全文获取类型
收费全文 | 2094篇 |
免费 | 183篇 |
国内免费 | 1篇 |
出版年
2023年 | 3篇 |
2022年 | 11篇 |
2021年 | 42篇 |
2020年 | 29篇 |
2019年 | 25篇 |
2018年 | 52篇 |
2017年 | 58篇 |
2016年 | 66篇 |
2015年 | 134篇 |
2014年 | 156篇 |
2013年 | 161篇 |
2012年 | 207篇 |
2011年 | 199篇 |
2010年 | 138篇 |
2009年 | 91篇 |
2008年 | 128篇 |
2007年 | 112篇 |
2006年 | 115篇 |
2005年 | 110篇 |
2004年 | 83篇 |
2003年 | 86篇 |
2002年 | 84篇 |
2001年 | 38篇 |
2000年 | 20篇 |
1999年 | 30篇 |
1998年 | 13篇 |
1997年 | 11篇 |
1996年 | 8篇 |
1995年 | 10篇 |
1994年 | 9篇 |
1993年 | 2篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 1篇 |
1982年 | 2篇 |
1977年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1969年 | 1篇 |
1967年 | 2篇 |
1961年 | 1篇 |
排序方式: 共有2278条查询结果,搜索用时 109 毫秒
31.
32.
Sohee Baek Nam Joo Kang Grzegorz M. Popowicz Marcelino Arciniega Sung Keun Jung Sanguine Byun Nu Ry Song Yong-Seok Heo Bo Yeon Kim Hyong Joo Lee Tad A. Holak Martin Augustin Ann M. Bode Robert Huber Zigang Dong Ki Won Lee 《Journal of molecular biology》2013,425(2):411-423
c-Jun NH2-terminal kinases (JNKs) and phosphatidylinositol 3-kinase (PI3-K) play critical roles in chronic diseases such as cancer, type II diabetes, and obesity. We describe here the binding of quercetagetin (3,3′,4′,5,6,7-hydroxyflavone), related flavonoids, and SP600125 to JNK1 and PI3-K by ATP-competitive and immobilized metal ion affinity-based fluorescence polarization assays and measure the effect of quercetagetin on JNK1 and PI3-K activities. Quercetagetin attenuated the phosphorylation of c-Jun and AKT, suppressed AP-1 and NF-κB promoter activities, and also reduced cell transformation. It attenuated tumor incidence and reduced tumor volumes in a two-stage skin carcinogenesis mouse model.Our crystallographic structure determination data show that quercetagetin binds to the ATP-binding site of JNK1. Notably, the interaction between Lys55, Asp169, and Glu73 of JNK1 and the catechol moiety of quercetagetin reorients the N-terminal lobe of JNK1, thereby improving compatibility of the ligand with its binding site. The results of a theoretical docking study suggest a binding mode of PI3-K with the hydroxyl groups of the catechol moiety forming hydrogen bonds with the side chains of Asp964 and Asp841 in the p110γ catalytic subunit. These interactions could contribute to the high inhibitory activity of quercetagetin against PI3-K. Our study suggests the potential use of quercetagetin in the prevention or therapy of cancer and other chronic diseases. 相似文献
33.
Adam S. Mastrocola Sang Hwa Kim Anthony T. Trinh Lance A. Rodenkirch Randal S. Tibbetts 《The Journal of biological chemistry》2013,288(34):24731-24741
The list of factors that participate in the DNA damage response to maintain genomic stability has expanded significantly to include a role for proteins involved in RNA processing. Here, we provide evidence that the RNA-binding protein fused in sarcoma/translocated in liposarcoma (FUS) is a novel component of the DNA damage response. We demonstrate that FUS is rapidly recruited to sites of laser-induced DNA double-strand breaks (DSBs) in a manner that requires poly(ADP-ribose) (PAR) polymerase activity, but is independent of ataxia-telangiectasia mutated kinase function. FUS recruitment is mediated by the arginine/glycine-rich domains, which interact directly with PAR. In addition, we identify a role for the prion-like domain in promoting accumulation of FUS at sites of DNA damage. Finally, depletion of FUS diminished DSB repair through both homologous recombination and nonhomologous end-joining, implicating FUS as an upstream participant in both pathways. These results identify FUS as a new factor in the immediate response to DSBs that functions downstream of PAR polymerase to preserve genomic integrity. 相似文献
34.
35.
