全文获取类型
收费全文 | 7847篇 |
免费 | 658篇 |
国内免费 | 6篇 |
专业分类
8511篇 |
出版年
2023年 | 28篇 |
2022年 | 81篇 |
2021年 | 122篇 |
2020年 | 63篇 |
2019年 | 109篇 |
2018年 | 153篇 |
2017年 | 113篇 |
2016年 | 237篇 |
2015年 | 363篇 |
2014年 | 424篇 |
2013年 | 436篇 |
2012年 | 551篇 |
2011年 | 559篇 |
2010年 | 348篇 |
2009年 | 328篇 |
2008年 | 450篇 |
2007年 | 433篇 |
2006年 | 393篇 |
2005年 | 396篇 |
2004年 | 399篇 |
2003年 | 349篇 |
2002年 | 313篇 |
2001年 | 303篇 |
2000年 | 242篇 |
1999年 | 214篇 |
1998年 | 76篇 |
1997年 | 79篇 |
1996年 | 58篇 |
1995年 | 57篇 |
1994年 | 37篇 |
1993年 | 27篇 |
1992年 | 77篇 |
1991年 | 83篇 |
1990年 | 50篇 |
1989年 | 54篇 |
1988年 | 46篇 |
1987年 | 44篇 |
1986年 | 32篇 |
1985年 | 35篇 |
1984年 | 33篇 |
1982年 | 20篇 |
1981年 | 17篇 |
1979年 | 19篇 |
1978年 | 22篇 |
1977年 | 23篇 |
1976年 | 24篇 |
1974年 | 24篇 |
1973年 | 19篇 |
1971年 | 20篇 |
1970年 | 17篇 |
排序方式: 共有8511条查询结果,搜索用时 15 毫秒
201.
Min Suk Kang Seung-Hoon Baek Yoon Sun Chun A. Zenobia Moore Natalie Landman Diego Berman Hyun Ok Yang Maho Morishima-Kawashima Satoko Osawa Satoru Funamoto Yasuo Ihara Gilbert Di Paolo Jeong Hill Park Sungkwon Chung Tae-Wan Kim 《The Journal of biological chemistry》2013,288(29):20868-20882
Amyloid β-peptide (Aβ) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aβ levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis. 相似文献
202.
John Joseph Sen Wang Jongseok Lee Jin Y. Ro Man-Kyo Chung 《The Journal of biological chemistry》2013,288(50):35690-35702
Multiple Ca2+-dependent processes are involved in capsaicin-induced desensitization of transient receptor potential vanilloid 1 (TRPV1), but desensitization of TRPV1 by heat occurs even in the absence of extracellular Ca2+, although the mechanisms are unknown. In this study, we tested the hypothesis that capsaicin and heat desensitize TRPV1 through distinct mechanisms involving distinct structural segments of TRPV1. In HEK293 cells that heterologously express TRPV1, we found that heat-induced desensitization was not affected by the inclusion of intracellular ATP or alanine mutation of Lys155, both of which attenuate capsaicin-induced desensitization, suggesting that heat-induced desensitization occurs through mechanisms distinct from capsaicin-induced desensitization. To determine protein domains involved in heat-induced desensitization, we generated chimeric proteins between TRPV1 and TRPV3, a heat-gated channel lacking heat-induced desensitization. We found that TRPV1 with the carboxyl-terminal domain (CTD) of TRPV3 retained heat activation but was impaired in heat-induced desensitization. Further experiments using chimeric or deletion mutants within TRPV1 CTD indicated that the distal half of CTD regulates the activation and desensitization of TRPV1 in modality-specific manners. Within the distal CTD, we identified two segments that distinctly regulated capsaicin- and heat-induced desensitization. The results suggest that the activation and desensitization of TRPV1 by capsaicin and heat can be modulated differentially and disproportionally through different regions of TRPV1 CTD. Identifying the domains involved in thermal regulation of TRPV1 may facilitate the development of novel anti-hyperalgesic approaches aimed at attenuating activation and enhancing desensitization of TRPV1 by thermal stimuli. 相似文献
203.
