全文获取类型
收费全文 | 78911篇 |
免费 | 6540篇 |
国内免费 | 4887篇 |
专业分类
90338篇 |
出版年
2024年 | 138篇 |
2023年 | 902篇 |
2022年 | 2076篇 |
2021年 | 3605篇 |
2020年 | 2326篇 |
2019年 | 2841篇 |
2018年 | 2873篇 |
2017年 | 2032篇 |
2016年 | 2874篇 |
2015年 | 4591篇 |
2014年 | 5301篇 |
2013年 | 5965篇 |
2012年 | 6903篇 |
2011年 | 6357篇 |
2010年 | 3822篇 |
2009年 | 3379篇 |
2008年 | 4117篇 |
2007年 | 3653篇 |
2006年 | 3175篇 |
2005年 | 2680篇 |
2004年 | 2277篇 |
2003年 | 1975篇 |
2002年 | 1731篇 |
2001年 | 1559篇 |
2000年 | 1565篇 |
1999年 | 1449篇 |
1998年 | 848篇 |
1997年 | 801篇 |
1996年 | 809篇 |
1995年 | 737篇 |
1994年 | 687篇 |
1993年 | 530篇 |
1992年 | 818篇 |
1991年 | 657篇 |
1990年 | 601篇 |
1989年 | 532篇 |
1988年 | 421篇 |
1987年 | 362篇 |
1986年 | 336篇 |
1985年 | 299篇 |
1984年 | 221篇 |
1983年 | 199篇 |
1982年 | 113篇 |
1981年 | 118篇 |
1980年 | 86篇 |
1979年 | 147篇 |
1978年 | 84篇 |
1977年 | 95篇 |
1975年 | 111篇 |
1974年 | 116篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
141.
Abstract— Analysis of whole autopsy brain from a patient with fucosidosis (α-fucosidase deficiency) revealed minor storage of H-antigen glycolipid [Fuc (α, 1→2) Gal-GlcNAc-Gal-Glc-Ceramide] and a slightly abnormal ganglioside composition in the form of a two-fold elevation of GM1 and the presence of a fucose-containing glycolipid (a minor component) which co-migrated with GD1a. The major storage materials in fucosidosis brain were an oligosaccharide (Fuc-Gal-GlcNAc-Man[Fuc-Gal-GlcNAc-Man]-ManGlcNAc) and a disaccharide [Fuc(α, 1→6)-GlcNAc] in the approximate ratio of 5:1. Lesser amounts of a related oligosaccharide (Gal-GlcNAc-Man[Gal-GlcNAc-Man]-Man-GlcNAc) were isolated from the brain of patients with GM1-gangliosidosis (Types I and II) where the major storage material is known to be GM1-ganglioside (Gal (β, 1→3)GalNAc(β, 1→4) [NeuNAcf(α, 2→3) Gal(β, 1→4)Glc-Ceramide). Similarly, a related oligosaccharide (GlcNAc-Man [GlcNAc-Man]-Man-GlcNAc) was isolated from the brain of a patient with a total deficiency of N-acetyl-β-d -hexosaminidase (Sandhoff variant of GM2-gangliosidosis) where the major storage products are known to be GM2-ganglioside (GalNAc (β 1→4) [NeuNAc (α, 2→3)Gal(β, 1→4)Glc-Ceramine) and its asialo derivative. These studies indicate that glycoproteins containing at least 2 mol of l -fucose per oligosaccharide unit are normally catabolized in human brain. Further, it appears that such glycoproteins are initially catabolized by an endo-N-acetylglucosaminidase to release an oligosaccharide which is then degraded by the sequential action of exo-glycosidases. 相似文献
142.
