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21.
Alex N. Bullock Julia Henckel Brian S. DeDecker Christopher M. Johnson Penka V. Nikolova Mark R. Proctor David P. Lane Alan R. Fersht 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(26):14338-14342
Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn2+ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25°C and 9.8 kcal/mol at 10°C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions. 相似文献
22.
Tie-mei Cao Hong-ni Han Ying-chun Duan Li-zhong Chen Yan-bo Ji Bing Wang Hai-yan Wang 《中国结合医学杂志》2002,8(1):36-40
Ankylosingspondylitis(AS)isarheumaticdiseasewithhighincidence,induc ingdisabilityandinvadingthespinalaxialjointasitschiefcharact 相似文献
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Joseph M Dhahbi Shelley X Cao Patricia L Mote Brian C Rowley John E Wingo Stephen R Spindler 《The Journal of nutrition》2002,132(1):31-37
Molecular chaperones assist in the biosynthesis and processing of proteins. Most chaperones are induced by physiological stresses. We have shown that dietary energy restriction decreases the mRNA and protein levels of many endoplasmic reticulum chaperones in the livers of mice. Here, we have investigated the response of chaperone mRNA to feeding. Control and 50% energy-restricted C3B10RF1 mice were deprived of food for 24 h, fed, and killed 0, 1.5, 5 or 12 h after feeding. Chaperone mRNAs were strongly induced as early as 1.5 h after feeding in control and energy-restricted mice. The integrated levels of these mRNA over 24 h were significantly lower in energy-restricted mice. The mRNA response to energy intake was mirrored over the course of days in the level of chaperone protein. A similar but smaller response to feeding was found in kidney and muscle. Puromycin and cycloheximide failed to inhibit the feeding response, suggesting that feeding releases chaperone expression from an unstable inhibitor. Studies with dibutyryl-cAMP- and glucagon-supplemented, normal and streptozotocin-diabetic mice suggest that glucagon and insulin may be mediators of the feeding response. Adrenalectomy enhanced the feeding induction, but dexamethasone administration had no effect. Thus, postprandial changes in insulin and glucagon may link chaperone gene expression to feeding, possibly in several tissues including liver. 相似文献
25.
Many important pharmaceutical agents, including vancomycin, bleomycin, cyclosporin, and several antibiotics, are produced by non‐ribosomal peptide synthetase (NRPS) enzymes in microorganisms. The NRPS pathway produces an extensive library of products using multienzyme complexes acting in an assembly‐line fashion. Engineering an NRPS system to produce an even greater variety of products, some of which may also have beneficial therapeutic value, would be an enormous advantage. Several approaches have been successful in generating novel NRPS products: mutational biosynthesis during which nonnatural substrates are fed to an organism; domain and module swapping between different species to generate hybrid enzymes; and rational site‐directed mutagenesis, based either on phylogeny or computational prediction, intended to switch substrate specificity and produce altered products. This review will highlight the progress in these areas and describe research in the future that will extend the capacity for re‐engineering NRPS systems. Drug Dev. Res. 66:9–18, 2006. © 2006 Wiley‐Liss, Inc. 相似文献
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27.
Kenneth K. H. Chao BS Eric Cheung BS William B. Armstrong MD Brian J. F. Wong MD 《Otolaryngology--head and neck surgery》2002,126(6):593
Objective: The study goal was to compare the laser spot size created using reflective and refractive micromanipulators with a CO2 laser and to determine the sensitivity of spot size to laser power. Study Design and Setting: A CO2 laser and operating microscope (400-mm focal length) was coupled to either a reflective (Cassegrain-like) or refractive micromanipulator. Laser spot size was determined by measuring the region of ablation created by laser irradiation of wood (dry tongue depressors), exposed photographic film, and agar gel using optical micrometry. Laser power varied from 0.5 to 20 W with pulse durations of 0.1 and 0.5 second. Results: The reflective micromanipulator demonstrated overall smaller spot sizes for a given laser power and lower incremental change in spot size with increasing power. The reflective design demonstrated less sensitivity to increases in laser power. Conclusions: Micromanipulator optical design can result in significant differences in laser spot size. The reflective device used in this study demonstrated less sensitivity to increasing laser power. (Otolaryngol Head Neck Surg 2002;126:593-597.) 相似文献
28.
Georgios K Glantzounis Henryk J Salacinski Wenxuan Yang Brian R Davidson Alexander M Seifalian 《Liver transplantation》2005,11(9):1031-1047
Oxidative stress is an important factor in many pathological conditions such as inflammation, cancer, ageing and organ response to ischemia-reperfusion. Humans have developed a complex antioxidant system to eliminate or attenuate oxidative stress. Liver ischemia-reperfusion injury occurs in a number of clinical settings, including liver surgery, transplantation, and hemorrhagic shock with subsequent fluid resuscitation, leading to significant morbidity and mortality. It is characterized by significant oxidative stress but accompanied with depletion of endogenous antioxidants. This review has 2 aims: firstly, to highlight the clinical significance of liver ischemia-reperfusion injury, the underlying mechanisms and the main pathways by which the antioxidants function, and secondly, to describe the new developments that are ongoing in antioxidant therapy and to present the experimental and clinical evidence about the role of antioxidants in modulating hepatic ischemia-reperfusion injury. 相似文献
29.
Michael Rosenzweig Martha Skinner Tatiana Prokaeva Roger Théberge Catherine Costello Brian M Drachman Lawreen H Connors 《Amyloid》2007,14(1):65-71
We report the identification of a new transthyretin (TTR) gene mutation and variant protein, Glu61Gly, in a 55-year-old man with progressive cardiomyopathy, mild peripheral neuropathy and bilateral carpal tunnel syndrome. A diagnosis of TTR-associated familial amyloidosis (ATTR) was considered after an endomyocardial biopsy revealed amyloid deposits in the heart of a patient who had no family history of amyloidosis and no evidence of a plasma cell dyscrasia. Serum screening for a TTR variant by isoelectric focusing (IEF) was positive and prompted further studies to identify the genetic abnormality and to characterize the amyloidogenic protein. Direct DNA sequence analysis of all four coding regions in the TTR gene demonstrated heterozygosity in exon 3. Near equal amounts of guanine (G) and adenine (A) were observed at the second base position of codon 61. The wild-type (GAG) and mutated (GGG) sequences found in codon 61 correspond to glutamic acid (Glu) and glycine (Gly) residues, amino acids which differ in mass by -72 Da. Mass spectrometric analyses of TTR immunoprecipitated from serum showed the presence of both wild-type and variant proteins. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. 相似文献
30.
本文报告用间接免疫荧光法检测特异性IgG抗体对流行性出血热的诊断意义。53例不同病期的出血热患者的血清,其间接荧光抗体的阳性率为49/53(占92.45%)。有77.36%的患者血清,检出IgG抗体的时间是在发病后的1~2周。血清中IgG的滴度与疾病的严重性无密切相关。另25例非EHF患者,其血清特异性IgG抗体均为阴性。可见检测特异性IgG抗体对EHF的诊断颇为有用。 相似文献