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The candidate H5N1 vaccine virus NIBRG-14 was created in response to a call from the World Health Organisation in 2004 to prepare candidate vaccine viruses (CVVs) to combat the threat of an H5N1 pandemic. NIBRG-14 was created by reverse genetics and is composed of the neuraminidase (NA) and modified haemagglutinin (HA) genes from A/Vietnam/1194/2004 and the internal genes of PR8, a high growing laboratory adapted influenza A(H1N1) strain. Due to time constraints, the non-coding regions (NCRs) of A/Vietnam/1194/2004 HA were not determined prior to creating NIBRG-14. Consequently, the sequence of the primers used to clone the modified A/Vietnam/1194/2004 HA was based upon previous experience of cloning H5N1 viruses. We report here that the HA 3' NCR sequence of NIBRG-14 is different to that of the parental wild type virus A/Vietnam/1194/2004; however this does not appear to impact on its growth or antigen yield. We introduced additional small changes into the 3'NCR of NIBRG-14; these had only minor effects on viral growth and antigen content. These findings may serve to assure the influenza vaccine community that generation of CVVs using best-guess NCR sequences, based on sequence alignments, are likely to produce robust viruses. 相似文献
994.
MB Henesy AL Britain B Zhu L Amable RE Honkanen JD Corbin SH Francis TC Rich 《PloS one》2012,7(8):e41711
Receptor desensitization is a ubiquitous regulatory mechanism that defines the activatable pool of receptors, and thus, the ability of cells to respond to environmental stimuli. In recent years, the molecular mechanisms controlling the desensitization of a variety of receptors have been established. However, little is known about the molecular mechanisms that underlie desensitization of natriuretic peptide receptors, including natriuretic peptide receptor-A (NPR-A). Here we report that calcineurin (protein phosphatase 2B, PP2B, PPP3C) regulates homologous desensitization of NPR-A in murine Leydig tumor (MA-10) cells. We demonstrate that both pharmacological inhibition of calcineurin activity and siRNA-mediated suppression of calcineurin expression potentiate atrial natriuretic peptide (ANP)-induced cGMP synthesis. Treatment of MA-10 cells with inhibitors of other phosphoprotein phosphatases had little or no effect on ANP-induced cGMP accumulation. In addition, overexpression of calcineurin blunts ANP-induced cGMP synthesis. We also present data indicating that the inhibition of calcineurin potentiates ANP-induced testosterone production. To better understand the contribution of calcineurin in the regulation of NPR-A activity, we examined the kinetics of ANP-induced cGMP signals. We observed transient ANP-induced cGMP signals, even in the presence of phosphodiesterase inhibitors. Inhibition of both calcineurin and phosphodiesterase dramatically slowed the decay in the response. These observations are consistent with a model in which calcineurin mediated dephosphorylation and desensitization of NPR-A is associated with significant inhibition of cGMP synthesis. PDE activity hydrolyzes cGMP, thus lowering intracellular cGMP toward the basal level. Taken together, these data suggest that calcineurin plays a previously unrecognized role in the desensitization of NPR-A and, thereby, inhibits ANP-mediated increases in testosterone production. 相似文献
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B Dave MD Landis LE Dobrolecki MF Wu X Zhang TF Westbrook SG Hilsenbeck D Liu MT Lewis DJ Tweardy JC Chang 《PloS one》2012,7(8):e30207
Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors. 相似文献
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The effect of periphyton stoichiometry and light on biological phosphorus immobilization and release in streams 总被引:1,自引:0,他引:1
W. M. Drake J. Thad Scott Michelle Evans-White Brian Haggard Andrew Sharpley Chris W. Rogers Erin M. Grantz 《Limnology》2012,13(1):97-106
Periphyton stoichiometry can vary substantially as a result of differences in stream nutrient availability. A decrease in
the periphyton carbon to phosphorus (C:P) ratio should decrease the demand for new P to be immobilized from stream water,
but no studies to our knowledge have explored the relationship between periphyton stoichiometry and net P immobilization and
release by periphyton. We sought to model biological P immobilization and release (flux) in streams by measuring periphyton
stoichiometry and light availability. We measured P flux to and from intact periphyton on stream cobbles (20–100 mm diameter)
in 1 L microcosms incubated with streamwater under variable light conditions. Net P immobilization occurred in 75% of microcosms,
net P release occurred in only 5% of microcosms, and 20% of microcosms had neither net immobilization nor net release. When
normalized to stream conditions, net P immobilization was highest when light availability was high (<60% canopy attenuation)
and the periphyton C:P ratio was also high. In contrast, net P release occurred only when light availability was low (>60%
canopy attenuation) and the periphyton C:P ratio was also low. A multiple regression model that included both periphyton stoichiometry
and light availability from the growing season only, and the interaction term of these two variables, explained 99% of the
variation in daily periphyton P flux observed in the study. These results indicate that in order to predict periphyton P immobilization,
periphyton stoichiometry and light availability should be considered together. Furthermore, the results indicate that net
P immobilization occurs even in very P-rich periphyton, which can act as a P sink when light availability is high. 相似文献
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Marta Coll Chiara Piroddi Camille Albouy Frida Ben Rais Lasram William W. L. Cheung Villy Christensen Vasiliki S. Karpouzi François Guilhaumon David Mouillot Michelle Paleczny Maria Lourdes Palomares Jeroen Steenbeek Pablo Trujillo Reg Watson Daniel Pauly 《Global Ecology and Biogeography》2012,21(4):465-480
Aim A large body of knowledge exists on individual anthropogenic threats that have an impact on marine biodiversity in the Mediterranean Sea, although we know little about how these threats accumulate and interact to affect marine species and ecosystems. In this context, we aimed to identify the main areas where the interaction between marine biodiversity and threats is more pronounced and to assess their spatial overlap with current marine protected areas in the Mediterranean. Location Mediterranean Sea. Methods We first identified areas of high biodiversity of marine mammals, marine turtles, seabirds, fishes and commercial or well‐documented invertebrates. We mapped potential areas of high threat where multiple threats are occurring simultaneously. Finally we quantified the areas of conservation concern for biodiversity by looking at the spatial overlap between high biodiversity and high cumulative threats, and we assessed the overlap with protected areas. Results Our results show that areas with high marine biodiversity in the Mediterranean Sea are mainly located along the central and north shores, with lower values in the south‐eastern regions. Areas of potential high cumulative threats are widespread in both the western and eastern basins, with fewer areas located in the south‐eastern region. The interaction between areas of high biodiversity and threats for invertebrates, fishes and large animals in general (including large fishes, marine mammals, marine turtles and seabirds) is concentrated in the coastal areas of Spain, Gulf of Lions, north‐eastern Ligurian Sea, Adriatic Sea, Aegean Sea, south‐eastern Turkey and regions surrounding the Nile Delta and north‐west African coasts. Areas of concern are larger for marine mammal and seabird species. Main conclusions These areas may represent good candidates for further research, management and protection activities, since there is only a maximum 2% overlap between existing marine protected areas (which cover 5% of the Mediterranean Sea) and our predicted areas of conservation concern for biodiversity. 相似文献
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