全文获取类型
收费全文 | 771篇 |
免费 | 64篇 |
出版年
2023年 | 15篇 |
2022年 | 17篇 |
2021年 | 29篇 |
2020年 | 13篇 |
2019年 | 14篇 |
2018年 | 18篇 |
2017年 | 24篇 |
2016年 | 17篇 |
2015年 | 49篇 |
2014年 | 49篇 |
2013年 | 43篇 |
2012年 | 63篇 |
2011年 | 63篇 |
2010年 | 43篇 |
2009年 | 20篇 |
2008年 | 28篇 |
2007年 | 36篇 |
2006年 | 28篇 |
2005年 | 32篇 |
2004年 | 18篇 |
2003年 | 31篇 |
2002年 | 24篇 |
2001年 | 25篇 |
2000年 | 21篇 |
1999年 | 13篇 |
1998年 | 9篇 |
1996年 | 6篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1990年 | 8篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 4篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1960年 | 2篇 |
排序方式: 共有835条查询结果,搜索用时 15 毫秒
81.
Woldeamanuel Birru Ross T. Fernley Lloyd D. Graham Julian Grusovin Ronald J. Hill Albert Hofmann Linda Howell Peter J. James Karen E. Jarvis Wynona M. Johnson Dionne A. Jones Christa Leitner Andris J. Liepa George O. Lovrecz Louis Lu Roland H. Nearn Brian J. O’Driscoll Tram Phan Matthew Pollard Kathleen A. Turner David A. Winkler 《Bioorganic & medicinal chemistry》2010,18(15):5647-5660
Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or ‘attractors’. We describe the synthesis, in vitro binding and selected in vivo toxicity data for γ-methylene γ-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket. 相似文献
82.
Ping Fu Guang Jun Liang Sahil S. Khot Robert Phan Leon A. Bach 《Journal of cellular physiology》2010,224(3):636-643
Insulin‐like growth factor binding protein‐6 (IGFBP‐6) inhibits the tumorigenic properties of IGF‐II‐dependent cancer cells by directly inhibiting IGF‐II actions. However, in some cases, IGFBP‐6 is associated with increased cancer cell tumorigenicity, which is unlikely to be due to IGF‐II inhibition. The mechanisms underlying the contradictory actions of IGFBP‐6 remain unclear. We recently generated an IGFBP‐6 mutant that does not bind IGFs (mIGFBP‐6) to address this issue. Although RD rhabdomyosarcoma cells express IGF‐II, we previously showed that mIGFBP‐6 promoted migration through an IGF‐independent, p38‐dependent pathway. We further studied the role of MAP kinases in IGFBP‐6‐induced migration of Rh30 rhabdomyosarcoma cells, which also express IGF‐II. In these cells, mIGFBP‐6 induced chemotaxis rather than chemokinesis. Both wild‐type (wt) and mIGFBP‐6 transiently induced phosphorylation of ERK1/2 and JNK1, but not p38. Inhibition of ERK1/2 phosphorylation completely prevented mIGFBP‐6‐induced ERK1/2 activation and cell migration, whereas a JNK inhibitor partially prevented migration. Interestingly, p38 pathway inhibition completely prevented mIGFBP‐6‐induced ERK1/2 and JNK1 activation and migration despite mIGFBP‐6 not activating p38. Furthermore, blocking the ERK1/2 pathway also inhibited mIGFBP‐6‐induced JNK1 activation. In contrast, IGFBP‐6 had no effect on Akt phosphorylation and an Akt inhibitor had no effect on migration. These results indicate that IGFBP‐6 promotes Rh30 rhabdomyosarcoma chemotaxis in an IGF‐independent manner, and that MAPK signaling pathways and their cross‐talk play an important role in this process. Therefore, besides decreasing Rh30 cell proliferation by inhibiting IGF‐II, IGFBP‐6 promotes their migration via a distinct pathway. Understanding these disparate actions of IGFBP‐6 may lead to the development of novel cancer therapeutics. J. Cell. Physiol. 224: 636–643, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
83.
Michael A. Kiebish Rob Bell Kui Yang Toan Phan Zhongdan Zhao William Ames Thomas N. Seyfried Richard W. Gross Jeffrey H. Chuang Xianlin Han 《Journal of lipid research》2010,51(8):2153-2170
Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality. Differences in cardiolipin species exist in a variety of tissues and diseases. It has been demonstrated that the cardiolipin profile is a key modulator of the functions of many mitochondrial proteins. However, the chemical mechanism(s) leading to normal and/or pathological distribution of cardiolipin species remain elusive. Herein, we describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecificity, and isomeric composition of cardiolipin species. Generated cardiolipin profiles were nearly identical to those determined by shotgun lipidomics. Importantly, the simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Finally, unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profiles. Collectively, we described, verified, and demonstrated a novel approach by integrating both lipidomic analysis and dynamic simulation to study cardiolipin biology. We believe this study provides a foundation to investigate cardiolipin metabolism and bioenergetic homeostasis in normal and disease states. 相似文献
84.
85.
86.
