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81.
Structural and kinetic analyses of the protease from an amprenavir-resistant human immunodeficiency virus type 1 mutant rendered resistant to saquinavir and resensitized to amprenavir 总被引:3,自引:0,他引:3 下载免费PDF全文
Markland W Rao BG Parsons JD Black J Zuchowski L Tisdale M Tung R 《Journal of virology》2000,74(16):7636-7641
Recent drug regimens have had much success in the treatment of human immunodeficiency virus (HIV)-infected individuals; however, the incidence of resistance to such drugs has become a problem that is likely to increase in importance with long-term therapy of this chronic illness. An analysis and understanding of the molecular interactions between the drug(s) and the mutated viral target(s) is crucial for further progress in the field of AIDS therapy. The protease inhibitor amprenavir (APV) generates a signature set of HIV type 1 (HIV-1) protease mutations associated with in vitro resistance (M46I/L, I47V, and I50V [triple mutant]). Passage of the triple-mutant APV-resistant HIV-1 strain in MT4 cells, in the presence of increasing concentrations of saquinavir (SQV), gave rise to a new variant containing M46I, G48V, I50V, and I84L mutations in the protease and a resulting phenotype that was resistant to SQV and, unexpectedly, resensitized to APV. This phenotype was consistent with a subsequent kinetic analysis of the mutant protease, together with X-ray crystallographic analysis and computational modeling which elucidated the structural basis of these observations. The switch in protease inhibitor sensitivities resulted from (i) the I50V mutation, which reduced the area of contact with APV and SQV; (ii) the compensating I84L mutation, which improved hydrophobic packing with APV; and (iii) the G-to-V mutation at residue 48, which introduced steric repulsion with the P3 group of SQV. This analysis establishes the fine detail necessary for understanding the loss of protease binding for SQV in the quadruple mutant and gain in binding for APV, demonstrating the powerful combination of virology, molecular biology, enzymology, and protein structural and modeling studies in the elucidation and understanding of viral drug resistance. 相似文献
82.
The reduction in electroporation voltages by the addition of a surfactant to planar lipid bilayers. 总被引:1,自引:0,他引:1 下载免费PDF全文
The effects of a nonionic surfactant, octaethyleneglycol mono n-dodecyl ether (C12E8), on the electroporation of planar bilayer lipid membranes made of the synthetic lipid 1-pamitoyl 2-oleoyl phosphatidylcholine (POPC), was studied. High-amplitude ( approximately 100-450 mV) rectangular voltage pulses were used to electroporate the bilayers, followed by a prolonged, low-amplitude ( approximately 65 mV) voltage clamp to monitor the ensuing changes in transmembrane conductance. The electroporation thresholds of the membranes were found for rectangular voltage pulses of given durations. The strength-duration relationship was determined over a range from 10 micros to 10 s. The addition of C12E8 at concentrations of 0.1, 1, and 10 microM to the bath surrounding the membranes decreased the electroporation threshold monotonically with concentration for all durations (p < 0.0001). The decrease from control values ranged from 10% to 40%, depending on surfactant concentration and pulse duration. For a 10-micros pulse, the transmembrane conductance 150 micros after electroporation (G150) increased monotonically with the surfactant concentration (p = 0.007 for 10 microM C12E8). These findings suggest that C12E8 incorporates into POPC bilayers, allowing electroporation at lower intensities and/or shorter durations, and demonstrate that surfactants can be used to manipulate the electroporation threshold of lipid bilayers. 相似文献
83.
The possible involvement of calcium in the regulation of ammonium-promoted senescence of detached rice leaves was investigated. Calcium effectively reduced ammonium-promoted senescence of detached rice leaves. The effect of ammonium on the senescence was also significantly reduced by the calcium ionophore A23187. Ammonium-promoted senescence of detached rice leaves may be mediated through blocking the entrance of calcium ions into the cytosol. 相似文献
84.
