全文获取类型
收费全文 | 32778篇 |
免费 | 2513篇 |
国内免费 | 2555篇 |
出版年
2024年 | 73篇 |
2023年 | 461篇 |
2022年 | 1136篇 |
2021年 | 1845篇 |
2020年 | 1228篇 |
2019年 | 1644篇 |
2018年 | 1486篇 |
2017年 | 1054篇 |
2016年 | 1504篇 |
2015年 | 2093篇 |
2014年 | 2514篇 |
2013年 | 2726篇 |
2012年 | 2980篇 |
2011年 | 2692篇 |
2010年 | 1595篇 |
2009年 | 1461篇 |
2008年 | 1708篇 |
2007年 | 1499篇 |
2006年 | 1245篇 |
2005年 | 974篇 |
2004年 | 804篇 |
2003年 | 768篇 |
2002年 | 576篇 |
2001年 | 504篇 |
2000年 | 471篇 |
1999年 | 442篇 |
1998年 | 278篇 |
1997年 | 261篇 |
1996年 | 264篇 |
1995年 | 234篇 |
1994年 | 220篇 |
1993年 | 154篇 |
1992年 | 202篇 |
1991年 | 184篇 |
1990年 | 130篇 |
1989年 | 98篇 |
1988年 | 81篇 |
1987年 | 69篇 |
1986年 | 39篇 |
1985年 | 44篇 |
1984年 | 24篇 |
1983年 | 32篇 |
1982年 | 16篇 |
1981年 | 19篇 |
1980年 | 7篇 |
1979年 | 5篇 |
1965年 | 1篇 |
1950年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Wei-hui Wu Qian Liu Xun Sun Ji-sheng Yu De-sheng Zhao Ye-ping Yu Jun-jie Luo Jia Hu Zhi-wu Yu Yu-fen Zhao Yan-mei Li 《Biochemical and biophysical research communications》2013
Amyloid-β (Aβ) peptides can exist in distinct forms including monomers, oligomers and fibrils, consisting of increased numbers of monomeric units. Among these, Aβ oligomers are implicated as the primary toxic species as pointed by multiple lines of evidence. It has been suggested that toxicity could be rendered by the soluble higher-molecular-weight (high-n) Aβ oligomers. Yet, the most culpable form in the pathogenesis of Alzheimer’s disease (AD) remains elusive. Moreover, the potential interaction among the insoluble fibrils that have been excluded from the responsible aggregates in AD development, Aβ monomers and high-n oligomers is undetermined. Here, we report that insoluble Aβ fibrillar seeds can interact with Aβ monomers at the stoichiometry of 1:2 (namely, each Aβ molecule of seed can bind to two Aβ monomers at a time) facilitating the fibrillization by omitting the otherwise mandatory formation of the toxic high-n oligomers during the fibril maturation. As a result, the addition of exogenous Aβ fibrillar seeds is seen to rescue neuronal cells from Aβ cytotoxicity presumably exerted by high-n oligomers, suggesting an unexpected protective role of Aβ fibrillar seeds. 相似文献
992.
Linlin Zhao Hao Guo Hong Chen Robert B. Petersen Ling Zheng Anlin Peng Kun Huang 《Biochemical and biophysical research communications》2013
Endoplasmic reticulum (ER) stress is associated with the development of diabetes. The present study sought to investigate the effect of Liraglutide, a glucagon like peptide 1 analogue, on ER stress in β-cells. We found that Liraglutide protected the pancreatic INS-1 cells from thapsigargin-induced ER stress and the ER stress associated cell apoptosis, mainly by suppressing the PERK and IRE1 pathways. We further tested the effects of Liraglutide in the Akita mouse, an ER-stress induced type 1 diabetes model. After administration of Liraglutide for 8 weeks, p-eIF2α and p-JNK were significantly decreased in the pancreas of the Akita mouse, while the treatment showed no significant impact on the levels of insulin of INS-cells. Taken together, our findings suggest that Liraglutide may protect pancreatic cells from ER stress and its related cell death. 相似文献
993.
