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Hatta Y Hershberger K Shinya K Proll SC Dubielzig RR Hatta M Katze MG Kawaoka Y Suresh M 《PLoS pathogens》2010,6(10):e1001139
Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans. 相似文献
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A multiplex real-time PCR assay was developed using molecular beacons for the detection of Vibrio cholerae by targeting four important virulence and regulatory genes. The specificity and sensitivity of this assay, when tested with pure culture and spiked environmental water samples, were high, surpassing those of currently published PCR assays for the detection of this organism. 相似文献
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1. After a wash-out period of 20 min with Krebs-Henseleit-buffer a 20 cm segment of proximal or distal small intestine of nonanaesthesized rats got a bolus infusion of 3 ml either triglycine, diglycine, glycine or an equimolar mixture of diglycine and glycine, respectively, in a concentration range of 20 to 1000 mmol/l glycine equivalents. With 9 ml of a peptide and amino acid free solution the gut was perfused in a single-pass perfusion and the whole fluid recovered was investigated by quantitative thin layer chromatography for triglycine, diglycine and glycine. 2. In the concentration range up to 170 mmol/l glycine equivalents the nitrogen absorption is independent of the substrates perfused. In the highest concentration range an additional increased disappearance of triglycine could be found. This change cannot be observed to the same extent for diglycine, glycine or the mixture of both. In contrast, in the highest concentration range the competition between glycine and diglycine results in a decrease of absorption. 3. The proximal or distal nitrogen absorption of all substrates is similar. 4. In the perfusate the peptide and its splitting products were investigated. 5. Based on the discrepancy between the disappearance of triglycine and the appearance of its splitting products it is assumed. 1. that the transport of intact triglycine is of quantitative importance in the highest concentration range and 2. that in the lower concentration range membrane digestion followed the transport of the splitting products prevails. 6. Extending Ugoley's model for dipeptides three general variations for membrane digestion of tripeptides are proposed. One of this is likely for the triglycine absorption. 相似文献
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Numerous transposed sequences of mitochondrial cytochrome oxidase I-II in aphids of the genus Sitobion (Hemiptera: Aphididae) 总被引:4,自引:1,他引:3
Polymerase chain reaction (PCR) products corresponding to 803 bp of the
cytochrome oxidase subunits I and II region of mitochondrial DNA (mtDNA
COI-II) were deduced to consist of multiple haplotypes in three Sitobion
species. We investigated the molecular basis of these observations. PCR
products were cloned, and six clones from one individual per species were
sequenced. In each individual, one sequence was found commonly, but also
two or three divergent sequences were seen. The divergent sequences were
shown to be nonmitochondrial by sequencing from purified mtDNA and Southern
blotting experiments. All seven nonmitochondrial clones sequenced to
completion were unique. Nonmitochondrial sequences have a high proportion
of unique sites, and very few characters are shared between
nonmitochondrial clones to the exclusion of mtDNA. From these data, we
infer that fragments of mtDNA have been transposed separately (probably
into aphid chromosomes), at a frequency only known to be equalled in
humans. The transposition phenomenon appears to occur infrequently or not
at all in closely related genera and other aphids investigated. Patterns of
nucleotide substitution in mtDNA inferred over a parsimony tree are very
different from those in transposed sequences. Compared with mtDNA,
nonmitochondrial sequences have less codon position bias, more even
exchanges between A, G, C and T, and a higher proportion of nonsynonymous
replacements. Although these data are consistent with the transposed
sequences being under less constraint than mtDNA, changes in the
nonmitochondrial sequences are not random: there remains significant
position bias, and probable excesses of synonymous replacements and of
conservative inferred amino acid replacements. We conclude that a
proportion of the inferred change in the nonmitochondrial sequences
occurred before transposition. We believe that Sitobion aphids (and other
species exhibiting mtDNA transposition) may be important for studying the
molecular evolution of mtDNA and pseudogenes. However, our data highlight
the need to establish the true evolutionary relationships between sequences
in comparative investigations.
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Guido Bischoff Zoltan B?r?cz Christian Proll Johannes Kleinheinz Gert von Bally Dieter Dirksen 《Biomedizinische Technik》2007,52(4):284-289
Optical topometric 3D sensors such as laser scanners and fringe projection systems allow detailed digital acquisition of human body surfaces. For many medical applications, however, not only the current shape is important, but also its changes, e.g., in the course of surgical treatment. In such cases, time delays of several months between subsequent measurements frequently occur. A modular 3D coordinate measuring system based on the fringe projection technique is presented that allows 3D coordinate acquisition including calibrated color information, as well as the detection and visualization of deviations between subsequent measurements. In addition, parameters describing the symmetry of body structures are determined. The quantitative results of the analysis may be used as a basis for objective documentation of surgical therapy. The system is designed in a modular way, and thus, depending on the object of investigation, two or three cameras with different capabilities in terms of resolution and color reproduction can be utilized to optimize the set-up. 相似文献
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Deep Sequencing of HIV-Infected Cells: Insights into Nascent Transcription and Host-Directed Therapy