Yu‐Kuang Liao Maël Brossard Dan‐Hua Hsieh Tzu‐Neng Lin Martin D. B. Charlton Shun‐Jen Cheng Chyong‐Hua Chen Ji‐Lin Shen Lung‐Teng Cheng Tung‐Po Hsieh Fang‐I Lai Shou‐Yi Kuo Hao‐Chung Kuo Pavlos G. Savvidis Pavlos G. Lagoudakis 《Liver Transplantation》2015,5(2)
A novel scheme for hybridizing inkjet‐printed thin film Cu(In,Ga)Se2 (CIGS) solar cells with self‐assembled clusters of nanocrystal quantum dots (NQDs), which provides a 10.9% relative enhancement of the photon conversion efficiency (PCE), is demonstrated. A non‐uniform layer of NQD aggregates is deposited between the transparent conductive oxide and a CdS/CIGS p‐n junction using low cost pulsed‐spray deposition. Hybridization significantly improves the external quantum efficiency of the hybrid devices in the absorption range of the NQDs and in the red to near‐IR parts of the spectrum. The low wavelength response enhancement is found to be induced by luminescent down‐shifting (LDS) from the NQD layer, while the increase at longer wavelengths is attributed to internal scattering from NQD aggregates. LDS is demonstrated using time‐resolved spectroscopy, and the morphology of the NQD layer is investigated in fluorescence microscopy and cross‐sectional transmission electron microscopy. The influence of the NQD dose on the PCE of the hybrid devices is investigated and an optimum value is obtained. The low costs and limited material consumptions associated with pulsed‐spray deposition make these flexible hybrid devices promising candidates to help push thin‐film photovoltaic technology towards grid parity. 相似文献
85.
Shing-Hsien Chou Ying-Chang Tung Yu-Sheng Lin Lung-Sheng Wu Chia-Pin Lin Eric Jein-Wein Liou Chee-Jen Chang Suefang Kung Pao-Hsien Chu 《PloS one》2015,10(6)
Background
The aim of the present study was to identify the long-term major adverse cardiovascular events (MACE) in treated periodontitis patients in Taiwan.Methods
From the National Health Insurance Research Database (2001-2010), adult patients (≥ 18 years) with treated periodontitis were identified. Comparison was made between patients with mild form and severe form of treated periodontitis after propensity score matching. The primary end point was the incidence of MACE.Results
A total of 32,504 adult patients with treated periodontitis were identified between 2001 and 2010. After propensity score matching, 27,146 patients were preserved for comparison, including 13,573 patients with mild form and 13,573 patients with severe form of treated periodontitis. During follow-up, 728 individuals in mild treated periodontitis group and 1,206 individuals in severe treated periodontitis group had at least 1 MACE event. After adjustment for gender, hyperlipidemia, hypertension and diabetes mellitus, severe treated periodontitis was associated with a mildly but significantly increased risk of MACE among older patients > 60 years of age (incidence rate ratio, 1.26; 95% confidence interval, 1.08–1.46). No association was found among younger patients ≤ 60 years of age.Conclusions
Severe form of treated periodontitis was associated with an increased risk of MACE among older Taiwanese patients, but not among younger Taiwanese patients. We should put more efforts on the improvement of periodontal health to prevent further MACE. 相似文献86.
87.
Phan Tu Quy Nguyen Khoa Hien Nguyen Chi Bao Doan Thanh Nhan Dang Van Khanh Nguyen Thi Ai Nhung Truong Quy Tung Nguyen Dinh Luyen Duong Tuan Quang 《Luminescence》2015,30(3):325-329
A new rhodamine–ethylenediamine–nitrothiourea conjugate (RT) was synthesized and its sensing property as a fluorescent chemodosimeter toward metal ions was explored in water media. Analytical results from absorption and fluorescence spectra revealed that the addition of Hg2+ ions to the aqueous solution of the chemodosimeter RT caused a distinct fluorescence OFF–ON response with a remarkable visual color change from colorless to pink; however, no clear spectral and color changes were observed from other metal ions including: Zn2+, Cu2+, Cd2+, Pb2+, Ag+, Fe2+, Cr3+, Co3+, Ni2+, Ca2+, Mg2+, K+ and Na+. The sensing results and the molecular structure suggested that a Hg2+‐induced a desulfurization reaction and cyclic guanylation of the thiourea moiety followed by ring‐opening of the rhodamine spirolactam in RT are responsible for a distinct fluorescence turn‐on signal, indicating that RT is a remarkably sensitive and selective chemodosimeter for Hg2+ ions in aqueous solution. Hg2+ within a concentration range from 0.1 to 25 μM can be determined using RT as a chemodosimeter and a detection limit of 0.04 μM is achieved. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
88.
89.
Hung-Chun Tung Fa-Yauh Lee Sun-Sang Wang Ming-Hung Tsai Jing-Yi Lee Teh-Ia Huo Hui-Chun Huang Chiao-Lin Chuang Han-Chieh Lin Shou-Dong Lee 《PloS one》2015,10(5)
Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X7 participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X7 antagonist and food additive) or vehicle from the 15th to 28th day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X7 receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications. 相似文献
90.