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81.
Cotter G Kaluski E Stangl K Pacher R Richter C Milo-Cotter O Perchenet L Kobrin I Kaplan S Rainisio M Frey A Neuhart E Vered Z Dingemanse J Torre-Amione G 《European journal of heart failure》2004,6(5):601-609
BACKGROUND: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). OBJECTIVE: To evaluate the effect of lower doses of tezosentan in patients with AHF. SUBJECTS AND METHODS: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. RESULTS: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. CONCLUSIONS: In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h. 相似文献
82.
83.
Chen CP Posy S Ben-Shaul A Shapiro L Honig BH 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(24):8531-8536
Cadherins constitute a family of cell-surface proteins that mediate intercellular adhesion through the association of protomers presented from juxtaposed cells. Differential cadherin expression leads to highly specific intercellular interactions in vivo. This cell-cell specificity is difficult to understand at the molecular level because individual cadherins within a given subfamily are highly similar to each other both in sequence and structure, and they dimerize with remarkably low binding affinities. Here, we provide a molecular model that accounts for these apparently contradictory observations. The model is based in part on the fact that cadherins bind to one another by "swapping" the N-terminal beta-strands of their adhesive domains. An inherent feature of strand swapping (or, more generally, the domain swapping phenomenon) is that "closed" monomeric conformations act as competitive inhibitors of dimer formation, thus lowering affinities even when the dimer interface has the characteristics of high-affinity complexes. The model describes quantitatively how small affinity differences between low-affinity cadherin dimers are amplified by multiple cadherin interactions to establish large specificity effects at the cellular level. It is shown that cellular specificity would not be observed if cadherins bound with high affinities, thus emphasizing the crucial role of strand swapping in cell-cell adhesion. Numerical estimates demonstrate that the strength of cellular adhesion is extremely sensitive to the concentration of cadherins expressed at the cell surface. We suggest that the domain swapping mechanism is used by a variety of cell-adhesion proteins and that related mechanisms to control affinity and specificity are exploited in other systems. 相似文献
84.
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86.
Chetanya Pandya Shoshana Brown Ursula Pieper Andrej Sali Debra Dunaway-Mariano Patricia C. Babbitt Yu Xia Karen N. Allen 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(36):E3381-E3387
Although the universe of protein structures is vast, these innumerable structures can be categorized into a finite number of folds. New functions commonly evolve by elaboration of existing scaffolds, for example, via domain insertions. Thus, understanding structural diversity of a protein fold evolving via domain insertions is a fundamental challenge. The haloalkanoic dehalogenase superfamily serves as an excellent model system wherein a variable cap domain accessorizes the ubiquitous Rossmann-fold core domain. Here, we determine the impact of the cap-domain insertion on the sequence and structure divergence of the core domain. Through quantitative analysis on a unique dataset of 154 core-domain-only and cap-domain-only structures, basic principles of their evolution have been uncovered. The relationship between sequence and structure divergence of the core domain is shown to be monotonic and independent of the corresponding type of domain insert, reflecting the robustness of the Rossmann fold to mutation. However, core domains with the same cap type share greater similarity at the sequence and structure levels, suggesting interplay between the cap and core domains. Notably, results reveal that the variance in structure maps to α-helices flanking the central β-sheet and not to the domain–domain interface. Collectively, these results hint at intramolecular coevolution where the fold diverges differentially in the context of an accessory domain, a feature that might also apply to other multidomain superfamilies.The universe of protein structures is vast and diverse, yet these innumerable structures can be categorized into a finite number of folds (1). Ideally, the protein fold has a robust yet evolvable architecture to deliver chemistry, bind interaction partners, or provide scaffolding. A popular strategy for the acquisition of new function(s) is the topological alteration of the fold to provide a new evolutionary platform. More frequently, existing and stable scaffolds are elaborated to attain diversity that is due to accumulation of stochastic, independent, and near-neutral mutations in the protein sequence. In a large number of cases, the expansion of functional space has been achieved by the tandem fusion of two or three domains to form evolutionary modules known as supradomains (2). An analysis of catalytic domains fused to the nucleotide-binding Rossmann domain has revealed that the sequential order of their connections is conserved because each pairing arose from a single recombination event (3). Another common structural embellishment is that of domain insertion(s) into existing folds (4)—a strategy that is ubiquitous in all structural classes, i.e., all α, all β, α + β, and α/β (5). For example, members of the A, B, and Y DNA polymerase superfamilies, Rab geranylgeranyl transferase superfamily, and alcohol dehydrogenase superfamily have inserted different domains into the native fold to fine tune their cellular functions (6–8). The analysis of such noncontiguous domain organization has been