Hyun Seok Kim Saurabh Mendiratta Jiyeon Kim Chad Victor Pecot Jill E. Larsen Iryna Zubovych Bo Yeun Seo Jimi Kim Banu Eskiocak Hannah Chung Elizabeth McMillan Sherry Wu Jef De Brabander Kakajan Komurov Jason E. Toombs Shuguang Wei Michael Peyton Noelle Williams Adi F. Gazdar Bruce A. Posner Rolf A. Brekken Anil K. Sood Ralph J. Deberardinis Michael G. Roth John D. Minna Michael A. White 《Cell》2013
204.
Huaiwei Liu Kristine Rose M. Ramos Kris Niño G. Valdehuesa Grace M. Nisola Won-Keun Lee Wook-Jin Chung 《Applied microbiology and biotechnology》2013,97(8):3409-3417
Ethylene glycol (EG) is an important platform chemical with steadily expanding global demand. Its commercial production is currently limited to fossil resources; no biosynthesis route has been delineated. Herein, a biosynthesis route for EG production from d-xylose is reported. This route consists of four steps: d-xylose?→?d-xylonate?→?2-dehydro-3-deoxy-d-pentonate?→?glycoaldehyde?→?EG. Respective enzymes, d-xylose dehydrogenase, d-xylonate dehydratase, 2-dehydro-3-deoxy-d-pentonate aldolase, and glycoaldehyde reductase, were assembled. The route was implemented in a metabolically engineered Escherichia coli, in which the d-xylose?→?d-xylulose reaction was prevented by disrupting the d-xylose isomerase gene. The most efficient construct produced 11.7 g?L?1 of EG from 40.0 g?L?1 of d-xylose. Glycolate is a carbon-competing by-product during EG production in E. coli; blockage of glycoaldehyde?→?glycolate reaction was also performed by disrupting the gene encoding aldehyde dehydrogenase, but from this approach, EG productivity was not improved but rather led to d-xylonate accumulation. To channel more carbon flux towards EG than the glycolate pathway, further systematic metabolic engineering and fermentation optimization studies are still required to improve EG productivity. 相似文献
205.
206.
207.
Tae-Wook Chung Hee-Jung Choi Ji-Yeon Lee Han-Sol Jeong Cheorl-Ho Kim Myungsoo Joo Jun-Yong Choi Chang-Woo Han So-Yeon Kim Jae-Sue Choi Ki-Tae Ha 《Biochemical and biophysical research communications》2013
Metastasis is major cause of malignant cancer-associated mortality. Fucoxanthin has effect on various pharmacological activities including anti-cancer activity. However, the inhibitory effect of fucoxanthin on cancer metastasis remains unclear. Here, we show that fucoxanthin isolated from brown alga Saccharina japonica has anti-metastatic activity. To check anti-metastatic properties of fucoxanthin, in vitro models including assays for invasion, migration, actin fiber organization and cancer cell–endothelial cell interaction were used. Fucoxanthin inhibited the expression and secretion of MMP-9 which plays a critical role in tumor invasion and migration, and also suppressed invasion of highly metastatic B16-F10 melanoma cells as evidenced by transwell invasion assay. In addition, fucoxanthin diminished the expressions of the cell surface glycoprotein CD44 and CXC chemokine receptor-4 (CXCR4) which play roles in migration, invasion and cancer–endothelial cell adhesion. Fucoxanthin markedly suppressed cell migration in wound healing assay and inhibited actin fiber formation. The adhesion of B16-F10 melanoma cells to the endothelial cells was significantly inhibited by fucoxanthin. Moreover, in experimental lung metastasis in vivo assay, fucoxanthin resulted in significant reduction of tumor nodules. Taken together, we demonstrate, for the first time, that fucoxanthin suppresses metastasis of highly metastatic B16-F10 melanoma cells in vitro and in vivo. 相似文献
208.
