全文获取类型
收费全文 | 2196篇 |
免费 | 229篇 |
专业分类
2425篇 |
出版年
2023年 | 12篇 |
2022年 | 20篇 |
2021年 | 35篇 |
2020年 | 15篇 |
2019年 | 31篇 |
2018年 | 31篇 |
2017年 | 24篇 |
2016年 | 56篇 |
2015年 | 90篇 |
2014年 | 80篇 |
2013年 | 98篇 |
2012年 | 146篇 |
2011年 | 152篇 |
2010年 | 106篇 |
2009年 | 84篇 |
2008年 | 124篇 |
2007年 | 106篇 |
2006年 | 126篇 |
2005年 | 113篇 |
2004年 | 94篇 |
2003年 | 85篇 |
2002年 | 104篇 |
2001年 | 29篇 |
2000年 | 32篇 |
1999年 | 41篇 |
1998年 | 30篇 |
1997年 | 18篇 |
1996年 | 14篇 |
1995年 | 23篇 |
1994年 | 15篇 |
1993年 | 15篇 |
1992年 | 25篇 |
1991年 | 15篇 |
1990年 | 22篇 |
1989年 | 22篇 |
1988年 | 21篇 |
1987年 | 15篇 |
1986年 | 22篇 |
1985年 | 18篇 |
1984年 | 22篇 |
1983年 | 21篇 |
1982年 | 25篇 |
1981年 | 12篇 |
1980年 | 15篇 |
1978年 | 14篇 |
1977年 | 17篇 |
1976年 | 16篇 |
1975年 | 12篇 |
1974年 | 16篇 |
1973年 | 19篇 |
排序方式: 共有2425条查询结果,搜索用时 0 毫秒
61.
Mostoslavsky R Chua KF Lombard DB Pang WW Fischer MR Gellon L Liu P Mostoslavsky G Franco S Murphy MM Mills KD Patel P Hsu JT Hong AL Ford E Cheng HL Kennedy C Nunez N Bronson R Frendewey D Auerbach W Valenzuela D Karow M Hottiger MO Hursting S Barrett JC Guarente L Mulligan R Demple B Yancopoulos GD Alt FW 《Cell》2006,124(2):315-329
The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes. 相似文献
62.
Joyce Sayegh Jian Cao Mike Ran Zou Alfonso Morales Lauren P. Blair Michael Norcia Denton Hoyer Alan J. Tackett Jane S. Merkel Qin Yan 《The Journal of biological chemistry》2013,288(13):9408-9417
JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 μm
in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy. 相似文献
63.
Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation 总被引:1,自引:0,他引:1 下载免费PDF全文
Cdc45 is required for initiation of DNA replication and fork progression, but its function in these processes remains unknown. We show that targeting Cdc45 to specific chromosomal sites in mammalian cells results in large-scale chromatin decondensation that strongly correlates with histone H1 phosphorylation. Cdk2 is recruited to sites of Cdc45 decondensation, and Cdk2 inhibitors reduce the level of decondensation. Targeting wild-type Cdk2, but not kinase-defective Cdk2, to chromatin is also effective at inducing decondensation involving phospho-H1. Cdc45, Cdk2, Cyclin A, and phospho-H1 associate with chromatin during S-phase, and Cdc45, Cdk2, and an active H1 kinase physically interact. Replicating DNA and phospho-H1 foci colocalize in vivo, and S-phase progression and H1 phosphorylation are directly related and Cdk2 dependent. Because Cdk2 colocalizes with replication foci and H1 regulates higher-order chromatin, we suggest a model in which Cdc45 recruits Cdk2 to replication foci, resulting in H1 phosphorylation, chromatin decondensation, and facilitation of fork progression. 相似文献
64.
65.
66.
67.
CD44 has been the subject of extensive research for more than 3 decades because of its role in breast cancer, in addition to many physiological processes, but interestingly, conflicting data implicate CD44 in both tumor suppression and tumor promotion. CD44 has been shown to promote protumorigenic signaling and advance the metastatic cascade. On the other hand, CD44 has been shown to suppress growth and metastasis. Histopathological studies of human breast cancer have correlated CD44 expression with both favorable and unfavorable clinical outcomes. In recent years, CD44 has garnered significant attention because of its utility as a stem cell marker and has surfaced as a potential therapeutic target, necessitating a greater understanding of CD44 in breast cancer. In this review, we attempt to unify the literature implicating CD44 in both tumor promotion and suppression, and explain its dualistic nature. 相似文献
68.
Joyce H. Hurley Laura J. Bloem Fred Pavalko† Jian Liu Mingting Tian Jay R. Simon‡§ & Lei Yu† 《Journal of neurochemistry》1999,72(1):413-421
Abstract : The most prominent structural feature of the G protein-coupled receptor superfamily is their seven hydrophobic domains, which are postulated to form membrane-spanning α helices. Some members of the G protein-coupled receptor family, specifically several serotonin (5-HT) receptors, possess eight hydrophobic domains. The importance of this extra hydrophobic domain, located at the N terminus of the receptor, is unknown. This question was addressed by deleting the extra hydrophobic region from the 5-HT2C receptor and comparing its function and topology with those of the wild-type receptor. Immunofluorescence microscopy was used to determine the location of the N terminus of the epitope-tagged wild-type and mutant receptors. The N terminus of both receptors was extracellular, suggesting that the extra hydrophobic domain does not change the topology of this receptor and is unlikely to be a membrane-spanning α helix. Radioligand-binding studies in transfected cells and expression studies in Xenopus oocytes demonstrated that seven hydrophobic domains were sufficient for normal function in these assays. Interestingly, the mutant receptor, now containing seven hydrophobic domains, is expressed at higher levels in transfected cells than the wild-type receptor containing eight hydrophobic domains, suggesting that the extra hydrophobic domain does impact the activity of this receptor by regulating its expression. 相似文献
69.
70.