全文获取类型
收费全文 | 475篇 |
免费 | 41篇 |
出版年
2023年 | 4篇 |
2022年 | 3篇 |
2021年 | 15篇 |
2020年 | 6篇 |
2019年 | 8篇 |
2018年 | 6篇 |
2017年 | 8篇 |
2016年 | 16篇 |
2015年 | 27篇 |
2014年 | 39篇 |
2013年 | 16篇 |
2012年 | 42篇 |
2011年 | 33篇 |
2010年 | 28篇 |
2009年 | 24篇 |
2008年 | 24篇 |
2007年 | 37篇 |
2006年 | 35篇 |
2005年 | 27篇 |
2004年 | 20篇 |
2003年 | 31篇 |
2002年 | 23篇 |
2001年 | 5篇 |
2000年 | 1篇 |
1999年 | 6篇 |
1998年 | 2篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1978年 | 1篇 |
1973年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有516条查询结果,搜索用时 15 毫秒
71.
Marie‐Josée Demers Sonya Thibodeau Dominique Noël Naoya Fujita Takashi Tsuruo Rémy Gauthier Mélina Arguin Pierre H. Vachon 《Journal of cellular biochemistry》2009,107(4):639-654
Herein, we investigated the survival roles of Fak, Src, MEK/Erk, and PI3‐K/Akt‐1 in intestinal epithelial cancer cells (HCT116, HT29, and T84), in comparison to undifferentiated and differentiated intestinal epithelial cells (IECs). We report that: (1) cancer cells display striking anoikis resistance, as opposed to undifferentiated/differentiated IECs; (2) under anoikis conditions and consequent Fak down‐activation, cancer cells nevertheless exhibit sustained Fak–Src interactions and Src/MEK/Erk activation, unlike undifferentiated/differentiated IECs; however, HCT116 and HT29 cells exhibit a PI3‐K/Akt‐1 down‐activation, as undifferentiated/differentiated IECs, whereas T84 cells do not; (3) cancer cells require MEK/Erk for survival, as differentiated (but not undifferentiated) IECs; however, T84 cells do not require Fak and HCT116 cells do not require PI3‐K/Akt‐1, in contrast to the other cells studied; (4) Src acts as a cornerstone in Fak‐mediated signaling to MEK/Erk and PI3‐K/Akt‐1 in T84 cells, as in undifferentiated IECs, whereas PI3‐K/Akt‐1 is Src‐independent in HCT116, HT29 cells, as in differentiated IECs; and (5) EGFR activity inhibition abrogates anoikis resistance in cancer cells through a loss of Fak–Src interactions and down‐activation of Src/MEK/Erk (T84, HCT116, HT29 cells) and PI3‐K/Akt‐1 (T84 cells). Hence, despite distinctions in signaling behavior not necessarily related to undifferentiated or differentiated IECs, intestinal epithelial cancer cells commonly display an EGFR‐mediated sustained activation of Src under anoikis conditions. Furthermore, such sustained Src activation confers anoikis resistance at least in part through a consequent sustenance of Fak–Src interactions and MEK/Erk activation, thus not only overriding Fak‐mediated signaling to MEK/Erk and/or PI3‐K/Akt‐1, but also the requirement of Fak and/or PI3‐K/Akt‐1 for survival. J. Cell. Biochem. 107: 639–654, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
72.
Huizhi Zhao Dong Wang Bing Liu Xingpeng Jiang Jing Zhang Ming Fan Zhengjie Fan Ying Chen Sonya Wei Song Wei Gao Tianzi Jiang Qinghua Cui 《Biochemical and biophysical research communications》2009,379(3):702-705
The fact that microRNAs play a role in almost all biological processes is well established, as is the importance of recombination in generating genome variability. However, the association between microRNAs and recombination remains largely unknown. In order to investigate the recombination patterns of microRNAs, we performed a comprehensive analysis of the recombination rate of human microRNAs. We observed that microRNAs that are expressed in several tissues tend to have lower recombination rates than tissue-specific microRNAs. Additionally, microRNAs that are associated with a number of diseases are also likely to have lower recombination rates. Furthermore, microRNAs with higher expression levels are found to have fewer recombination events. These findings reveal patterns in recombination rates of microRNAs that could help in understanding the function, evolution, and disease-related roles of microRNAs. 相似文献
73.