Guo‐Dong Sean Tan Guoyang William Toh Erik Birgersson Jeffrey Robens Danny van Noort Hwa Liang Leo 《Biotechnology and bioengineering》2013,110(6):1663-1673
In vitro drug testing requires long‐term maintenance of hepatocyte liver specific functions. Hepatocytes cultured at a higher seeding density in a sandwich configuration exhibit an increased level of liver specific functions when compared to low density cultures due to the better cell to cell contacts that promote long term maintenance of polarity and liver specific functions. However, culturing hepatocytes at high seeding densities in a standard 24‐well plate poses problems in terms of the mass transport of nutrients and oxygen to the cells. In view of this drawback, we have developed a polydimethylsiloxane (PDMS) bioreactor that was able to maintain the long‐term liver specific functions of a hepatocyte sandwich culture at a high seeding density. The bioreactor was fabricated with PDMS, an oxygen permeable material, which allowed direct oxygenation and perfusion to take place simultaneously. The mass transport of oxygen and the level of shear stress acting on the cells were analyzed by computational fluid dynamics (CFD). The combination of both direct oxygenation and perfusion has a synergistic effect on the liver specific function of a high density hepatocyte sandwich culture over a period of 9 days. Biotechnol. Bioeng. 2013; 110: 1663–1673. © 2012 Wiley Periodicals, Inc. 相似文献
36.
Jun Park Yong Hwa Jo Chang Hoon Cho Wonchae Choe Insug Kang Hyung Hwan Baik Kyung-Sik Yoon 《Biochemical and biophysical research communications》2013,430(1):429-435
DNA DSBs are induced by IR or radiomimetic drugs such as doxorubicin. It has been indicated that cells from ataxia-telangiectasia patients are highly sensitive to radiation due to defects in DNA repair, but whether they have impairment in apoptosis has not been fully elucidated. A-T cells showed increased sensitivity to high levels of DNA damage, however, they were more resistant to low doses. Normal cells treated with combination of KU55933, a specific ATM kinase inhibitor, and doxorubicin showed increased resistance as they do in a similar manner to A-T cells. A-T cells have higher viability but more DNA breaks, in addition, the activations of p53 and apoptotic proteins (Bax and caspase-3) were deficient, but Akt expression was enhanced. A-T cells subsequently underwent premature senescence after treatment with a low dose of doxorubicin, which was confirmed by G2 accumulation, senescent morphology, and SA-β-gal positive until 15 days repair incubation. Finally, A-T cells are radio-resistant at low doses due to its defectiveness in detecting DNA damage and apoptosis, but the accumulation of DNA damage leads cells to premature senescence. 相似文献
37.
Wahyu Indra Duwi Fanata Kyoung Hwan Lee Bo Hwa Son Jae Yong Yoo Rikno Harmoko Ki Seong Ko Nirmal Kumar Ramasamy Kyung Hwa Kim Doo‐Byoung Oh Hyun Suk Jung Jae‐Yean Kim Sang Yeol Lee Kyun Oh Lee 《The Plant journal : for cell and molecular biology》2013,73(6):966-979
To explore the physiological significance of N‐glycan maturation in the plant Golgi apparatus, gnt1, a mutant with loss of N‐acetylglucosaminyltransferase I (GnTI) function, was isolated in Oryza sativa. gnt1 exhibited complete inhibition of N‐glycan maturation and accumulated high‐mannose N‐glycans. Phenotypic analyses revealed that gnt1 shows defective post‐seedling development and incomplete cell wall biosynthesis, leading to symptoms such as failure in tiller formation, brittle leaves, reduced cell wall thickness, and decreased cellulose content. The developmental defects of gnt1 ultimately resulted in early lethality without transition to the reproductive stage. However, callus induced from gnt1 seeds could be maintained for periods, although it exhibited a low proliferation rate, small size, and hypersensitivity to salt stress. Shoot regeneration and dark‐induced leaf senescence assays indicated that the loss of GnTI function results in reduced sensitivity to cytokinin in rice. Reduced expression of A‐type O. sativa response regulators that are rapidly induced by cytokinins in gnt1 confirmed that cytokinin signaling is impaired in the mutant. These results strongly support the proposed involvement of N‐glycan maturation in transport as well as in the function of membrane proteins that are synthesized via the endomembrane system. 相似文献
38.
Yongqi Deng Zhiwei Yang Gerald W. Shipps Sie-Mun Lo Robert West Joyce Hwa Shuqin Zheng Constance Farley Jean Lachowicz Margaret van Heek Alan S. Bass Dinesh P. Sinha Craig R. Mahon Mark E. Cartwright 《Bioorganic & medicinal chemistry letters》2013,23(3):791-796
Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. 相似文献
39.
40.
Manuel de Lera Ruiz Junying Zheng Michael Y. Berlin Kevin D. McCormick Robert G. Aslanian Robert West Joyce Hwa Jean Lachowicz Margaret van Heek 《Bioorganic & medicinal chemistry letters》2013,23(21):6004-6009
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test. 相似文献