Browsing by Issue Date, starting with "2014-07-21"
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- Influenza A(H1N1)pdm09 resistance and cross-decreased susceptibility to oseltamivir and zanamivir antiviral drugsPublication . Correia, V.; Santos, L.; Gíria, M.; Almeida-Santos, M.; Rebelo-de-Andrade, H.Neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are currently the only effective antiviral drugs available worldwide for the management of influenza. The potential development of resistance is continually threatening their use, rationalizing and highlighting the need for a close and sustained evaluation of virus susceptibility. This study aimed to analyze and characterize the phenotypic and genotypic NAIs susceptibility profiles of A(H1N1)pdm09 viruses circulating in Portugal from 2009 to 2010/2011. A total of 144 cases of A(H1N1)pdm09 virus infection from community and hospitalized patients were studied, including three suspected cases of clinical resistance to oseltamivir. Oseltamivir resistance was confirmed for two of the suspected cases. Neuraminidase (NA) H275Y resistant marker was found in viruses from both cases but for one it was only present in 26.2% of virus population, raising questions about the minimal percentage of resistant virus that should be considered relevant. Cross-decreased susceptibility to oseltamivir and zanamivir (2-4 IC50 fold-change) was detected on viruses from two potentially linked community patients from 2009. Both viruses harbored the NA I223V mutation. NA Y155H mutation was found in 18 statistical non-outlier viruses from 2009, having no impact on virus susceptibility. The mutations at NA N369K and V241I may have contributed to the significantly higher baseline IC50 value obtained to oseltamivir for 2010/2011 viruses, compared to viruses from the pandemic period. These results may contribute to a better understanding of the relationship between phenotype and genotype, which is currently challenging, and to the global assessment of A(H1N1)pdm09 virus susceptibility profile and baseline level to NAIs.
- Translational inhibitory conditions and mechanistic target of rapamycin (mTOR) protein expression – an internal ribosome entry site (IRES) solves the problemPublication . Marques-Ramos, Ana; Menezes, Juliane; Lacerda, Rafaela; Teixeira, Alexandre; Romão, LuísaRegulation of mRNA translation plays a major role in controlling gene expression, since it allows rapid cellular responses to external stimuli. Translational control can be transcript-specific via cis-acting elements, such as internal ribosome entry sites (IRESs). mRNA translation initiation driven by IRES elements is independent of some canonical initiation factors that are inhibited by cellular stresses or in some physiological/pathophysiologic settings. Accordingly, IRES-dependent translation allows continued protein synthesis in conditions of global canonical mRNA translation inhibition. The mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase that senses cellular nutrient- and energy- status, acting namely on the protein synthesis machinery. Major advances are emerging regarding the effects and regulators of mTOR signaling pathway, however, regulation of mTOR gene expression, specifically at the translational level, is not well known. Here, it is shown that the 5’ untranslated region (5’UTR) of the human mTOR mRNA contains an IRES element that allows cap-independent translation of mTOR. In addition, it is demonstrated that IRES-dependent translation of mTOR is stimulated by hypoxia with associated eIF2α phosphorylation. The anti- and pro-apoptotic outcomes of the response to endoplasmic reticulum (ER) stress also stimulate mTOR IRES activity, with a more pronounced effect in the pro-apoptotic phase with associated eIF2α phosphorylation. Furthermore, it is illustrated that mTOR IRES activity is potentiated by mTORC1 inactivation, suggesting a feedback loop in order to maintain mTOR expression. These data point out a novel regulatory mechanism of mTOR gene expression that integrates the protein profile rearrangement triggered by global translational inhibitory conditions.
- Microarray em diagnóstico pré-natalPublication . Correia, Hildeberto