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1.
NF Gnädig S Beaucourt G Campagnola AV Bordería M Sanz-Ramos P Gong H Blanc OB Peersen M Vignuzzi 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(34):E2294-E2303
Based on structural data of the RNA-dependent RNA polymerase, rational targeting of key residues, and screens for Coxsackievirus B3 fidelity variants, we isolated nine polymerase variants with mutator phenotypes, which allowed us to probe the effects of lowering fidelity on virus replication, mutability, and in vivo fitness. These mutator strains generate higher mutation frequencies than WT virus and are more sensitive to mutagenic treatments, and their purified polymerases present lower-fidelity profiles in an in vitro incorporation assay. Whereas these strains replicate with WT-like kinetics in tissue culture, in vivo infections reveal a strong correlation between mutation frequency and fitness. Variants with the highest mutation frequencies are less fit in vivo and fail to productively infect important target organs, such as the heart or pancreas. Furthermore, whereas WT virus is readily detectable in target organs 30 d after infection, some variants fail to successfully establish persistent infections. Our results show that, although mutator strains are sufficiently fit when grown in large population size, their fitness is greatly impacted when subjected to severe bottlenecking, which would occur during in vivo infection. The data indicate that, although RNA viruses have extreme mutation frequencies to maximize adaptability, nature has fine-tuned replication fidelity. Our work forges ground in showing that the mutability of RNA viruses does have an upper limit, where larger than natural genetic diversity is deleterious to virus survival. 相似文献
2.
Marcelo R. A. de Figueiredo Anita Küpper Jenna M. Malone Tijana Petrovic Ana Beatriz T. B. de Figueiredo Grace Campagnola Olve B. Peersen Kasavajhala V. S. K. Prasad Eric L. Patterson Anireddy S. N. Reddy Martin F. Kube Richard Napier Franck E. Dayan Christopher Preston Todd A. Gaines 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(9)
3.
艾滋病合并隐球菌脑膜炎18例临床分析 总被引:6,自引:1,他引:6
目的 提高对艾滋病 (AIDS)合并隐球菌脑膜炎的认识。方法 对赤道几内亚巴塔地区医院 18例AIDS合并隐球菌脑膜炎患者进行临床综合分析。结果 18例AIDS合并隐球菌脑膜炎患者的临床主要表现为 :发热、剧烈头痛、极度乏力、肢体痛、脑膜刺激征及消瘦与脱水等。脑脊液 (CSF)培养均为新型隐球菌生长 ;涂片及隐球菌多糖荚膜抗原 (ELISA法 )检测的阳性率分别为 77 8% (14/ 18) ,94 4% (17/ 18)。结论 隐球菌脑膜炎为AIDS常见机会性感染及主要致死病因之一。 相似文献
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6.
SP Attard-Montalto C Camacho-Hübner AM Cotterill L D'Souza-Li S Daley K Bartlett D Halliday OB Eden 《Acta paediatrica (Oslo, Norway : 1992)》1998,87(1):54-60
Changes in insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) were correlated with protein synthesis and breakdown using [1- 13C]leucine before chemotherapy and during subsequent febrile neutropenia (FN) in eight children with cancer, aged 6.3–17.5 y. IGF-I levels were similar to age-matched controls before chemotherapy (mean ±SEM: 250 ±28 and 228 ±22 μg l-1, respectively). During FN, IGF-I fell to 156 ±22 /ng l -1(p= 0:02), and rose to 276 ±27 μ g l -1 with recovery at 6 months (p = 0:004). Similarly, IGFBP-3 decreased from 4.0 ±0.2mgl-1 before chemotherapy to 3.0 ±0.3 mgl-1 during FN (p= 0:01), and returned to 4.1 ±0.2mgl -1 at 6 months (p= 0:01). IGF-I correlated with IGFBP-3 (r=+0:7, p <0:001). Scanning densitometry showed a decrease in IGFBP-3 from 94 to 54% during FN, when the presence of IGFBP-3 protease activity was observed. Compared with normal human serum, IGFBP-2 was elevated throughout the study. IGFBP-1 increased from 14.6 ±3.5 to 30.6 ±2.8/ngl-1 (p = 0:004), whereas serum insulin decreased from 26.5 ±6.8 to 7.8 ±0.8 mUl-1 (p= 0:03) before and during FN, respectively. Whilst IGF-I and IGFBP-3 fell, daytime growth hormone increased from 3.3 ±0.6 to 6.7±0.8mUl -1 (p= 0:01), and cortisol from 197 ±48 to 594±98nmoll -1 (p = 0:005). Albumin decreased from 47 ±2 to 38 ±2gl-1 (p= 0:004) and improved to 47 ±2gl-1 with recovery (p= 0:003). Protein synthesis increased from 4.5 ±0.4 to 5.0 ±0.6gkg-1 d-1 before chemotherapy and during FN, while protein breakdown rose from 5.4 ±0.4 to 6.3 ±0.4kg-1d-1. Increasing protein breakdown was related to falling IGF-I and IGFBP-3 levels. Modification of IGFBP-3 by circulating proteolytic activity may alter IGF bioavailability, allowing protein synthesis to increase during periods of severe catabolic stress. 相似文献
7.
E Hesketh OB Eden HR Gattamaneni RHA Campbell MEM Jenney L Lashford 《Acta paediatrica (Oslo, Norway : 1992)》1998,87(4):452-454
Four children with spinal cord compression due to malignant tumours are presented. The severity of the condition was not initially recognized by parents, or the nature of the likely cause by the initial physicians. Lower limb asymmetrical weakness, clear-cut sensory levels, and marked pain indicate need for urgent imaging and exclusion of a space occupying lesion. In 1997 diagnosis of Guillain-Barré syndrome should not be made without careful prior spinal imaging. 相似文献
8.
The release of certain cytokines, e.g. tumour necrosis factor (TNF)- alpha,
in the amniotic fluid has been suggested to be a cause of preterm birth.
The predisposition to excessive liberation of cytokines from peripheral
leukocytes has been shown to depend partly on the individual's HLA-DR
genotype. The HLA-DR1 and -DR3 alleles have previously been reported as
being associated with a TNF-alpha high responder status and have also been
associated with unexplained recurrent spontaneous abortions. In the present
study, HLA-DR typing was performed in 10 women who had experienced
recurrent very early preterm births resulting in perinatal death, or late
spontaneous abortions under a clinical picture resembling that
traditionally attributed to cervical incompetence. All patients had had at
least one mid-trimester miscarriage in spite of the insertion of a cervical
cerclage. Nine out of 10 (90%) patients had the HLA-DR phenotypes DR1
and/or DR3 compared with 37% in the background population (P < 0.005).
The results suggest that HLA-DR-associated immunological factors might play
a part in recurrent late spontaneous abortions and extremely preterm births
under a cervical incompetence-like picture, at least in the subset of cases
not treatable by cervical cerclage.
相似文献
9.
This study investigated the dental health of children (aged 1-14 years) diagnosed with cancer 4-36 months earlier. Sixty patients were examined and interviewed; 43% had untreated decay and only 35% had seen a dentist since their malignancy had been diagnosed. A significant source of bacterial infection is not being treated in this at risk population. The level of dental disease and lack of dental prevention indicates a need to integrate medical and dental care. 相似文献
10.
O Kambur R Talka OB Ansah VK Kontinen A Pertovaara E Kalso PT M?nnist? 《British journal of pharmacology》2010,161(7):1553-1565