class="elsevierStyleInf">1</span> treatment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>G) is in agreement with the widely described antiviral effect of this drug.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> This activity, initially attributed to the induction of HSP-70 proteins, can also be triggered by other pathways, such as nuclear factor-κ B regulation<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">13,14</span></a> and, more recently, by a mechanism targeting the small ribosomal subunit (40S) and the eukaryotic initiation factors eIF3s.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> This virus-induced vacuolization seems not to be crucial for viral replication and is probably caused by the interference of BVDV NS3 protein on the smooth endoplasmic reticulum.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a> Furthermore, the targeting of viral proteins by cyclopentenone prostaglandins was already reported by Kalantari et al.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The fact that treatment with 5<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> inhibited BVDV production 94%, but did not block virus-induced vacuolization in host cells suggests that the vacuoles are, indeed, not involved in viral replication and that PGA<span class="elsevierStyleInf">1</span> probably reached its saturation point. Our data suggest that the antiviral activity of PGA<span class="elsevierStyleInf">1</span> is not associated with the inhibition of vacuole production, although the viral-induced vacuoles almost disappeared when higher concentrations of PGA<span class="elsevierStyleInf">1</span> were used.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Our work shows that the antiviral activity of PGA<span class="elsevierStyleInf">1</span> during BVDV interaction with MDBK cells does not rely on a significant reduction in virus-induced cytoplasmic vacuolization, but in the viral titers reduction. Since the antiviral effects of PGs on BVDV had not been described, this is the first report of the parameters involved in the protection of MDBK cells from BVDV infection.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">This work was supported by <span class="elsevierStyleGrantSponsor" id="gs1">Programa Nacional de Apoio ao Desenvolvimento da Metrologia</span>, <span class="elsevierStyleGrantSponsor" id="gs2">Qualidade e Tecnologia (Pronametro) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)</span>.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:3 [ "identificador" => "xres1091250" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1034372" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-09-22" "fechaAceptado" => "2017-12-28" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1034372" "palabras" => array:5 [ 0 => "Bovine viral diarrhea virus" 1 => "BVDV" 2 => "Prostaglandins" 3 => "Prostaglandin A<span class="elsevierStyleInf">1</span>" 4 => "Virus-induced vacuolization" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bovine viral diarrhea virus can cause acute disease in livestock, leading to economic losses. We show that Prostaglandin A<span class="elsevierStyleInf">1</span> inhibits bovine viral diarrhea virus replication in Madin-Darby bovine kidney cells (94% inhibition using 5<span class="elsevierStyleHsp" style=""></span>μg/mL). Light and electron microscopy of infected cells shows that Prostaglandin A<span class="elsevierStyleInf">1</span> also prevents virus-induced vacuolization, but at higher concentrations (10<span class="elsevierStyleHsp" style=""></span>μg/mL).</p></span>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2858 "Ancho" => 2500 "Tamanyo" => 934356 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Light microscopy analysis of bovine viral diarrhea virus (BVDV) infected cells treated with prostaglandin A<span class="elsevierStyleInf">1</span> (PGA<span class="elsevierStyleInf">1</span>). MDBK cells were treated with PGA<span class="elsevierStyleInf">1</span> for 36<span class="elsevierStyleHsp" style=""></span>h, and then subjected to panoptic staining. Low and high magnification images of untreated mock-infected cells (A, B), and of infected cells kept untreated (C, D) or treated with 5 (E) and 10 (F) μg/mL PGA<span class="elsevierStyleInf">1</span>. Although 5<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> strongly blocked BVDV replication (E), it did not inhibit the vacuolization process (arrows). Vacuolization inhibition was only achieved after treatment with 10<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> (F). Scale bars: 8<span class="elsevierStyleHsp" style=""></span>μm.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3301 "Ancho" => 2500 "Tamanyo" => 2238447 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Transmission electron microscopy (TEM) analysis of bovine viral diarrhea virus (BVDV)-infected cells treated with prostaglandin A<span class="elsevierStyleInf">1</span> (PGA<span class="elsevierStyleInf">1</span>). Infected and non-infected MDBK cells were treated with PGA<span class="elsevierStyleInf">1</span> for 36<span class="elsevierStyleHsp" style=""></span>h, and then processed for routine TEM. Vacuoles (v) were rare or absent in the majority of sections from non-infected cells (A), but were abundant in BVDV-infected cells not treated with PGA<span class="elsevierStyleInf">1</span> (B). Many of these structures exhibited extracellular content, as shown by ruthenium red labeling (arrows) in traditional (C) and <span class="elsevierStyleItalic">en face</span> (D) sections. Treatment with 1<span class="elsevierStyleHsp" style=""></span>μg/mL (E) or 2.5<span class="elsevierStyleHsp" style=""></span>μg/mL (F) PGA<span class="elsevierStyleInf">1</span> could not prevent BVDV-induced vacuolization in infected cells, which had large vacuoles (arrows) with multilamellar structures (arrowheads), and often surrounded by smaller vesicles-containing vacuoles (thin arrows). (G) Treatment with 10<span class="elsevierStyleHsp" style=""></span>g/mL PGA<span class="elsevierStyleInf">1</span>, however, dramatically reduced virus-induced vacuolization. n, nucleus. Scale bars: (A) 5<span class="elsevierStyleHsp" style=""></span>μm; (B, G) 2<span class="elsevierStyleHsp" style=""></span>μm; (C, E) 500<span class="elsevierStyleHsp" style=""></span>nm; (D, F) 1<span class="elsevierStyleHsp" style=""></span>μm.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">MDBK cells were infected with BVDV and treated with different concentrations of PGA<span class="elsevierStyleInf">1</span>. The percentage of BVDV replication inhibition was calculated by measuring the virus yield in the supernatant of infected cells 36<span class="elsevierStyleHsp" style=""></span>h after PGA<span class="elsevierStyleInf">1</span> treatment. While 1.0<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span> inhibited 50% of BDVD production, the highest concentration tested in this assay (5<span class="elsevierStyleHsp" style=""></span>μg/mL PGA<span class="elsevierStyleInf">1</span>) blocked replication by >90%.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PGA<span class="elsevierStyleInf">1</span> concentration (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">TCID<span class="elsevierStyleInf">50</span>/mL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% Inhibition \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleItalic">0</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleItalic">0.5</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.6<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">4</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleItalic">1.0</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">4</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleItalic">2.5</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.9<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">4</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.3<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">94 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1865909.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Effect of prostaglandin A<span class="elsevierStyleInf">1</span> (PGA<span class="elsevierStyleInf">1</span>) on bovine viral diarrhea virus (BVDV) replication in MDBK cells, expressed as the TCID<span class="elsevierStyleInf">50</span> and the percentage of replication inhibition.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bovine viral diarrhoea virus: biology, diagnosis and control" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 16 | 0 | 16 |
| 2024 October | 56 | 6 | 62 |
| 2024 September | 35 | 2 | 37 |
| 2024 August | 38 | 5 | 43 |
| 2024 July | 20 | 5 | 25 |
| 2024 June | 16 | 2 | 18 |
| 2024 May | 17 | 7 | 24 |
| 2024 April | 31 | 3 | 34 |
| 2024 March | 23 | 5 | 28 |
| 2024 February | 16 | 8 | 24 |
| 2024 January | 94 | 12 | 106 |
| 2023 December | 39 | 19 | 58 |
| 2023 November | 38 | 4 | 42 |
| 2023 October | 78 | 7 | 85 |
| 2023 September | 44 | 3 | 47 |
| 2023 August | 56 | 3 | 59 |
| 2023 July | 40 | 4 | 44 |
| 2023 June | 57 | 2 | 59 |
| 2023 May | 80 | 4 | 84 |
| 2023 April | 65 | 1 | 66 |
| 2023 March | 55 | 4 | 59 |
| 2023 February | 39 | 10 | 49 |
| 2023 January | 38 | 6 | 44 |
| 2022 December | 47 | 7 | 54 |
| 2022 November | 39 | 10 | 49 |
| 2022 October | 40 | 6 | 46 |
| 2022 September | 29 | 14 | 43 |
| 2022 August | 40 | 14 | 54 |
| 2022 July | 30 | 8 | 38 |
| 2022 June | 28 | 20 | 48 |
| 2022 May | 28 | 7 | 35 |
| 2022 April | 51 | 12 | 63 |
| 2022 March | 51 | 15 | 66 |
| 2022 February | 28 | 12 | 40 |
| 2022 January | 57 | 35 | 92 |
| 2021 December | 23 | 23 | 46 |
| 2021 November | 59 | 11 | 70 |
| 2021 October | 56 | 16 | 72 |
| 2021 September | 34 | 16 | 50 |
| 2021 August | 52 | 12 | 64 |
| 2021 July | 27 | 8 | 35 |
| 2021 June | 28 | 10 | 38 |
| 2021 May | 32 | 10 | 42 |
| 2021 April | 77 | 22 | 99 |
| 2021 March | 27 | 11 | 38 |
| 2021 February | 31 | 8 | 39 |
| 2021 January | 37 | 13 | 50 |
| 2020 December | 34 | 10 | 44 |
| 2020 November | 29 | 6 | 35 |
| 2020 October | 27 | 9 | 36 |
| 2020 September | 27 | 9 | 36 |
| 2020 August | 21 | 21 | 42 |
| 2020 July | 24 | 15 | 39 |
| 2020 June | 17 | 9 | 26 |
| 2020 May | 20 | 15 | 35 |
| 2020 April | 20 | 9 | 29 |
| 2020 March | 13 | 14 | 27 |
| 2020 February | 17 | 16 | 33 |
| 2020 January | 13 | 14 | 27 |
| 2019 December | 17 | 18 | 35 |
| 2019 November | 16 | 12 | 28 |
| 2019 October | 21 | 14 | 35 |
| 2019 September | 21 | 17 | 38 |
| 2019 August | 9 | 3 | 12 |
| 2019 July | 12 | 16 | 28 |
| 2019 June | 14 | 9 | 23 |
| 2019 May | 7 | 11 | 18 |
| 2019 February | 1 | 1 | 2 |
| 2018 November | 107 | 23 | 130 |
| 2018 October | 34 | 17 | 51 |
| 2018 September | 0 | 12 | 12 |
| 2018 August | 0 | 15 | 15 |
| 2018 July | 0 | 11 | 11 |
| 2018 June | 0 | 10 | 10 |
| 2018 May | 0 | 7 | 7 |
| 2018 April | 0 | 20 | 20 |
| 2018 March | 0 | 24 | 24 |
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