全文获取类型
收费全文 | 31953篇 |
免费 | 2757篇 |
国内免费 | 2855篇 |
出版年
2024年 | 55篇 |
2023年 | 382篇 |
2022年 | 723篇 |
2021年 | 1481篇 |
2020年 | 1108篇 |
2019年 | 1366篇 |
2018年 | 1303篇 |
2017年 | 991篇 |
2016年 | 1412篇 |
2015年 | 2089篇 |
2014年 | 2445篇 |
2013年 | 2541篇 |
2012年 | 3033篇 |
2011年 | 2812篇 |
2010年 | 1679篇 |
2009年 | 1573篇 |
2008年 | 1837篇 |
2007年 | 1590篇 |
2006年 | 1456篇 |
2005年 | 1253篇 |
2004年 | 1213篇 |
2003年 | 949篇 |
2002年 | 798篇 |
2001年 | 560篇 |
2000年 | 458篇 |
1999年 | 403篇 |
1998年 | 304篇 |
1997年 | 242篇 |
1996年 | 220篇 |
1995年 | 207篇 |
1994年 | 167篇 |
1993年 | 110篇 |
1992年 | 138篇 |
1991年 | 108篇 |
1990年 | 118篇 |
1989年 | 103篇 |
1988年 | 68篇 |
1987年 | 63篇 |
1986年 | 43篇 |
1985年 | 47篇 |
1984年 | 46篇 |
1983年 | 28篇 |
1982年 | 18篇 |
1981年 | 10篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1967年 | 2篇 |
1964年 | 1篇 |
1962年 | 1篇 |
1950年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Jing Jin Yuxiang Zheng William E. Boeglin Alan R. Brash 《Journal of lipid research》2013,54(3):754-761
Leukotriene (LT)A4 and closely related allylic epoxides are pivotal intermediates in lipoxygenase (LOX) pathways to bioactive lipid mediators that include the leukotrienes, lipoxins, eoxins, resolvins, and protectins. Although the structure and stereochemistry of the 5-LOX product LTA4 is established through comparison to synthetic standards, this is the exception, and none of these highly unstable epoxides has been analyzed in detail from enzymatic synthesis. Understanding of the mechanistic basis of the cis or trans epoxide configuration is also limited. To address these issues, we developed methods involving biphasic reaction conditions for the LOX-catalyzed synthesis of LTA epoxides in quantities sufficient for NMR analysis. As proof of concept, human 15-LOX-1 was shown to convert 15S-hydroperoxy-eicosatetraenoic acid (15S-HPETE) to the LTA analog 14S,15S-trans-epoxy-eicosa-5Z,8Z,10E,12E-tetraenoate, confirming the proposed structure of eoxin A4. Using this methodology we then showed that recombinant Arabidopsis AtLOX1, an arachidonate 5-LOX, converts 5S-HPETE to the trans epoxide LTA4 and converts 5R-HPETE to the cis epoxide 5-epi-LTA4, establishing substrate chirality as a determinant of the cis or trans epoxide configuration. The results are reconciled with a mechanism based on a dual role of the LOX nonheme iron in LTA epoxide biosynthesis, providing a rational basis for understanding the stereochemistry of LTA epoxide intermediates in LOX-catalyzed transformations. 相似文献
952.
Dao‐Zhong Jin Ming‐Lei Guo Bing Xue Li‐Min Mao John Q. Wang 《Journal of neurochemistry》2013,127(5):620-631
Two glutamate receptors, metabotropic glutamate receptor 5 (mGluR5), and ionotropic NMDA receptors (NMDAR), functionally interact with each other to regulate excitatory synaptic transmission in the mammalian brain. In exploring molecular mechanisms underlying their interactions, we found that Ca2+/calmodulin‐dependent protein kinase IIα (CaMKIIα) may play a central role. The synapse‐enriched CaMKIIα directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state‐dependent: inactive CaMKIIα binds to mGluR5 at a high level whereas the active form of the kinase (following Ca2+/calmodulin binding and activation) loses its affinity for the receptor. Ca2+ also promotes calmodulin to bind to mGluR5 at a region overlapping with the CaMKIIα‐binding site, resulting in a competitive inhibition of CaMKIIα binding to mGluR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mGluR5. Activation of mGluR5 Ca2+‐dependently dissociates CaMKIIα from the receptor and simultaneously promotes CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα‐sensitive site. Together, the long intracellular C‐terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mGluR5‐dependent Ca2+ transients differentially regulate CaMKIIα interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to cross‐talk between the two receptors.
953.
Eunsook S. Jin A. Dean Sherry Craig R. Malloy 《The Journal of biological chemistry》2013,288(5):2914-2922
Studies of glycerol metabolism in the heart have largely emphasized its role in triglyceride synthesis. However, glycerol may also be oxidized in the citric acid cycle, and glycogen synthesis from glycerol has been reported in the nonmammalian myocardium. The intent of this study was to test the hypothesis that glycerol may be metabolized to glycogen in mammalian heart. Isolated rat hearts were supplied with a mixture of substrates including glucose, lactate, pyruvate, octanoate, [U-13C3]glycerol, and 2H2O to probe various metabolic pathways including glycerol oxidation, glycolysis, the pentose phosphate pathway, and carbon sources of stored glycogen. NMR analysis confirmed that glycogen production from the level of the citric acid cycle did not occur and that the glycerol contribution to oxidation in the citric acid cycle was negligible in the presence of alternative substrates. Quite unexpectedly, 13C from [U-13C3]glycerol appeared in glycogen in carbon positions 4–6 of glucosyl units but none in positions 1–3. The extent of [4,5,6-13C3]glucosyl unit enrichment in glycogen was enhanced by insulin but decreased by H2O2. Given that triose phosphate isomerase is generally assumed to fully equilibrate carbon tracers in the triose pool, the marked 13C asymmetry in glycogen can only be attributed to conversion of [U-13C3]glycerol to [U-13C3]dihydroxyacetone phosphate and [U-13C3]glyceraldehyde 3-phosphate followed by rearrangements in the nonoxidative branch of the pentose phosphate pathway involving transaldolase that places this 13C-enriched 3-carbon unit only in the bottom half of hexose phosphate molecules contributing to glycogen. 相似文献
954.