Swers JS Widom A Phan U Springer TA Wittrup KD 《Biochemical and biophysical research communications》2006,350(3):508-513
We have characterized the IgG form of a previously isolated and engineered single-chain Fv (scFv), named RR2r3s4-1, that binds to human PSGL-1. This fully human IgG was determined to have a Kd of 1.8+/-0.7 nM by fluorescence quenching titration. It better inhibits P-selectin-PSGL-1 interactions than a commercially available murine monoclonal antibody KPL1 and better inhibits neutrophil rolling than KPL1. Thus, RR2r3s4-1 is the most effective antibody at inhibiting P-selectin-PSGL-1 interactions known. Specificity analysis reveals that RR2r3s4-1 does not cross react with murine PSGL-1 and thus requires more than tyrosine sulfate for binding to human PSGL-1. This evidence demonstrates the therapeutic potential of this antibody as a potent anti-inflammatory therapeutic. 相似文献
87.
Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia 总被引:1,自引:0,他引:1
de Jong MD Simmons CP Thanh TT Hien VM Smith GJ Chau TN Hoang DM Chau NV Khanh TH Dong VC Qui PT Cam BV Ha do Q Guan Y Peiris JS Chinh NT Hien TT Farrar J 《Nature medicine》2006,12(10):1203-1207
Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment. 相似文献
88.
Christopher G. Ford Subramaniapillai Kolappan Hanh T. H. Phan Matthew K. Waldor Hanne C. Winther-Larsen Lisa Craig 《The Journal of biological chemistry》2012,287(43):36258-36272
Vibrio cholerae colonize the small intestine where they secrete cholera toxin, an ADP-ribosylating enzyme that is responsible for the voluminous diarrhea characteristic of cholera disease. The genes encoding cholera toxin are located on the genome of the filamentous bacteriophage, CTXφ, that integrates as a prophage into the V. cholerae chromosome. CTXφ infection of V. cholerae requires the toxin-coregulated pilus and the periplasmic protein TolA. This infection process parallels that of Escherichia coli infection by the Ff family of filamentous coliphage. Here we demonstrate a direct interaction between the N-terminal domain of the CTXφ minor coat protein pIII (pIII-N1) and the C-terminal domain of TolA (TolA-C) and present x-ray crystal structures of pIII-N1 alone and in complex with TolA-C. The structures of CTXφ pIII-N1 and V. cholerae TolA-C are similar to coliphage pIII-N1 and E. coli TolA-C, respectively, yet these proteins bind via a distinct interface that in E. coli TolA corresponds to a colicin binding site. Our data suggest that the TolA binding site on pIII-N1 of CTXφ is accessible in the native pIII protein. This contrasts with the Ff family phage, where the TolA binding site on pIII is blocked and requires a pilus-induced unfolding event to become exposed. We propose that CTXφ pIII accesses the periplasmic TolA through retraction of toxin-coregulated pilus, which brings the phage through the outer membrane pilus secretin channel. These data help to explain the process by which CTXφ converts a harmless marine microbe into a deadly human pathogen. 相似文献
89.
Brassinosteroids (BRs) and polyamines (PAs) are well-established growth regulators playing key roles in stress management among plants. In the present study, we evaluated the effects of epibrassinolide (EBL, an active BR) and spermidine (Spd, an active PA) on the tolerance of radish to oxidative stress induced by Cr (VI) metal. Our investigation aimed to study the impacts of EBL (10(-9) M) and/or Spd (1 mM) on the biochemical and physiological responses of radish (Raphanus sativus L.) under Cr-stress. Applications of EBL and/or Spd were found to improve growth of Cr-stressed seedlings in terms of root length, shoot length and fresh weight. Our data also indicated that applications of EBL and Spd have significant impacts, particularly when applied together, on the endogenous titers of PAs, free and bound forms of IAA and ABA in seedlings treated with Cr-stress. Additionally, co-applications of EBL and Spd modulated more remarkably the titers of antioxidants (glutathione, ascorbic acid, proline, glycine betaine and total phenol) and activities of antioxidant enzymes (guaicol peroxidase, catalase, superoxide dismutase and glutathione reductase) in Cr-stressed plants than their individual applications. Attenuation of Cr-stress by EBL and/or Spd (more efficient with EBL and Spd combination) was also supported by enhanced values of stress indices, such as phytochelatins, photosynthetic pigments and total soluble sugars, and reduction in malondialdehyde and H(2)O(2) levels in Cr-treated seedlings. Diminution of ROS production and enhanced ROS scavenging capacities were also noted for EBL and/or Spd under Cr-stress. However, no significant reduction in Cr uptake was observed for co-application of EBL and Spd when compared to their individual treatments in Cr-stressed seedlings. Taken together, our results demonstrate that co-applications of EBL and Spd are more effective than their independent treatments in lowering the Cr-induced oxidative stress in radish, leading to improved growth of radish seedlings under Cr-stress. 相似文献
90.
Ho Dang Trung N Le Thi Phuong T Wolbers M Nguyen Van Minh H Nguyen Thanh V Van MP Thieu NT Van TL Song DT Thi PL Thi Phuong TN Van CB Tang V Ngoc Anh TH Nguyen D Trung TP Thi Nam LN Kiem HT Thi Thanh TN Campbell J Caws M Day J de Jong MD Van Vinh CN Van Doorn HR Tinh HT Farrar J Schultsz C;VIZIONS CNS Infection Network 《PloS one》2012,7(5):e37825