全文获取类型
收费全文 | 1736篇 |
免费 | 125篇 |
出版年
2022年 | 7篇 |
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 13篇 |
2018年 | 16篇 |
2017年 | 17篇 |
2016年 | 41篇 |
2015年 | 61篇 |
2014年 | 88篇 |
2013年 | 106篇 |
2012年 | 148篇 |
2011年 | 192篇 |
2010年 | 131篇 |
2009年 | 97篇 |
2008年 | 104篇 |
2007年 | 84篇 |
2006年 | 75篇 |
2005年 | 67篇 |
2004年 | 86篇 |
2003年 | 79篇 |
2002年 | 74篇 |
2001年 | 10篇 |
2000年 | 11篇 |
1999年 | 16篇 |
1998年 | 32篇 |
1997年 | 12篇 |
1996年 | 19篇 |
1995年 | 16篇 |
1994年 | 16篇 |
1993年 | 12篇 |
1992年 | 12篇 |
1991年 | 18篇 |
1990年 | 16篇 |
1989年 | 9篇 |
1988年 | 16篇 |
1987年 | 9篇 |
1986年 | 4篇 |
1985年 | 13篇 |
1984年 | 15篇 |
1983年 | 9篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1977年 | 4篇 |
1976年 | 6篇 |
1974年 | 5篇 |
1973年 | 4篇 |
1972年 | 5篇 |
排序方式: 共有1861条查询结果,搜索用时 31 毫秒
131.
Lee KS Raymond LD Schoen B Raymond GJ Kett L Moore RA Johnson LM Taubner L Speare JO Onwubiko HA Baron GS Caughey WS Caughey B 《The Journal of biological chemistry》2007,282(50):36525-36533
Hemin (iron protoporphyrin IX) is a crucial component of many physiological processes acting either as a prosthetic group or as an intracellular messenger. Some unnatural, synthetic porphyrins have potent anti-scrapie activity and can interact with normal prion protein (PrPC). These observations raised the possibility that hemin, as a natural porphyrin, is a physiological ligand for PrPC. Accordingly, we evaluated PrPC interactions with hemin. When hemin (3-10 microM) was added to the medium of cultured cells, clusters of PrPC formed on the cell surface, and the detergent solubility of PrPC decreased. The addition of hemin also induced PrPC internalization and turnover. The ability of hemin to bind directly to PrPC was demonstrated by hemin-agarose affinity chromatography and UV-visible spectroscopy. Multiple hemin molecules bound primarily to the N-terminal third of PrPC, with reduced binding to PrPC lacking residues 34-94. These hemin-PrPC interactions suggest that PrPC may participate in hemin homeostasis, sensing, and/or uptake and that hemin might affect PrPC functions. 相似文献
132.
The porous properties of brain tissue are important for understanding normal and abnormal cerebrospinal fluid flow in the brain. In this study, a poroviscoelastic model was fitted to the stress relaxation response of white matter in unconfined compression performed under a range of low strain rates. A set of experiments was also performed on the tissue samples using a no-slip boundary condition. Results from these experiments demonstrated that the rheological response of the white matter is primarily governed by the intrinsic viscoelastic properties of the solid phase. The permeability of white matter was found to be of the order of 10(-12) m4/Ns. 相似文献
133.
The regulation of molecular motors is an important cellular problem, as motility in the absence of cargo results in futile adenosine triphosphate hydrolysis. When not transporting cargo, the microtubule (MT)-based motor Kinesin-1 is kept inactive as a result of a folded conformation that allows autoinhibition of the N-terminal motor by the C-terminal tail. The simplest model of Kinesin-1 activation posits that cargo binding to nonmotor regions relieves autoinhibition. In this study, we show that binding of the c-Jun N-terminal kinase-interacting protein 1 (JIP1) cargo protein is not sufficient to activate Kinesin-1. Because two regions of the Kinesin-1 tail are required for autoinhibition, we searched for a second molecule that contributes to activation of the motor. We identified fasciculation and elongation protein zeta1 (FEZ1) as a binding partner of kinesin heavy chain. We show that binding of JIP1 and FEZ1 to Kinesin-1 is sufficient to activate the motor for MT binding and motility. These results provide the first demonstration of the activation of a MT-based motor by cellular binding partners. 相似文献
134.
Staufen1 regulates diverse classes of mammalian transcripts 总被引:4,自引:0,他引:4
Kim YK Furic L Parisien M Major F DesGroseillers L Maquat LE 《The EMBO journal》2007,26(11):2670-2681
135.
