全文获取类型
收费全文 | 475篇 |
免费 | 68篇 |
国内免费 | 1篇 |
出版年
2021年 | 4篇 |
2019年 | 3篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 16篇 |
2014年 | 18篇 |
2013年 | 19篇 |
2012年 | 23篇 |
2011年 | 30篇 |
2010年 | 28篇 |
2009年 | 14篇 |
2008年 | 31篇 |
2007年 | 45篇 |
2006年 | 32篇 |
2005年 | 35篇 |
2004年 | 36篇 |
2003年 | 41篇 |
2002年 | 25篇 |
2001年 | 9篇 |
2000年 | 7篇 |
1999年 | 6篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1993年 | 8篇 |
1992年 | 5篇 |
1991年 | 9篇 |
1990年 | 8篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1987年 | 5篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1941年 | 1篇 |
排序方式: 共有544条查询结果,搜索用时 15 毫秒
71.
Dull RO Cluff M Kingston J Hill D Chen H Hoehne S Malleske DT Kaur R 《American journal of physiology. Lung cellular and molecular physiology》2012,302(9):L816-L828
Lung endothelial cells respond to changes in vascular pressure through mechanotransduction pathways that alter barrier function via non-Starling mechanism(s). Components of the endothelial glycocalyx have been shown to participate in mechanotransduction in vitro and in systemic vessels, but the glycocalyx's role in mechanosensing and pulmonary barrier function has not been characterized. Mechanotransduction pathways may represent novel targets for therapeutic intervention during states of elevated pulmonary pressure such as acute heart failure, fluid overload, and mechanical ventilation. Our objective was to assess the effects of increasing vascular pressure on whole lung filtration coefficient (K(fc)) and characterize the role of endothelial heparan sulfates in mediating mechanotransduction and associated increases in K(fc). Isolated perfused rat lung preparation was used to measure K(fc) in response to changes in vascular pressure in combination with superimposed changes in airway pressure. The roles of heparan sulfates, nitric oxide, and reactive oxygen species were investigated. Increases in capillary pressure altered K(fc) in a nonlinear relationship, suggesting non-Starling mechanism(s). nitro-l-arginine methyl ester and heparanase III attenuated the effects of increased capillary pressure on K(fc), demonstrating active mechanotransduction leading to barrier dysfunction. The nitric oxide (NO) donor S-nitrosoglutathione exacerbated pressure-mediated increase in K(fc). Ventilation strategies altered lung NO concentration and the K(fc) response to increases in vascular pressure. This is the first study to demonstrate a role for the glycocalyx in whole lung mechanotransduction and has important implications in understanding the regulation of vascular permeability in the context of vascular pressure, fluid status, and ventilation strategies. 相似文献
72.
Skin regeneration in adult axolotls: a blueprint for scar-free healing in vertebrates 总被引:1,自引:0,他引:1
While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. 相似文献
73.
Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load 总被引:1,自引:0,他引:1
The biogenesis of endoplasmic reticulum (ER) exit sites (ERES) involves the formation of phosphatidylinositol-4 phosphate (PI4) and Sec16, but it is entirely unknown how ERES adapt to variations in cargo load. Here, we studied acute and chronic adaptive responses of ERES to an increase in cargo load for ER export. The acute response (within minutes) to increased cargo load stimulated ERES fusion events, leading to larger but less ERES. Silencing either PI4-kinase IIIα (PI4K-IIIα) or Sec16 inhibited the acute response. Overexpression of secretory cargo for 24 h induced the unfolded protein response (UPR), upregulated COPII, and the cells formed more ERES. This chronic response was insensitive to silencing PI4K-IIIα, but was abrogated by silencing Sec16. The UPR was required as the chronic response was absent in cells lacking inositol-requiring protein 1. Mathematical model simulations further support the notion that increasing ERES number together with COPII levels is an efficient way to enhance the secretory flux. These results indicate that chronic and acute increases in cargo load are handled differentially by ERES and are regulated by different factors. 相似文献
74.
Randal C. Burns Robert M. Rees Larry J. Stockmeyer Darrell D.E. Long 《Cluster computing》2001,4(4):295-306
File systems provide an interface for applications to obtain exclusive access to files, in which a process holds privileges to a file that cannot be preempted and restrict the capabilities of other processes. Local file systems do this by maintaining information about the privileges of current file sessions, and checking subsequent sessions for compatibility. Implementing exclusive access in this manner for distributed file systems degrades performance by requiring every new file session to be registered with a lock server that maintains global session state. We present two techniques for improving the performance of session management in the distributed environment. We introduce a distributed lock for managing file access, called a semi-preemptible lock, that allows clients to cache privileges. Under a semi-preemptible lock, a file system creates new sessions without messages to the lock manager. This improves performance by exploiting locality – the affinity of files to clients. We also present data structures and algorithms for the dynamic evaluation of locks that allow a distributed file system to efficiently manage arbitrarily complex locking. In this case, complex means that an object can be locked in a large number of unique modes. The combination of these techniques results in a distributed locking scheme that supports fine-grained concurrency control with low memory and message overhead and with the assurance that their locking system is correct and avoids unnecessary deadlocks. 相似文献
75.
