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361.
The pyoverdin receptor FpvA, a TonB-dependent receptor involved in iron uptake by Pseudomonas aeruginosa (review) 总被引:1,自引:0,他引:1
Folschweiller N Schalk IJ Celia H Kieffer B Abdallah MA Pattus F 《Molecular membrane biology》2000,17(3):123-133
Iron is an important element, essential for the growth of almost all living cells. Because of the high insolubility of iron(III) in aerobic conditions, many gram-negative bacteria produce, under iron limitation, small iron-chelating compounds called siderophores, together with new outer-membrane proteins, which function as receptors for the ferrisiderophores. Pseudomonas aeruginosa, an important human opportunistic pathogen, produces at least three known siderophores when grown in iron-deficient conditions: pyochelin, salicylate and pyoverdin. This review focuses on pyoverdin and on the ability of FpvA to bind iron-free and ferric-PaA pyoverdin, in the light of recent information gained from biochemical and biophysical studies and of the recently solved 3D-structures of the related ferrichrome FhuA and enterobactin FepA receptors in Escherichia coli. 相似文献
362.
JC Sullivan EZ Zhang DJ Bartels A Tigges JL Dorrian AD Kwong TL Kieffer 《Virology journal》2012,9(1):147
ABSTRACT: BACKGROUND: Development of compensatory mutations within the HIV p7/p1 and p1/p6 protease cleavage site region has been observed in HIV-infected patients treated with protease inhibitors. Mechanisms of fitness compensation may occur in HCV populations upon treatment of HCV protease inhibitors as well. FINDINGS: In this study, we investigated whether substitutions in protease cleavage site regions of HCV occur in response to a treatment regimen containing the NS3/4A protease inhibitor telaprevir (TVR). Evaluation of viral populations from 569 patients prior to treatment showed that the four NS3/4A cleavage sites were well conserved. Few changes in the cleavage site regions were observed in the 159 patients who failed TVR combination treatment, and no residues displayed evidence of directional selection after the acquisition of TVR-resistance. CONCLUSIONS: Cleavage site mutations did not occur after treatment with the HCV protease inhibitor telaprevir. 相似文献
363.
Adiwijaya BS Kieffer TL Henshaw J Eisenhauer K Kimko H Alam JJ Kauffman RS Garg V 《PLoS computational biology》2012,8(1):e1002339
We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents. 相似文献
364.
XV Thomas J de Bruijne JC Sullivan TL Kieffer CK Ho SP Rebers M de Vries HW Reesink CJ Weegink R Molenkamp J Schinkel 《PloS one》2012,7(7):e41191
Background & Aims
Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment.Methods
Fifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103) were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline.Results
Resistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing.Conclusion
In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare. 相似文献365.
366.
The swimming performance of juvenile shortnose sturgeon (~16 cm TL, ~20 g), Acipenser brevirostrum, was quantified with regards to temperature (5 to 25°C) using both increased (Ucrit) and fixed velocity (endurance) tests in a laboratory setting. Sturgeons were found to show reduced Ucrit values at 5 and 10°C (25.99 and 28.86 cm s?1 respectively), with performance beginning to plateau at 15°C through 25°C (33.99 cm s?1). For the endurance protocol, fish were tested at speeds of 35, 40 and 45 cm s?1 at 5, 15 and 25°C. Performance within a single speed was similar at all temperatures, indicating the usage of anaerobic metabolism to fuel locomotion at these higher velocities. Overall, shortnose sturgeon demonstrated high tolerance towards a wide range of temperatures but showed few differences between performance levels at colder or warmer water conditions. 相似文献
367.
SET8-mediated methylations of histone H4 lysine 20 mark silent heterochromatic domains in apicomplexan genomes 总被引:4,自引:0,他引:4 下载免费PDF全文
Sautel CF Cannella D Bastien O Kieffer S Aldebert D Garin J Tardieux I Belrhali H Hakimi MA 《Molecular and cellular biology》2007,27(16):5711-5724
Posttranslational histone modifications modulate chromatin-templated processes in various biological systems. H4K20 methylation is considered to have an evolutionarily ancient role in DNA repair and genome integrity, while its function in heterochromatin function and gene expression is thought to have arisen later during evolution. Here, we identify and characterize H4K20 methylases of the Set8 family in Plasmodium and Toxoplasma, two medically important members of the protozoan phylum Apicomplexa. Remarkably, parasite Set8-related proteins display H4K20 mono-, di-, and trimethylase activities, in striking contrast to the monomethylase-restricted human Set8. Structurally, few residues forming the substrate-specific channel dictate enzyme methylation multiplicity. These enzymes are cell cycle regulated and focally enriched at pericentric and telomeric heterochromatin in both parasites. Collectively, our findings provide new insights into the evolution of Set8-mediated biochemical pathways, suggesting that the heterochromatic function of the marker is not restricted to metazoans. Thus, these lower eukaryotes have developed a diverse panel of biological stages through their high capacity to differentiate, and epigenetics only begins to emerge as a strong determinant of their biology. 相似文献
368.
