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91.
Cheng CY Gilson T Dallaire F Ketner G Branton PE Blanchette P 《Journal of virology》2011,85(2):765-775
Although human adenovirus type 5 (Ad5) has been widely studied, relatively little work has been done with other human adenovirus serotypes. The Ad5 E4orf6 and E1B55K proteins form Cul5-based E3 ubiquitin ligase complexes to degrade p53, Mre11, DNA ligase IV, integrin α3, and almost certainly other targets, presumably to optimize the cellular environment for viral replication and perhaps to facilitate persistence or latency. As this complex is essential for the efficient replication of Ad5, we undertook a systematic analysis of the structure and function of corresponding E4orf6/E1B55K complexes from other serotypes to determine the importance of this E3 ligase throughout adenovirus evolution. E4orf6 and E1B55K coding sequences from serotypes representing all subgroups were cloned, and each pair was expressed and analyzed for their capacity to assemble the Cullin-based ligase complex and to degrade substrates following plasmid DNA transfection. The results indicated that all formed Cullin-based E3 ligase complexes but that heterogeneity in both structure and function existed. Whereas Cul5 was present in the complexes of some serotypes, others recruited primarily Cul2, and the Ad16 complex clearly bound both Cul2 and Cul5. There was also heterogeneity in substrate specificity. Whereas all serotypes tested appeared to degrade DNA ligase IV, complexes from some serotypes failed to degrade Mre11, p53, or integrin α3. Thus, a major evolutionary pressure for formation of the adenovirus ligase complex may lie in the degradation of DNA ligase IV; however, it seems possible that the degradation of as-yet-unidentified critical targets or, perhaps even more likely, appropriate combinations of substrates plays a central role for these adenoviruses. 相似文献
92.
Frénal K Xu CQ Wolff N Wecker K Gurrola GB Zhu SY Chi CW Possani LD Tytgat J Delepierre M 《Proteins》2004,56(2):367-375
The gamma-KTx-type scorpion toxins specific for K+ channels were found to interact with ERG channels on the turret region, while alpha-KTx3.2 Agitoxin-2 binds to the pore region of the Shaker K+ channel, and alpha-KTx5.3 BmP05 binds to the intermediate region of the small-conductance calcium-activated K-channel (SK(Ca)). In order to explore the critical residues for gamma-KTx binding, we determined the NMR structure of native gamma-KTx1.1 (CnErg1), a 42 amino acid residues scorpion toxin isolated from the venom of the Mexican scorpion Centruro?des noxius Hoffmann, and we used computational evolutionary trace (ET) analysis to predict possible structural and functional features of interacting surfaces. The 1H-NMR three-dimensional solution structure of native ergtoxin (CnErg1) was solved using a total of 452 distance constraints, 13 3J(NH-Halpha) and 10 hydrogen bonds. The structure is characterized by 2 segments of alpha-helices and a triple-stranded antiparallel beta-sheet stabilized by 4 disulfide bridges. The ET and structural analysis provided indication of the presence of two important amino acid residue clusters, one hydrophobic and the other hydrophilic, that should be involved in the surface contact between the toxin and the channel. Some features of the proposed interacting surface are discussed. 相似文献
93.
John R. Koethe Andrew O. Westfall Dora K. Luhanga Gina M. Clark Jason D. Goldman Priscilla L. Mulenga Ronald A. Cantrell Benjamin H. Chi Isaac Zulu Michael S. Saag Jeffrey S. A. Stringer 《PloS one》2010,5(3)
Background
The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree).Methodology
Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months.Principal Findings
From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites.Conclusions
A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings.Trial Registration
Clinicaltrials.gov NCT00929604相似文献94.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia 总被引:6,自引:0,他引:6
Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. 相似文献
95.
Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function 总被引:20,自引:0,他引:20
Jang HH Lee KO Chi YH Jung BG Park SK Park JH Lee JR Lee SS Moon JC Yun JW Choi YO Kim WY Kang JS Cheong GW Yun DJ Rhee SG Cho MJ Lee SY 《Cell》2004,117(5):625-635
Although a great deal is known biochemically about peroxiredoxins (Prxs), little is known about their real physiological function. We show here that two cytosolic yeast Prxs, cPrxI and II, which display diversity in structure and apparent molecular weights (MW), can act alternatively as peroxidases and molecular chaperones. The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch. These in vivo changes are primarily guided by the active peroxidase site residue, Cys(47), which serves as an efficient "H(2)O(2)-sensor" in the cells. The chaperone function of these proteins enhances yeast resistance to heat shock. 相似文献
96.