Zheng Liu Ning Sun Shangjun Yang Yanhong Zhao Xiaoqin Wang Xingyu Hao Zhijun Qiao 《Biologia》2013,68(4):577-586
Compared with C3 plants, C4 plants possess a mechanism to concentrate CO2 around the ribulose-1,5-bisphosphate carboxylase/oxygenase in chloroplasts of bundle sheath cells so that the carboxylation reaction work at a much more efficient rate, thereby substantially eliminate the oxygenation reaction and the resulting photorespiration. It is observed that C4 photosynthesis is more efficient than C3 photosynthesis under conditions of low atmospheric CO2, heat, drought and salinity, suggesting that these factors are the important drivers to promote C4 evolution. Although C4 evolution took over 66 times independently, it is hypothesized that it shared the following evolutionary trajectory: 1) gene duplication followed by neofunctionalization; 2) anatomical and ultrastructral changes of leaf architecture to improve the hydraulic systems; 3) establishment of two-celled photorespiratory pump; 4) addition of transport system; 5) co-option of the duplicated genes into C4 pathway and adaptive changes of C4 enzymes. Based on our current understanding on C4 evolution, several strategies for engineering C4 rice have been proposed to increase both photosynthetic efficiency and yield significantly in order to avoid international food crisis in the future, especially in the developing countries. Here we summarize the latest progresses on the studies of C4 evolution and discuss the strategies to introduce two-celled C4 pathway into rice. 相似文献
994.
The jasmonic acid signaling pathway is linked to auxin homeostasis through the modulation of YUCCA8 and YUCCA9 gene expression 总被引:1,自引:0,他引:1
995.
996.
Zhe Liang Viktor Demko Robert C. Wilson Kenneth A. Johnson Rafi Ahmad Pierre‐François Perroud Ralph Quatrano Sen Zhao Kamran Shalchian‐Tabrizi Marisa S. Otegui Odd‐Arne Olsen Wenche Johansen 《The Plant journal : for cell and molecular biology》2013,75(5):742-754
DEK1, the single calpain of land plants, is a member of the ancient membrane bound TML–CysPc–C2L calpain family that dates back 1.5 billion years. Here we show that the CysPc–C2L domains of land plant calpains form a separate sub‐clade in the DEK1 clade of the phylogenetic tree of plants. The charophycean alga Mesostigma viride DEK1‐like gene is clearly divergent from those in land plants, suggesting that a major evolutionary shift in DEK1 occurred during the transition to land plants. Based on genetic complementation of the Arabidopsis thaliana dek1‐3 mutant using CysPc–C2L domains of various origins, we show that these two domains have been functionally conserved within land plants for at least 450 million years. This conclusion is based on the observation that the CysPc–C2L domains of DEK1 from the moss Physcomitrella patens complements the A. thaliana dek1‐3 mutant phenotype. In contrast, neither the CysPc–C2L domains from M. viride nor chimeric animal–plant calpains complement this mutant. Co‐evolution analysis identified differences in the interactions between the CysPc–C2L residues of DEK1 and classical calpains, supporting the view that the two enzymes are regulated by fundamentally different mechanisms. Using the A. thaliana dek1‐3 complementation assay, we show that four conserved amino acid residues of two Ca2+‐binding sites in the CysPc domain of classical calpains are conserved in land plants and functionally essential in A. thaliana DEK1. 相似文献
997.
Zheng Zhang Sriram Jakkaraju Joy Blain Kenneth Gogol Lei Zhao Robert C. Hartley Courtney A. Karlsson Bart L. Staker Thomas E. Edwards Lance J. Stewart Peter J. Myler Michael Clare Darren W. Begley James R. Horn Timothy J. Hagen 《Bioorganic & medicinal chemistry letters》2013,23(24):6860-6863
Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. 相似文献
998.
Zhinxin Zhao Roberto Gambari Kenneth Ka-Ho Lee Stanton Hon-Lung Kok Raymond Siu-Ming Wong Fung-Yi Lau Johnny Cheuk-On Tang Kim-Hung Lam Chor-Hing Cheng Desmond Kwok Po Hau Chung-Hin Chui Wai-Yeung Wong Wai-Kwok Wong 《Bioorganic & medicinal chemistry letters》2013,23(8):2373-2376
We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified. 相似文献
999.
Cui-rong Zhao Rui-qi Wang Gang Li Xiao-xia Xue Chang-jun Sun Xian-jun Qu Wen-bao Li 《Bioorganic & medicinal chemistry letters》2013,23(7):1989-1992
New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity. 相似文献
1000.
Simeon Bowers Ying-zi Xu Shendong Yuan Gary D. Probst Roy K. Hom Wayman Chan Andrei W. Konradi Hing L. Sham Yong L. Zhu Paul Beroza Hu Pan Eric Brecht Nanhua Yao Julie Lougheed Danny Tam Zhao Ren Lany Ruslim Michael P. Bova Dean R. Artis 《Bioorganic & medicinal chemistry letters》2013,23(7):2181-2186
The structure–activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio. 相似文献