全文获取类型
收费全文 | 23920篇 |
免费 | 2031篇 |
国内免费 | 1730篇 |
出版年
2024年 | 6篇 |
2023年 | 250篇 |
2022年 | 367篇 |
2021年 | 1197篇 |
2020年 | 883篇 |
2019年 | 1040篇 |
2018年 | 1032篇 |
2017年 | 751篇 |
2016年 | 1071篇 |
2015年 | 1473篇 |
2014年 | 1726篇 |
2013年 | 1892篇 |
2012年 | 2249篇 |
2011年 | 1928篇 |
2010年 | 1172篇 |
2009年 | 1026篇 |
2008年 | 1203篇 |
2007年 | 1065篇 |
2006年 | 921篇 |
2005年 | 809篇 |
2004年 | 694篇 |
2003年 | 628篇 |
2002年 | 545篇 |
2001年 | 484篇 |
2000年 | 416篇 |
1999年 | 406篇 |
1998年 | 258篇 |
1997年 | 263篇 |
1996年 | 258篇 |
1995年 | 246篇 |
1994年 | 222篇 |
1993年 | 139篇 |
1992年 | 208篇 |
1991年 | 151篇 |
1990年 | 135篇 |
1989年 | 111篇 |
1988年 | 75篇 |
1987年 | 99篇 |
1986年 | 60篇 |
1985年 | 60篇 |
1984年 | 44篇 |
1983年 | 32篇 |
1982年 | 32篇 |
1981年 | 21篇 |
1980年 | 10篇 |
1979年 | 8篇 |
1978年 | 3篇 |
1977年 | 5篇 |
1975年 | 2篇 |
1974年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
101.
Identification,Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening
JianMin Jia XiaoLi Xu Fang Liu XiaoKe Guo MingYe Zhang MengChen Lu LiLi Xu JinLian Wei Jia Zhu ShengLie Zhang ShengMiao Zhang HaoPeng Sun QiDong You 《PloS one》2013,8(4)
Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization. 相似文献
102.
Man Lung Yeung Jade Lee Lee Teng Lilong Jia Chaoyu Zhang Chengxi Huang Jian-Piao Cai Runhong Zhou Kwok-Hung Chan Hanjun Zhao Lin Zhu Kam-Leung Siu Sin-Yee Fung Susan Yung Tak Mao Chan Kelvin Kai-Wang To Jasper Fuk-Woo Chan Zongwei Cai Susanna Kar Pui Lau Kwok-Yung Yuen 《Cell》2021,184(8):2212-2228.e12
103.
Tao Tan Jun Wu Chenyang Si Shaoxing Dai Youyue Zhang Nianqin Sun E Zhang Honglian Shao Wei Si Pengpeng Yang Hong Wang Zhenzhen Chen Ran Zhu Yu Kang Reyna Hernandez-Benitez Llanos Martinez Martinez Estrella Nuñez Delicado W. Travis Berggren Juan Carlos Izpisua Belmonte 《Cell》2021,184(8):2020-2032.e14
104.
Weimin Zhou Min Zhu Ming Gui Lihua Huang Zhi Long Li Wang Hui Chen Yinghao Yin Xianzhen Jiang Yingbo Dai Yuxin Tang Leye He Kuangbiao Zhong 《PloS one》2014,9(10)
Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of prostate cancer (PCa) has not been investigated. In a case-control study of 196 PCa patients and 196 age-paired healthy controls in a Chinese Han population, the association between mtDNA copy number in PBLs and PCa risk was evaluated. The relative mtDNA copy number was measured using quantitative real-time PCR; samples from three cases and two controls could not be assayed, leaving 193 cases and 194 controls for analysis. PCa patients had significantly higher mtDNA copy numbers than controls (medians 0.91 and 0.82, respectively; P<0.001). Dichotomized at the median value of mtDNA copy number in the controls, high mtDNA copy number was significantly associated with an increased risk of PCa (adjusted odds ratio = 1.85, 95% confidence interval: 1.21–2.83). A significant dose-response relationship was observed between mtDNA copy number and risk of PCa in quartile analysis (P
trend = 0.011). Clinicopathological analysis showed that high mtDNA copy numbers in PCa patients were significantly associated with high Gleason score and advanced tumor stage, but not serum prostate-specific antigen level (P = 0.002, 0.012 and 0.544, respectively). These findings of the present study indicate that increased mtDNA copy number in PBLs is significantly associated with an increased risk of PCa and may be a reflection of tumor burden. 相似文献
105.