Some self-consistent two-state sliding filament models of muscle contraction. 总被引:6,自引:1,他引:5 下载免费PDF全文
The general formalism required to treat two-state sliding filament models of muscle contraction, including free energy considerations, is first reviewed and amplified. This formalism is then used to examine, and modify as needed, three models studied previously by Podolsky and Nolan, in which cross-bridge attachment-detachment and ATP turnover are not tightly coupled. No attempt is made here to establish an optimal, self-consistent model of this type because our interest is primarily in methadology rather than in fitting experimental results. But it appears from this preliminary study that such a model, with satisfactory mechanical and thermodynamic properties, could be found. An extremely simple but unrealistic two-state model is also studied which is of interest because it demonstrates the fact that it is possible, in principle at least, for sliding filament models to work with very high thermodynamic efficiencies (50-100 percent). An appendix is included that is concerned with the form of the dependence of certain first-order rate constants on the concentrations of ATP, ADP, and P. 相似文献
143.
144.
145.
146.
W Samuel Fagg Naiyou Liu Ulrich Braunschweig Karen
Larissa Pereira
de
Castro Xiaoting Chen Frederick
S Ditmars Steven
G Widen John Paul Donohue Katalin Modis William
K Russell Jeffrey H Fair Matthew
T Weirauch Benjamin
J Blencowe Mariano
A Garcia-Blanco 《Nucleic acids research》2022,50(9):5313
Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Mechanistically, we find that QKI represses inclusion of exon 7 in BIN1 pre-mRNA via an exonic ACUAA motif, and this is concomitant with intron removal and cleavage from chromatin. Collectively, our results uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm. 相似文献
147.
148.
Shih-Ho Wang Chin-Hu Wu Chin-Chuan Tsai Tai-Yu Chen Kuen-Jang Tsai Chao-Ming Hung Chia-Yi Hsu Chia-Wei Wu Tsung-Hua Hsieh 《Current issues in molecular biology》2022,44(5):2107
Taraxacum officinale (dandelion) is often used in traditional Chinese medicine for the treatment of cancer; however, the downstream regulatory genes and signaling pathways mediating its effects on breast cancer remain unclear. The present study aimed to explore the effects of luteolin, the main biologically active compound of T. officinale, on gene expression profiles in MDA-MB-231 and MCF-7 breast cancer cells. The results revealed that luteolin effectively inhibited the proliferation and motility of the MDA-MB-231 and MCF-7 cells. The mRNA expression profiles were determined using gene expression array analysis and analyzed using a bioinformatics approach. A total of 41 differentially expressed genes (DEGs) were found in the luteolin-treated MDA-MB-231 and MCF-7 cells. A Gene Ontology analysis revealed that the DEGs, including AP2B1, APP, GPNMB and DLST, mainly functioned as oncogenes. The human protein atlas database also found that AP2B1, APP, GPNMB and DLST were highly expressed in breast cancer and that AP2B1 (cut-off value, 75%) was significantly associated with survival rate (p = 0.044). In addition, a Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were involved in T-cell leukemia virus 1 infection and differentiation. On the whole, the findings of the present study provide a scientific basis that may be used to evaluate the potential benefits of luteolin in human breast cancer. Further studies are required, however, to fully elucidate the role of the related molecular pathways. 相似文献
149.
Bingqing Xia Xurui Shen Yang He Xiaoyan Pan Feng-Liang Liu Yi Wang Feipu Yang Sui Fang Yan Wu Zilei Duan Xiaoli Zuo Zhuqing Xie Xiangrui Jiang Ling Xu Hao Chi Shuangqu Li Qian Meng Hu Zhou Yubo Zhou Xi Cheng Xiaoming Xin Lin Jin Hai-Lin Zhang Dan-Dan Yu Ming-Hua Li Xiao-Li Feng Jiekai Chen Hualiang Jiang Gengfu Xiao Yong-Tang Zheng Lei-Ke Zhang Jingshan Shen Jia Li Zhaobing Gao 《Cell research》2021,31(8):847-860
Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.Subject terms: Cell death, Molecular biology 相似文献
150.
Lin Zhang Yiming Chen Fahui Li Lihui Zhang Jinhong Feng Lei Zhang 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1918
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells. 相似文献