74.
Zheng GZ Bhatia P Kolasa T Patel M El Kouhen OF Chang R Uchic ME Miller L Baker S Lehto SG Honore P Wetter JM Marsh KC Moreland RB Brioni JD Stewart AO 《Bioorganic & medicinal chemistry letters》2006,16(18):4936-4940
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models. 相似文献
75.
The role of mutation rate in optimizing key features of evolutionary dynamics has recently been investigated in various computational models. Here, we address the related question of how maximum mutation size affects the formation of species in a simple computational evolutionary model. We find that the number of species is maximized for intermediate values of a mutation size parameter μ; the result is observed for evolving organisms on a randomly changing landscape as well as in a version of the model where negative feedback exists between the local population size and the fitness provided by the landscape. The same result is observed for various distributions of mutation values within the limits set by μ. When organisms with various values of μ compete against each other, those with intermediate μ values are found to survive. The surviving values of μ from these competition simulations, however, do not necessarily coincide with the values that maximize the number of species. These results suggest that various complex factors are involved in determining optimal mutation parameters for any population, and may also suggest approaches for building a computational bridge between the (micro) dynamics of mutations at the level of individual organisms and (macro) evolutionary dynamics at the species level. 相似文献
76.
Simmonds MJ Meiselman HJ Marshall-Gradisnik SM Pyne M Kakanis M Keane J Brenu E Christy R Baskurt OK 《Biorheology》2011,48(5):293-304
The present study was designed to investigate the oxidant susceptibility of red blood cells (RBC) from four species (echidna, human, koala, Tasmanian devil) based on changes in cellular deformability. These species were specifically chosen based on differences in lifestyle and/or biology associated with varied levels of oxidative stress. The major focus was the influence of superoxide radicals generated within the cell (phenazine methosulfate, PMS, 50 μM) or in the extracellular medium (xanthine oxidase-hypoxanthine, XO-HX, 0.1 U/ml XO) on RBC deformability at various shear stresses (SS). RBC deformability was assessed by laser-diffraction analysis using a "slit-flow ektacytometer". Both superoxide-generating treatments resulted in significant increases of methemoglobin for all species (p < 0.01), with Tasmanian devil RBC demonstrating the most sensitivity to either treatment. PMS caused impaired RBC deformability for all species, but vast interspecies variations were observed: human and koala cells exhibited a similar sigmoid-like response to SS, short-beaked echidna values were markedly lower and only increased slightly with SS, while Tasmanian devil RBC were extremely rigid. The effect of XO-HX on RBC deformability was less when compared with PMS (i.e., smaller increase in rigidity) with the exception of Tasmanian devil RBC which exhibited essentially no deformation even at the highest SS; Tasmanian devil RBC response to XO-HX was thus comparable to that observed with PMS. Our findings indicate that ektacytometry can be used to determine the oxidant susceptibility of RBC from different species which varies significantly among mammals representing diverse lifestyles and evolutionary histories. These differences in susceptibility are consistent with species-specific discrepancies between observed and allometrically-predicted life spans and are compatible with the oxidant theory of aging. 相似文献
77.
Lee SY Buhimschi IA Dulay AT Ali UA Zhao G Abdel-Razeq SS Bahtiyar MO Thung SF Funai EF Buhimschi CS 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(5):3226-3236
Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130. 相似文献
78.
Eric J. Sturman Timothy J. Rydel Meiying Zheng Jeffrey W. Seale Sonya Franklin 《Protein science : a publication of the Protein Society》2014,23(11):1491-1497
For almost half a century, the structure of the full‐length Bacillus thuringiensis (Bt) insecticidal protein Cry1Ac has eluded researchers, since Bt‐derived crystals were first characterized in 1965. Having finally solved this structure we report intriguing details of the lattice‐based interactions between the toxic core of the protein and the protoxin domains. The structure provides concrete evidence for the function of the protoxin as an enhancer of native crystal packing and stability. 相似文献
79.
80.
Joaquín A. Blaya Sonya S. Shin Martin Yagui Carmen Contreras Peter Cegielski Gloria Yale Carmen Suarez Luis Asencios Jaime Bayona Jihoon Kim Hamish S. F. Fraser 《PloS one》2014,9(4)