facilitated by the availability of structures bearing insertions of domains that also occur as independent folds. It has been estimated that 9% of domain combinations observed in protein-structure databases are insertions (5). However, the way in which the sequence–structure relationship changes within a protein fold in the context of such domain insertions has yet to be fully understood. In this study, we assess how the insertion of an accessory domain affects the sequence–structure relationship of the Rossmann fold, a superfold used by at least 10 different protein superfamilies (9).Function-driven changes come with their own costs: most molecular modifications of proteins tend to be thermodynamically destabilizing (10). Although long hypothesized (11), it has been shown only recently that the stability of a fold promotes evolvability by allowing a high degree of structural plasticity (12). As a consequence, protein folds follow a power-law distribution where a few intrinsically stable folds, referred to as superfolds, have numerous members, and a multitude of folds have few members (9). Due to this interplay between stability and evolvability, it has been suggested that superfolds are compatible with a much larger set of sequences than other folds (13). This proposal raises the question of how protein sequence and structural diversity are related to one another. Pioneering work by Chothia and Lesk (14) illustrated that structural similarity is correlated with sequence similarity. Although the 3D structure retains the common fold during neutral drift, it undergoes subtle changes as sequence diverges, mainly due to packing modifications and backbone conformational changes. In a focused study, Halaby et al. (15) have shown that sequence diverges to a greater extent than structure in the Ig fold. More recently, Panchenko and coworkers noted a similar trend in a systematic study spanning 81 homologous protein families (16).We queried how large inserts into a protein fold shape the relationship between sequence and structure divergence, using as a model system, the Haloalkanoate Dehalogenase Superfamily (HADSF), where the inserts into a Rossmann catalytic domain impart substrate specificity. The HADSF is a highly successful family, and, with close to 80,000 members to date (17), it is one of the largest enzyme superfamilies. The HADSF is well-represented in all domains of life, and the majority of its members catalyze phosphate ester hydrolysis (18, 19). HADSF members have attained functional diversity via accessorization of the conserved core Rossmann-fold domain by the insertion of a cap domain. The Rossmann fold is a primordial nucleotide-binding fold that plays a significant role in maintenance and evolution of life (6). Structurally, it is organized as a three-layered sandwich made up of multiple α/β units. The fold is similar across superfamilies, apart from stochastic thermal fluctuations and structural divergence. Notably, the inserted cap domains in the HADSF have not yet been observed as independent folds in extant organisms (the term domain is defined here as an apparently stable arrangement of secondary structural units). The presence of the cap domains leads to a natural classification of the superfamily into different structural classes—C0 (no or minimal cap insert), C1 (α-helical cap insert after the first strand), C2 (α-helical and β-strand cap insert after the third strand, further subdivided into C2a and C2b depending on topology), and C1 + C2 (inserts in both positions), based on topology and location of the insert (20) (SI Appendix, Fig. S1). These characteristics make the HADSF an excellent model system for the study of the sequence–structure–function relationship in multidomain proteins.The unique cap–core architecture of the HADSF raises several intriguing biophysical and biochemical questions regarding molecular evolution. In a typical HADSF member, the substrate leaving group and the phosphoryl group are bound by the cap and core domains, respectively. However, binding and catalysis cannot be independent of one another (reflected in the definition of the specificity constant kcat/Km). How this functional codependence between the two domains manifests itself in the structure is an important question with implications for evolution and rational design of multidomain proteins. As cap and core domains form a single polypeptide chain, substrate binding and catalysis are inherently linked although the details of this linkage have yet to be defined. Another perplexing issue is the evolutionary mechanism of cap-domain evolution. Did it involve a rapid stage where the cap domain was grafted onto the core domain, followed by a slow stage where neutral mutations were accumulated? Or was there a gradual and continuous change where a small cap domain was inserted followed by subsequent duplication and elaboration? Herein, we attempt to answer such questions by analyzing a unique dataset of core-domain-only and cap-domain-only structures using quantitative informatics analyses. The relationship between sequence and structure divergence in the core fold is shown to be monotonic, as is generally the case, and notably, to be independent of the corresponding cap type. However, core domains with the same cap type bear a greater similarity at the sequence and structure level than do the core domains with different cap types, suggesting interplay between the cap and core domains. Surprisingly, we find that the variation between cap types maps to the flanking helices of the Rossmann fold rather than to the interface, suggesting that the core has changed more globally to accommodate the cap. Overall, our results suggest that the structure space of a superfamily has an underlying organizing principle despite its diversity. 相似文献
87.