Stewart CR Wilson LM Zhang Q Pham CL Waddington LJ Staples MK Stapleton D Kelly JW Howlett GJ 《Biochemistry》2007,46(18):5552-5561
Apolipoprotein amyloid deposits and lipid oxidation products are colocalized in human atherosclerotic tissue. In this study we show that the primary ozonolysis product of cholesterol, 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al (KA), rapidly promotes human apolipoprotein (apo) C-II amyloid fibril formation in vitro. Previous studies show that hydrophobic aldehydes, including KA, modify proteins by the formation of a Schiff base with the lysine epsilon-amino group or N-terminal amino group. High-performance liquid chromatography, mass spectrometry, and proteolysis of KA-modified apoC-II revealed that KA randomly modified six different lysine residues, with primarily one KA attached per apoC-II molecule. Competition experiments showed that an aldehyde scavenging compound partially inhibited the ability of KA to hasten apoC-II fibril formation. Conversely, the acid derivative of KA, lacking the ability to form a Schiff base, accelerated apoC-II fibril formation, albeit to a lesser extent, suggesting that amyloidogenesis triggered by KA involves both covalent and noncovalent mechanisms. The viability of a noncovalent mechanism mediated by KA has been observed previously with alpha-synuclein aggregation, implicated in Parkinson's disease. Electron microscopy demonstrated that fibrils formed in the presence of KA had a similar morphology to native fibrils; however, the isolated KA-apoC-II covalent adducts in the absence of unmodified apoC-II formed fibrillar structures with altered ropelike morphologies. KA-mediated fibril formation by apoC-II was inhibited by the addition of the amine-containing compound hydralazine and the lipid-binding protein apoA-I. These in vitro studies suggest that the oxidized small molecule pool could trigger or hasten the aggregation of apoC-II to form amyloid deposits. 相似文献
136.
Molinari AJ Trybulski EJ Bagli J Croce S Considine J Qi J Ali K Demaio W Lihotz L Cochran D 《Bioorganic & medicinal chemistry letters》2007,17(21):5796-5800
Small molecule agonists and antagonists of the V(2)-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan). 相似文献
137.
Biological solutions to transport network design 总被引:3,自引:0,他引:3
Bebber DP Hynes J Darrah PR Boddy L Fricker MD 《Proceedings. Biological sciences / The Royal Society》2007,274(1623):2307-2315
Transport networks are vital components of multicellular organisms, distributing nutrients and removing waste products. Animal and plant transport systems are branching trees whose architecture is linked to universal scaling laws in these organisms. In contrast, many fungi form reticulated mycelia via the branching and fusion of thread-like hyphae that continuously adapt to the environment. Fungal networks have evolved to explore and exploit a patchy environment, rather than ramify through a three-dimensional organism. However, there has been no explicit analysis of the network structures formed, their dynamic behaviour nor how either impact on their ecological function. Using the woodland saprotroph Phanerochaete velutina, we show that fungal networks can display both high transport capacity and robustness to damage. These properties are enhanced as the network grows, while the relative cost of building the network decreases. Thus, mycelia achieve the seemingly competing goals of efficient transport and robustness, with decreasing relative investment, by selective reinforcement and recycling of transport pathways. Fungal networks demonstrate that indeterminate, decentralized systems can yield highly adaptive networks. Understanding how these relatively simple organisms have found effective transport networks through a process of natural selection may inform the design of man-made networks. 相似文献
138.
139.
Baumgartner WA Cohen KB Fox LM Acquaah-Mensah G Hunter L 《Bioinformatics (Oxford, England)》2007,23(13):i41-i48
MOTIVATION: Knowledge base construction has been an area of intense activity and great importance in the growth of computational biology. However, there is little or no history of work on the subject of evaluation of knowledge bases, either with respect to their contents or with respect to the processes by which they are constructed. This article proposes the application of a metric from software engineering known as the found/fixed graph to the problem of evaluating the processes by which genomic knowledge bases are built, as well as the completeness of their contents. RESULTS: Well-understood patterns of change in the found/fixed graph are found to occur in two large publicly available knowledge bases. These patterns suggest that the current manual curation processes will take far too long to complete the annotations of even just the most important model organisms, and that at their current rate of production, they will never be sufficient for completing the annotation of all currently available proteomes. 相似文献
140.
Ducharme NA Williams JA Oztan A Apodaca G Lapierre LA Goldenring JR 《American journal of physiology. Cell physiology》2007,293(3):C1059-C1072
Transcytosis through the apical recycling system of polarized cells is regulated by Rab11a and a series of Rab11a-interacting proteins. We have identified a point mutant in Rab11 family interacting protein 2 (Rab11-FIP2) that alters the function of Rab11a-containing trafficking systems. Rab11-FIP2(S229A/R413G) or Rab11-FIP2(R413G) cause the formation of a tubular cisternal structure containing Rab11a and decrease the rate of polymeric IgA transcytosis. The R413G mutation does not alter Rab11-FIP interactions with any known binding partners. Overexpression of Rab11-FIP2(S229A/R413G) alters the localization of a subpopulation of the apical membrane protein GP135. In contrast, Rab11-FIP2(129-512) alters the localization of early endosome protein EEA1. The distributions of both Rab11-FIP2(S229A/R413G) and Rab11-FIP2(129-512) were not dependent on the integrity of the microtubule cytoskeleton. The results indicate that Rab11-FIP2 regulates trafficking at multiple points within the apical recycling system of polarized cells. Rab11a; immunoglobulin A; trafficking; apical recycling; GP135; early endosome; EEA1; Eps15 homology domain 相似文献