Myung-Chul Chung Aarthi Narayanan Taissia G. Popova Fatah Kashanchi Charles L. Bailey Serguei G. Popov 《Biochemical and biophysical research communications》2013,430(1):125-130
Bacillus anthracis, a causative agent of anthrax, is able to germinate and survive within macrophages. A recent study suggested that B. anthracis-derived nitric oxide (bNO) is a key aspect of bacterial defense that protects bacterial DNA from oxidative burst in the macrophages. However, the virulent effect of bNO in host cells has not been investigated. Here, we report that bNO contributes macrophage killing by S-nitrosylation of bioenergetic-relating proteins within mitochondria. Toxigenic Sterne induces expression of the bnos gene and produces bNO during early stage of infection. Nitroso-proteomic analysis coupled with a biotin-switch technique demonstrated that toxigenic infection induces protein S-nitrosylation in B. anthracis-susceptible RAW264.7. For each target enzyme tested (complex I, complex III and complex IV), infection by B. anthracis Sterne caused enzyme inhibition. Nω-nitro-l-arginine methyl ester, a NO synthase inhibitor, reduced S-nitrosylation and partially restored cell viability evaluated by intracellular ATP levels in macrophages. Our data suggest that bNO leads to energy depletion driven by impaired mitochondrial bioenergetic machinery that ultimately contributes to macrophage death. This novel mechanism of anthrax pathogenesis may offer specific approach to the development of therapeutics. 相似文献
209.
Chul-Hong Park Byung Yeoup Chung Seung Sik Lee Hyoung-Woo Bai Jae Young Cho Cheorun Jo Tae Hoon Kim 《Bioorganic & medicinal chemistry letters》2013,23(4):1099-1103
Radiolytic transformation of the isoflavonoid rotenone (1) with γ-irradiation afforded two new degraded products, rotenoisins A (2) and (3). The structures of the two new rotenone derivatives were elucidated on the basis of spectroscopic methods. The new products 2 and 3 exhibited significantly enhanced inhibitory activities against pancreatic lipase and adipocyte differentiation in 3T3-L1 cells when compared to parent rotenone. 相似文献
210.
Chiou‐Chu Su Chung Jan Chang Che‐Ming Chang Hsien‐Tzung Shih Kuo‐Ching Tzeng Fuh‐Jyh Jan Chin‐Wen Kao Wen‐Ling Deng 《Journal of Phytopathology》2013,161(6):389-396
Characteristic symptoms of Pierce's disease (PD) in grapevines (Vitis vinifera L.) were observed in 2002 in the major grape production fields of central Taiwan. Disease severity in vineyards varied, and all investigated grape cultivars were affected. Diseased tissues were collected from fields for subsequent isolation and characterization of the causal agent of the disease (Xylella fastidiosa). Koch's postulates were fulfilled by artificially inoculating two purified PD bacteria to grape cultivars Kyoho, Honey Red and Golden Muscat. The inoculated plants developed typical leaf‐scorching symptoms, and similar disease severity developed in the three cultivars from which the bacterium was readily re‐isolated, proving that the leaf scorch of grapevines in Taiwan is caused by the fastidious X. fastidiosa. This confirmed PD of grapevines is also the first report from the Asian Continent. Phylogenetic analyses were performed by comparing the 16S rRNA gene and 16S‐23S rRNA internal transcribed spacer region (16S‐23S ITS) of 12 PD strains from Taiwan with the sequences of 13 X. fastidiosa strains from different hosts and different geographical areas. Results showed that the PD strains of Taiwan were closely related to the American X. fastidiosa grape strains but not to the pear strains of Taiwan, suggesting that the X. fastidiosa grape and pear strains of Taiwan may have evolved independently from each other. 相似文献