Gary E Gilbert Randal J Kaufman Andrew A Arena Hongzhi Miao Steven W Pipe 《The Journal of biological chemistry》2002,277(8):6374-6381
Factor VIII binds to phospholipid membranes and to von Willebrand factor (vWf) via its second C domain, which has lectin homology. The crystal structure of the C2 domain has prompted a model in which membrane binding is mediated by two hydrophobic spikes, each composed of a pair of residues displayed on a beta-hairpin turn, and also by net positive charge and specific interactions with phospho-l-serine. To test this model, we prepared 16 factor VIII mutants in which single or multiple amino acids were changed to alanine. Mutants at Arg(2215), Arg(2220), Lys(2227), Lys(2249), Gln(2213), Asn(2217), and Phe(2196)/Thr(2197) had specific activities that were >70% of the wild type. Mutants at Arg(2209), Lys(2227), Trp(2313), and Arg(2320) were degraded within the cell. Hydrophobic spike mutants at Met(2199)/Phe(2200), Leu(2251)/Leu(2252), and Met(2199)/Phe(2200)/Leu(2251)/Leu(2252) (4-Ala) exhibited 43, 59, and 91% reduction in specific activity in the activated partial thromboplastin time assay. In a phospholipid-limiting factor Xa activation assay, these mutants had a 65, 85, and 96% reduction in specific activity. Equilibrium binding of fluorescent, sonicated phospholipid vesicles to mutants immobilized on Superose beads was measured by flow cytometry. The affinities for phospholipid were reduced approximately 20-, 30-, and >35-fold for 2199/2200, 2251/2252, and 4-Ala, respectively. A dimeric form of mature vWf bound to immobilized factor VIII and the same mutants, but the affinities of the mutants were reduced approximately 5-, 10-, and >20-fold, respectively. In a competition, solution phase enzyme-linked immunosorbent assay, plasma vWf bound factor VIII and the same mutants with the affinities for the mutants reduced >5-, >5-, and >50-fold, respectively. We conclude that the two hydrophobic spikes are constituents of both the phospholipid-binding and vWf-binding motifs. In plasma, vWf apparently binds the inherently sticky membrane-binding motif, preventing nonspecific interactions. 相似文献
76.
Following insemination of sea urchin eggs, both the rate of Ca uptake by the eggs and the rate of Ca efflux from the eggs increase (see text for references). We find that both of these components of the egg's Ca response are absent following partial activation with ammonia. This suggests that the so-called “late events” of fertilization, which are activated by ammonia treatment, are not mediated directly by changes in egg Ca. 相似文献
77.
The X-ray structure of a variant of basic pancreatic trypsin inhibitor (BPTI) has been analyzed to determine the structural accommodation resulting from removal of a disulfide cross-link in a protein. The disulfide removed, Cys30-Cys51, has been implicated in both the folding pathway of the protein and its overall thermal stability. In the variant studied, C30A/C51A, the disulfide cysteines were replaced by less bulky alanines. The atomic displacements observed for C30A/C51A indicate a set of concerted shifts of two segments of chains, which together significantly diminish a packing defect at the site of the removed cysteine sulfur atoms. The observed structural changes are distributed asymmetrically around the sites of mutation, indicating that the adjacent beta-sheet is more resistant to the perturbation than the alpha-helix on the opposite side of the disulfide bond. The thermal parameters of groups involved in the structural accommodation are not significantly altered. A comparison of the X-ray structures reported for native BPTI determined in three different crystal forms indicates that the magnitude of its conformational variability exceeds that of the structural changes caused by the disulfide removal. This emphasizes the necessity of using isomorphous crystal systems to determine the relatively small effects due to mutation. 相似文献
78.
79.
Zac Yates Kannan Gunasekaran Hongxing Zhou Zhonghua Hu Zhi Liu Randal R. Ketchem Boxu Yan 《The Journal of biological chemistry》2010,285(24):18662-18671
Hydroxyl radicals induce hinge cleavage in a human IgG1 molecule via initial radical formation at the first hinge Cys231 followed by electron transfer to the upper hinge residues. To enable engineering of a stable monoclonal antibody hinge, we investigated the role of the hinge His229 residue using structure modeling and site-directed mutagenesis. Direct involvement of His229 in the reaction mechanism is suggested by a 75–85% reduction of the hinge cleavage for variants in which His229 was substituted with either Gln, Ser, or Ala. In contrast, mutation of Lys227 to Gln, Ser, or Ala increased hinge cleavage. However, the H229S/K227S double mutant shows hinge cleavage levels similar to that of the single H229S variant, further revealing the importance of His229. Examination of the hinge structure shows that His229 is capable of forming hydrogen bonds with surrounding residues. These observations led us to hypothesize that the imidazole ring of His229 may function to facilitate the cleavage by forming a transient radical center that is capable of extracting a proton from neighboring residues. The work presented here suggests the feasibility of engineering a new generation of monoclonal antibodies capable of resisting hinge cleavage to improve product stability and efficacy. 相似文献
80.