955.
Simone Kurz Chunsheng Jin ) Alba Hykollari Daniel Gregorich Barbara Giomarelli Gerardo R. Vasta Iain B. H. Wilson Katharina Paschinger 《The Journal of biological chemistry》2013,288(34):24410-24428
The eastern oyster (Crassostrea virginica) has become a useful model system for glycan-dependent host-parasite interactions due to the hijacking of the oyster galectin CvGal1 for host entry by the protozoan parasite Perkinsus marinus, the causative agent of Dermo disease. In this study, we examined the N-glycans of both the hemocytes, which via CvGal1 are the target of the parasite, and the plasma of the oyster. In combination with HPLC fractionation, exoglycosidase digestion, and fragmentation of the glycans, mass spectrometry revealed that the major N-glycans of plasma are simple hybrid structures, sometimes methylated and core α1,6-fucosylated, with terminal β1,3-linked galactose; a remarkable high degree of sulfation of such glycans was observed. Hemocytes express a larger range of glycans, including core-difucosylated paucimannosidic forms, whereas bi- and triantennary glycans were found in both sources, including structures carrying sulfated and methylated variants of the histo-blood group A epitope. The primary features of the oyster whole hemocyte N-glycome were also found in dominin, the major plasma glycoprotein, which had also been identified as a CvGal1 glycoprotein ligand associated with hemocytes. The occurrence of terminal blood group moieties on oyster dominin and on hemocyte surfaces can account in part for their affinity for the endogenous CvGal1. 相似文献
956.
957.
Jingjing Ben Yan Zhang Rongmei Zhou Haiyang Zhang Xudong Zhu Xiaoyu Li Hanwen Zhang Nan Li Xiaodan Zhou Hui Bai Qing Yang Donghai Li Yong Xu Qi Chen 《The Journal of biological chemistry》2013,288(27):20076-20084
Atherosclerosis is considered a disease of chronic inflammation largely initiated and perpetuated by macrophage-dependent synthesis and release of pro-inflammatory mediators. Class A scavenger receptor (SR-A) expressed on macrophages plays a key role in this process. However, how SR-A-mediated pro-inflammatory response is modulated in macrophages remains ill defined. Here through immunoprecipitation coupled with mass spectrometry, we reported major vault protein (MVP) as a novel binding partner for SR-A. The interaction between SR-A and MVP was confirmed by immunofluorescence staining and chemical cross-linking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-α production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-α synthesis in macrophages via the caveolin- instead of clathrin-mediated endocytic pathway linked to p38 and JNK, but not ERK, signaling pathways. Importantly, fucoidan invoked an enrichment of MVP in lipid raft, a caveolin-reliant membrane structure, and enhanced the interaction among SR-A, caveolin, and MVP. Finally, we demonstrated that MVP elimination ameliorated SR-A-mediated apoptosis in macrophages. As such, MVP may fine-tune SR-A activity in macrophages which contributes to the development of atherosclerosis. 相似文献
958.
Divyendu Singh Rongsu Qi Jarrat L. Jordan Lani San Mateo C. Cheng Kao 《The Journal of biological chemistry》2013,288(12):8258-8268
LL-37 is an antimicrobial peptide produced by human cells that can down-regulate the lipopolysaccharide-induced innate immune responses and up-regulate double-stranded (ds) RNA-induced innate responses through Toll-like receptor 3 (TLR3). The murine LL-37 ortholog, mCRAMP, also inhibited lipopolysaccharide-induced responses, but unlike LL-37, it inhibited viral-induced responses in mouse cells. A fluorescence polarization assay showed that LL-37 was able to bind dsRNA better than mCRAMP. In the human lung epithelial cell line BEAS-2B, LL-37, but not mCRAMP, colocalized with TLR3, and the colocalization was increased in the presence of dsRNA. The presence of poly(I:C) increased the accumulation of LL-37 in Rab5 endosomes. Signaling by cells induced with both LL-37 and poly(I:C) was sensitive to inhibitors that affect clathrin-independent trafficking, whereas signaling by poly(I:C) alone was not, suggesting that the LL-37-poly(I:C) complex trafficked to signaling endosomes by a different mechanism than poly(I:C) alone. siRNA knockdown of known LL-37 receptors identified that FPRL1 was responsible for TLR3 signaling induced by LL-37-poly(I:C). These results show that LL-37 and mCRAMP have different activities in TLR3 signaling and that LL-37 can redirect trafficking of poly(I:C) to effect signaling by TLR3 in early endosomes in a mechanism that involves FPRL1. 相似文献
959.