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Sinisa Bjelic Yakov Kipnis Ling Wang Zbigniew Pianowski Sergey Vorobiev Min Su Jayaraman Seetharaman Rong Xiao Gregory Kornhaber John F. Hunt Liang Tong Donald Hilvert David Baker 《Journal of molecular biology》2014
Designed retroaldolases have utilized a nucleophilic lysine to promote carbon–carbon bond cleavage of β-hydroxy-ketones via a covalent Schiff base intermediate. Previous computational designs have incorporated a water molecule to facilitate formation and breakdown of the carbinolamine intermediate to give the Schiff base and to function as a general acid/base. Here we investigate an alternative active-site design in which the catalytic water molecule was replaced by the side chain of a glutamic acid. Five out of seven designs expressed solubly and exhibited catalytic efficiencies similar to previously designed retroaldolases for the conversion of 4-hydroxy-4-(6-methoxy-2-naphthyl)-2-butanone to 6-methoxy-2-naphthaldehyde and acetone. After one round of site-directed saturation mutagenesis, improved variants of the two best designs, RA114 and RA117, exhibited among the highest kcat (> 10− 3 s− 1) and kcat/KM (11–25 M− 1 s− 1) values observed for retroaldolase designs prior to comprehensive directed evolution. In both cases, the > 105-fold rate accelerations that were achieved are within 1–3 orders of magnitude of the rate enhancements reported for the best catalysts for related reactions, including catalytic antibodies (kcat/kuncat = 106 to 108) and an extensively evolved computational design (kcat/kuncat > 107). The catalytic sites, revealed by X-ray structures of optimized versions of the two active designs, are in close agreement with the design models except for the catalytic lysine in RA114. We further improved the variants by computational remodeling of the loops and yeast display selection for reactivity of the catalytic lysine with a diketone probe, obtaining an additional order of magnitude enhancement in activity with both approaches. 相似文献
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Irving J. Zamora Barbara Stoll Cecilia G. Ethun Fariha Sheikh Ling Yu Douglas G. Burrin Mary L. Brandt Oluyinka O. Olutoye 《PloS one》2015,10(6)
To identify early markers of necrotizing enterocolitis (NEC), we hypothesized that continuous abdominal near-infrared spectroscopy (A-NIRS) measurement of splanchnic tissue oxygen saturation and intermittent plasma intestinal fatty-acid binding protein (pI-FABP) measured every 6 hours can detect NEC prior to onset of clinical symptoms. Premature piglets received parenteral nutrition for 48-hours after delivery, followed by enteral feeds every three hours until death or euthanasia at 96-hours. Continuous A-NIRS, systemic oxygen saturation (SpO2), and heart rate were measured while monitoring for clinical signs of NEC. Blood samples obtained at 6-hour intervals were used to determine pI-FABP levels by ELISA. Piglets were classified as fulminant-NEC (f-NEC), non-fulminant-NEC (nf-NEC) and No-NEC according to severity of clinical and histologic features. Of 38 piglets, 37% (n=14) developed nf-NEC, 18% (n=7) developed f-NEC and 45% (n=17) had No-NEC. There were significant differences in baseline heart rate (p=0.008), SpO2 (p<0.001) and A-NIRS (p<0.001) among the three groups. A-NIRS values of NEC piglets remained lower throughout the study with mean for f-NEC of 69±3.8%, 71.9±4.04% for nf-NEC, and 78.4±1.8% for No-NEC piglets (p<0.001). A-NIRS <75% predicted NEC with 97% sensitivity and 97% specificity. NEC piglets demonstrated greater variability from baseline in A-NIRS than healthy piglets (10.1% vs. 6.3%; p=0.04). Mean pI-FABP levels were higher in animals that developed NEC compared to No-NEC piglets (0.66 vs. 0.09 ng/mL;p<0.001). In f-NEC piglets, pI-FABP increased precipitously after feeds (0.04 to 1.87 ng/mL;p<0.001). pI-FABP levels increased in parallel with disease progression and a value >0.25ng/mL identified animals with NEC (68% sensitivity and 90% specificity). NIRS is a real-time, non-invasive tool that can serve as a diagnostic modality for NEC. In premature piglets, low A-NIRS in the early neonatal period and increased variability during initial feeds are highly predictive of NEC, which is then confirmed by rising plasma I-FABP levels. These modalities may help identify neonates with NEC prior to clinical manifestations of disease. 相似文献
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干旱荒漠区生态环境质量遥感动态监测——以古尔班通古特沙漠为例 总被引:1,自引:0,他引:1
利用遥感生态指数(RSEI)对区域生态变化进行评价,可以快速、高效、客观地获取研究区生态环境变化状况.本研究以两期Landsat数据为数据源,计算研究区绿度、湿度、热度、干度4个生态因子的遥感生态指数,并基于主成分分析法确定其权重,对古尔班通古特沙漠2006—2017年间的生态环境时空格局进行定性和定量评价.结果表明: 湿度和绿度对古尔班通古特沙漠生态环境质量起正面作用,而热度和干度对生态环境质量起负面作用,其中代表绿度指标的归一化植被指数(NDVI)的贡献最大.2006—2017年间,古尔班通古特沙漠的RSEI有所下降,其均值从0.294下降至0.243,降幅达20.1%,研究区的生态环境状况呈现整体变差的趋势.古尔班通古特沙漠中部生态环境较为稳定,东北部植被覆盖密集区及南缘灌溉区生态环境质量变好,沙漠南部及西北部区域生态环境质量变差. 相似文献
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Radiation and Environmental Biophysics - Objective of the present study was to investigate the tolerant radiation dose of nasal mucosa by observing and analyzing patients who received... 相似文献
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在病理情况下,特别是细胞损伤时,细胞内酶会释放到体液中,造成体液中酶量或酶活性的改变,酶可作为诊断指标来使用。与其他指标相比,酶具有更高的诊断特异性和灵敏度。临床上病毒感染所引起的传染性疾病很多,严重感染者可遗留后遗症甚至造成死亡。血清酶指标可以为病毒感染疾病的诊断、治疗及预后提供重要的参考价值。本研究就近年来国内外对病毒感染所造成血清酶活性的改变及临床运用作一综述。 相似文献
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