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1.
The influence of ionic strength and composition on the binding and inhibition of human leukocyte elastase by glycosaminoglycans with variable degree and position of sulfation was investigated. The kinetic mechanism of inhibition had a hyperbolic, mixed-type character with a competitive component that was promoted by low ionic strength, reduced by phosphate ions, and which also depended on the substrate and glycosaminoglycan structure. Enzyme binding was a cooperative phenomenon that varied with ionic strength and composition. The inhibition patterns correlated with the cationic character of elastase and with the distribution of arginines on its molecular surface, most notably with residues located in the vicinity of the substrate binding region. The order of affinity for elastase binding was chondroitin 4-sulfate < chondroitin 6-sulfate < dermatan sulfate, iduronate-containing derivatives being superior with respect to the glucuronate-containing counterparts. Additional sulfation at both the 4- and 6- positions or at the N- and 4-positions of the N-acetylgalactosamine moiety decidedly improved the inhibitory efficiency. The results highlight a fundamental physiological role of enzyme-glycosaminoglycan interactions. In the azurophil granule of the human polymorphonuclear neutrophil, elastase and other enzymes are bound to a matrix of chondroitin 4-sulfate because this is the only glycosaminoglycan that simultaneously offers good binding for enzyme compartmentalization together with prompt release from the bound state at the onset of phagocytosis.  相似文献   
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Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.  相似文献   
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The partitioning of corrosion inhibitor (CI) products is a measure of their potential to protect oilfield pipelines. In this paper the hydrophilic–lipophilic deviation (HLD) model is first used to quantify their partitioning in terms of the characteristic curvature (C c,act) of a series of anionic (alkoxylated phosphate esters) and cationic (alkoxylated amines, aromatic amines, imidazoline acetates and quaternary amines) actives. This parameter is expressed over a range of pHs within which pipeline corrosion occurs. The HLD model is next used to predict the partitioning of each active from water into toluene at increased salinities. Linear mixing rules are lastly used to predict the characteristic curvature of Product A (C c,mix) as a function of the C c,act of a subset of actives.  相似文献   
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OBJECTIVES: The purpose of this study was to determine the safety and efficacy of three dosing regimens of intracoronary urokinase for facilitated angioplasty of chronic total native coronary artery occlusions. BACKGROUND: Percutaneous transluminal coronary angioplasty of chronically occluded (>3 months) native coronary arteries is associated with low initial success secondary to an inability to pass the guide wire beyond the occlusion. METHODS: Patients were enrolled if a chronic total occlusion >3 months old could not be crossed with standard angioplasty equipment. Of the 101 patients enrolled, 41 had successful guide wire passage and were excluded from urokinase treatment. The remaining 60 patients were randomized to receive one of three intracoronary dosing regimens of urokinase over 8 h (group A = 0.8 million U; group B = 1.6 million U; group C = 3.2 million U), and angioplasty was again attempted after completion of the urokinase infusion in 58 patients. RESULTS: Coronary angioplasty was successful in 32 patients (53%) (group A 52%, group B 50%, group C 59%, p = 0.86). This study had a 90% power to detect at least a 50% difference between dosing groups at alpha 0.05. Bleeding complications requiring blood transfusion did not differ significantly among the dosing groups (A 0%, B 15%, C 6%, p = 0.14), although major bleeding episodes were less common in group A (p < 0.05). There were no major procedural or in-hospital complications. Angiographic follow-up in 69% of the patients with successful angioplasty revealed target vessel patency in 91% but an angiographic restenosis rate of 59%. CONCLUSIONS: A prolonged supraselective intracoronary infusion of urokinase can be safely administered and may facilitate angioplasty of chronic total occlusions. Lower doses of urokinase are equally effective and result in fewer bleeding complications than do higher dosage regimens. Vessel patency is frequently maintained, but restenosis remains a problem.  相似文献   
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Survey data from 113 female physicians, 634 male physicians, and 41 female dentists were compared. Instruments designed to assess work satisfaction, work stress, marital satisfaction, family competence, and psychiatric symptoms and treatment were used, thereby exploring important life domains concurrently. The results suggest that female physicians are much more like both male physicians and female dentists than anticipated. Generally, female physicians describe high levels of work satisfaction, moderate levels of work stress, average-to-high levels of marital satisfaction, and relatively low levels of psychiatric distress. Their lower levels of practice income remain something of an enigma as gender remains the most powerful predictor of income and is not replaced in statistical analyses by specialty, hours worked, or other significant variables. Finally, female physicians who find higher levels of satisfaction in work also report higher levels of marital satisfaction and fewer psychiatric symptoms. For these women, a highly satisfying medical career does not apparently need to be experienced at the cost of marital or personal distress.  相似文献   
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Confirmatory factor analysis of data (from 5 samples, n?=?484 full-time employed management students; n?=?550 public administrators; n?=?214 university administrators; n?=?250 bank managers and employees in Bangladesh; and n?=?578 managers and employees) on the 28 items of the Rahim Organizational Conflict Inventory—II were performed with LISREL 7. The results provided support for the convergent and discriminant validities of the subscales measuring the 5 styles of handling interpersonal conflict (integrating, obliging, dominating, avoiding, and compromising) and general support for the invariance of the 5-factor model across referent roles (i.e., superiors, subordinates, and peers), organizational levels (top, middle, lower, and nonmanagement), and 4 of the 5 samples. (PsycINFO Database Record (c) 2010 APA, all rights reserved)  相似文献   
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Modern approach to distribution systems planning requires developing tools able to interpret and analyze the stochastic nature of large power system problems. At the same time, it has to be able to optimize multiple, conflicting goals that appear in today’s open market environment. The presented evolutionary algorithm is based on a Multiple Vehicle Routing Problem adjusted for solving active electric distribution networks. An original approach to fuzzy number modeling is used for active power sources, consumption substations and distributed generation. This model, besides shorter computational time and less memory usage, is applicable to any form of fuzzy number shape required by the planner in modeling the stochastic nature of elements. An idea of defuzzification using pessimism is presented and compared to the solutions obtained without pessimism included. Application of the original universal fuzzy number modeling, using FER-fuzzy modeling, is demonstrated on multi-objective evolutionary algorithm and applied to real Croatian distribution network.  相似文献   
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In this paper, we discuss applications of max–min fairness (MMF) in survivable networks. We focus on two specific applications intended to face failure situations and provide several computational results for each of them. The first application, called simple robust routing, generalizes the multipath routing in order to achieve acceptable levels of traffic demand satisfaction in case of single link failures while avoiding classical rerouting procedures. Such a method can be seen as a special case of dedicated resource recovery schemes. The second application is concerned with two shared resource restoration strategies and the corresponding problems of computing the MMF minimum traffic demand satisfaction ratio vectors associated with the set of single link failures. We consider the local rerouting and end-to-end rerouting without stub-release strategies. Computational results for realistic network instances provide a comparison of different routing and rerouting strategies in terms of traffic satisfaction rate. The question of estimating the bandwidth overhead, which can be required by the “simple robust routing scheme” in comparison with the classical restoration schemes, is also studied and answers based on computational results are provided. This work is in continuation of our earlier works on MMF (Nace et al., IEEE Trans Netw 14:1272–1281, 2006; Nace et al., Comput Oper Res 35:557–573, 2008).  相似文献   
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