BmBKTx1, a novel Ca2+-activated K+ channel blocker purified from the Asian scorpion Buthus martensi Karsch 总被引:1,自引:0,他引:1
Xu CQ Brône B Wicher D Bozkurt O Lu WY Huys I Han YH Tytgat J Van Kerkhove E Chi CW 《The Journal of biological chemistry》2004,279(33):34562-34569
BmBKTx1 is a novel short chain toxin purified from the venom of the Asian scorpion Buthus martensi Karsch. It is composed of 31 residues and is structurally related to SK toxins. However, when tested on the cloned rat SK2 channel, it only partially inhibited rSK2 currents, even at a concentration of 1 microm. To screen for other possible targets, BmBKTx1 was then tested on isolated metathoracic dorsal unpaired median neurons of Locusta migratoria, in which a wide variety of ion channels are expressed. The results suggested that BmBKTx1 could specifically block voltage-gated Ca(2+)-activated K(+) currents (BK-type). This was confirmed by testing the BmBKTx1 effect on the alpha subunits of BK channels of the cockroach (pSlo), fruit fly (dSlo), and human (hSlo), heterologously expressed in HEK293 cells. The IC(50) for channel blocking by BmBKTx1 was 82 nm for pSlo and 194 nm for dSlo. Interestingly, BmBKTx1 hardly affected hSlo currents, even at concentrations as high as 10 microm, suggesting that the toxin might be insect specific. In contrast to most other scorpion BK blockers that also act on the Kv1.3 channel, BmBKTx1 did not affect this channel as well as other Kv channels. These results show that BmBKTx1 is a novel kind of blocker of BK-type Ca(2+)-activated K(+) channels. As the first reported toxin active on the Drosophila Slo channel dSlo, it will also greatly facilitate studying the physiological role of BK channels in this model organism. 相似文献
97.
人体和动物模型的体表物理信息地形图的研究 总被引:1,自引:0,他引:1
对人体头面、躯干、四肢、耳廓各局部几十个及整个人体等体表部位正、背面等210个部位进行超微弱冷光和温度测量,输入电子计算机,经特殊的自编程序处理,获得十分清晰的,由3000多数据构成的各个局部或人体整体的冷光和温度地形图。 对家兔左、右耳廓、胸腹部、背部都分别观察32个部位的冷光与体表温度,经计算机分析处理,每观察区域获得约由2000个数据构成的精确的冷光、温度地形分市图。并可见不同生理、病理状态及不同病程家兔体表冷光、温度等地形图呈有规律的改变。 此外,我们还编制了以体表左右相应对称部位差值为分析数据进行地形图分析的程序,用以人体和动物体表物理信息对称规律的研究。 本工作以图形的形式显示物理参量在体表的广泛的分布规律,以揭示机体内部的不同生理、病理状态。本方法定位准确、直观醒目,为研究体表信息及机体生命活动规律提供了与逐点直接测量方法相互补充的有益的新手段。 相似文献
98.
Chi Liu Hui-jun Liu Yang Xiang Yu-rong Tan Xiao-lin Zhu Xiao-qun Qin 《Molecular and cellular biochemistry》2010,341(1-2):259-269
Integrin beta 4 (ITGB4) is a structural adhesion molecule which engages in maintaining the integrity of airway epithelial cells. Its specific cytomembrane structural feature strongly indicates that ITGB4 may engage in many signaling pathways and physiologic processes. However, in addition to adhesion, the specific biologic significance of ITGB4 in airway epithelial cells is almost unknown. In this article, we investigated the expression and functional properties of ITGB4 in airway epithelial cells in vivo and in vitro. Human bronchial epithelial cell line (16HBE14O-cells) and primary rat tracheal epithelial cells (RTE cells) were used to determine ITGB4 expression under ozone tress or mechanical damage, respectively. An ovalbumin (OVA)-challenged asthma model was used to investigate ITGB4 expression after antigen exposure in vivo. In addition, an ITGB4 overexpression vector and ITGB4 silence virus vector were constructed and transfected into RTE cells. Then, wound repair ability and anti-oxidation capacity was evaluated. Our results demonstrated that, on the edge of mechanically wounded cell areas, ITGB4 expression was increased after mechanical injury. After ozone stress, upregulation expression of ITGB4 was also detected. In the OVA-challenged asthma model, ITGB4 expression was decreased on airway epithelial cells accompanying with structural disruption and damage of anti-oxidation capacity. Besides, our study revealed that upregulation of ITGB4 promotes wound repair ability and anti-oxidative ability, while such abilities were blocked when ITGB4 was silenced. Taken together, these results showed that ITGB4 was a new interesting molecule involved in the regulation of wound repair and anti-oxidation processes for airway epithelial cells. 相似文献
99.
100.
Emmanuel Ngeufa Happi Alain Tadjong Tcho Jovita Chi Sirri Jean Duplex Wansi Beate Neumann Hans-Georg Stammler Jean Wandji Norbert Sewald 《Phytochemistry letters》2012,5(3):423-426
Two new tirucallane triterpenoids, 21-methoxy-21,23-epoxy-tirucalla-7,24-dien-3α-ol (1) and 21-methoxy-21,23-epoxy-tirucalla-7,24-diene-1α,3α-diol (2), together with thirteen known compounds were isolated from the CH2Cl2 extract of the stem bark of Araliopsis synopsis. The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data and comparison with previously known analogs. Compounds 1–10 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with MICs > 1 mg/mL. However, compounds 5–10 exhibited high cytotoxic activity against the human Caucasian prostate adenocarcinoma cell PC-3 line, with IC50 8.5–12.5 μM compared to the standard Doxorubicin with IC50 = 0.9 μM, while compounds 1, 3 and 4 showed low activity. 相似文献