Background
Genetic variation in the human population is a key determinant of influenza disease severity. A single nucleotide polymorphism in the antiviral gene IFITM3 was linked to outcomes during the 2009 H1N1 pandemic. To identify variant host genes associated with increased virus replication and severe disease, we performed a quantitative trait locus analysis on pro-inflammatory cytokine production 48 hours after intranasal infection with highly pathogenic H5N1 influenza virus.Results
Pro-inflammatory cytokines CCL2, TNFα and IFN-α, were measured by ELISA in lung homogenates of DBA/2J (D2), C57BL/6J (B6) and 44 different BXD recombinant inbred mouse strains. Virus titer was also assessed in a subset of these animals. CCL2 (8-fold), TNFα (24-fold) and IFN-α (8-fold) concentrations varied significantly among the different BXD RI strains. Importantly, cytokine concentration correlated very well (r =0.86-0.96, P <0.0001) with virus titer suggesting that early cytokine production is due to increased virus infection and replication. Linkage analysis of cytokine concentration revealed a significant locus on chromosome 6 associated with differences in TNFα, IFN-α and CCL2 cytokine concentration (LRS =26). This locus accounted for nearly 20% of the observed phenotypic variation in the BXD population studied. Sequence and RNA expression analysis identified several candidate host genes containing missense mutations or deletions; Samd9l, Ica1, and Slc25a13. To study the role of Slc25a13, we obtained Slc25a13 knockout line, but upon challenge with H5N1 influenza virus observed no effect on CCL2 production, or morbidity and mortality.Conclusion
A novel genetic locus on chromosome 6 modulates early pro-inflammatory cytokine production and virus replication after highly pathogenic influenza virus infection. Candidate genes, Samd9l and Ica1, may be important for the control of influenza virus infection and pathogenesis.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1017) contains supplementary material, which is available to authorized users. 相似文献369.
Eric L. Haseltine Sandra De Meyer Inge Dierynck Doug J. Bartels Anne Ghys Andrew Davis Eileen Z. Zhang Ann M. Tigges Joan Spanks Gaston Picchio Tara L. Kieffer James C. Sullivan 《PLoS computational biology》2014,10(8)
For patients infected with hepatitis C virus (HCV), the combination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and ribavirin (RBV) significantly increases the chances of sustained virologic response (SVR) over treatment with Peg-IFN and RBV alone. If patients do not achieve SVR with telaprevir-based treatment, their viral population is often significantly enriched with telaprevir-resistant variants at the end of treatment. We sought to quantify the evolutionary dynamics of these post-treatment resistant variant populations. Previous estimates of these dynamics were limited by analyzing only population sequence data (20% sensitivity, qualitative resistance information) from 388 patients enrolled in Phase 3 clinical studies. Here we add clonal sequence analysis (5% sensitivity, quantitative) for a subset of these patients. We developed a computational model which integrates both the qualitative and quantitative sequence data, and which forms a framework for future analyses of drug resistance. The model was qualified by showing that deep-sequence data (1% sensitivity) from a subset of these patients are consistent with model predictions. When determining the median time for viral populations to revert to 20% resistance in these patients, the model predicts 8.3 (95% CI: 7.6, 8.4) months versus 10.7 (9.9, 12.8) months estimated using solely population sequence data for genotype 1a, and 1.0 (0.0, 1.4) months versus 0.9 (0.0, 2.7) months for genotype 1b. For each individual patient, the time to revert to 20% resistance predicted by the model was typically comparable to or faster than that estimated using solely population sequence data. Furthermore, the model predicts a median of 11.0 and 2.1 months after treatment failure for viral populations to revert to 99% wild-type in patients with HCV genotypes 1a or 1b, respectively. Our modeling approach provides a framework for projecting accurate, quantitative assessment of HCV resistance dynamics from a data set consisting of largely qualitative information. 相似文献
370.