循环中胰岛素样生长因子-Ⅰ水平调节结肠癌的生长和转移研究 总被引:1,自引:0,他引:1
目的 探讨血清中肝特异性胰岛素样生长因子 Ⅰ (IGF Ⅰ )水平在刺激小鼠结肠癌生长和转移中的作用。方法 我们实验中所用的肝脏特异性IGF Ⅰ基因缺失 (LID)小鼠 ,其循环中IGF Ⅰ水平仅为正常小鼠 (对照组小鼠 )的 2 5 %。将Colon 3 8腺癌组织块 (碎片 )植入LID和对照组小鼠的盲肠表面。总共 15 6只 5周龄的雄鼠 (其中 82只LID小鼠 ,74只对照鼠 )接受了肿瘤移植。小鼠被随机分成两组 :一组接受腹腔注射重组人IGF 1(rhIGF 1) ,每天 2次 ,共 6周 ,另一组接受生理盐水注射。结果 接受rhIGF Ⅰ注射组的LID和对照小鼠 ,血清IGF 1和IGFBP 3水平均升高。在生理盐水注射组中 ,对照鼠的盲肠肿瘤的发生率和肝脏转移率显著高于LID小鼠。和盐水注射组相比 ,腹腔注射rhIGF 1组中 ,LID和对照组小鼠均有显著的盲肠癌发生率和肝脏转移率。对照小鼠的肝脏转移结节数明显高于LID鼠。结肠癌组织VEGF的表达和血管的密度依赖于血液中IGF Ⅰ水平。结论 血液循环中IGF I水平在结肠癌发展和转移中起了重要作用。 相似文献
88.
This paper describes the profile of the Israel Society for the Prevention of Alcoholism (ISPA), which is a nation-wide, public, non-profit association. It portrays various aspects of ISPA treatment and rehabilitation facilities-the residential treatment center, the rehabilitative hostel and the 'warm home' for homeless alcoholics. It depicts ISPA prevention activities, prevention materials and its usage of the media, and deals with ISPA involvement in policy issues. The paper also addresses the research reality of ISPA and its scientific journal, and refers to the society's structure and its future. 相似文献
89.
Shoshana Naider-Steinhart Michal Katz-Leurer 《The American journal of occupational therapy》2007,61(4):392-398
OBJECTIVE: In this study we sought to describe upper-extremity proximal and distal muscle activity in typically developing children during a handwriting task and to explore the relationship between muscle activity and speed and quality of writing. METHOD: We evaluated 35 third- and fourth-grade Israeli children using the Alef-Alef Ktav Yad Hebrew Handwriting Test. Simultaneously, we recorded the participants' upper trapezius and thumb muscle activity by surface electromyography. Using the coefficient of variation (standard deviation divided by mean amplitude) as a measure of variability within each muscle, we analyzed differences in muscle activity variability within and between muscles. RESULTS: The proximal muscle displayed significantly less variability than the distal muscles. Decreased variability in proximal muscle activity was associated with decreased variability in distal muscle activity, and decreased variability in the distal muscles was significantly associated with faster speed of writing. CONCLUSION: The lower amount of variability exhibited in the proximal muscle compared with the distal muscles seems to indicate that the proximal muscle functions as a stabilizer during a handwriting task. In addition, decreased variability in both proximal and distal muscle activity appears to be more economical and is related to faster writing speed. Knowledge of the type of proximal and distal muscle activity used during handwriting can help occupational therapists plan treatment for children with handwriting disabilities. 相似文献
90.
P. Ben Meir A. Sagi L. Rosenberg D. Hauben Y. Ben Yakar H. Zirkin D. Mahler 《European journal of plastic surgery》1987,10(4):155-158
Summary Two cases of malignant fibrous histiocytoma are presented. The clinicopathologic findings are also reported. The disease was of fast growing pattern and the outcome of one of the cases very rapid. The relative literature is reviewed and the histogenesis is emphasized. 相似文献