Liang Zhu Hui Zhao Jianguo Sun Stanley Pounds Hui Zhang 《Biometrical journal. Biometrische Zeitschrift》2013,55(1):5-16
This paper discusses regression analysis of longitudinal data in which the observation process may be related to the longitudinal process of interest. Such data have recently attracted a great deal of attention and some methods have been developed. However, most of those methods treat the observation process as a recurrent event process, which assumes that one observation can immediately follow another. Sometimes, this is not the case, as there may be some delay or observation duration. Such a process is often referred to as a recurrent episode process. One example is the medical cost related to hospitalization, where each hospitalization serves as a single observation. For the problem, we present a joint analysis approach for regression analysis of both longitudinal and observation processes and a simulation study is conducted that assesses the finite sample performance of the approach. The asymptotic properties of the proposed estimates are also given and the method is applied to the medical cost data that motivated this study. 相似文献
106.
107.
108.
Yijing Chu Chengzhan Zhu Qianqian Wang Meixin Liu Wei Wan Jun Zhou Rendong Han Jing Yang Wenqiang Luo Chong Liu Huansheng Zhou Min Li Fengsheng Yu Yuanhua Ye 《Journal of cellular and molecular medicine》2021,25(9):4434-4443
Our previous studies have shown that the Adipose-derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA-seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour-inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC-treated group (P < .05), by inhibiting PAX8. In addition, an overexpression of PAX8 could elevate the proliferation of ovarian cancer cells. Moreover, Co-IP assays in ovarian cancer cells revealed that an interaction existed between endogenous PAX8 and TAZ. And the PAX8 levels regulated the degradation of TAZ. The bioluminescence images captured in vivo manifested that the proliferation and the PAX8 expression level in ovarian cancers increased in the ADMSC-treated group, and the effect of ADSCs in promoting tumours was weakened through inhibiting PAX8. Our findings indicate that the PAX8 expression increment could contribute a role in promoting the ADSC-induced ovarian cancer cell proliferation through TAZ stability regulation. 相似文献
109.
Nan Cheng Chang Jin Ping Jin Dan Zhu Zuoxu Hou 《Journal of cellular and molecular medicine》2021,25(13):6137-6147
High glucose promoted expression of AKT3, a direct target gene of miR-29b, by regulating circHIPK3 that functioned as ceRNA to sponge and down-regulate miR-29b. As a potential target gene of miR-29b, AKT3 plays a crucial role in the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury, and this study aimed to investigate the potential role of high glucose in the outcome of I/R injury. qPCR and luciferase assay were carried out to investigate the relationship between the expression of circHIPK3, miR-29b and ATK3 mRNA. Immunohistochemistry and TUNEL were performed to analyse the relationship between AKT3 expression and apoptosis of myocardiocytes in vivo. No obvious difference in myocardial functions was observed between I/R and control rats under hyperglycaemia (HG) and normal glucose (NG) conditions, except that the infarct size/area at risk (IS/AR) ratio and the amount of h-FABP expression were different under HG and NG conditions. The expression of circHIPK3 and ATK3 was significantly elevated in the rats preconditioned by NG, whereas the expression of miR-29a was remarkably decreased. Meanwhile, the apoptosis of myocardial tissue was reduced in the rats preconditioned by NG. Luciferase assay confirmed that miR-29a played a repressive role in the expression of circHIPK3 and ATK3. And subsequent study indicated that the over-expressed AKT3 could rescue the increased cell apoptosis rate induced by the knockdown of circHIPK3. In this study, we demonstrated that high glucose protects cardiomyocytes against I/R associated injury by suppressing apoptosis and high glucose promoted the expression of AKT3 by regulating the expression of circHIPK3/miR-29b. 相似文献
110.
Lu Wang Bin Deng Panpan Yan Huanghui Wu Chunhui Li Hongrui Zhu Jiwei Du Lichao Hou 《Journal of cellular and molecular medicine》2021,25(7):3449-3459
Tumour necrosis factor-α (TNF-α), a crucial cytokine, has various homeostatic and pathogenic bioactivities. The aim of this study was to assess the neuroprotective effect of ketamine against TNF-α-induced motor dysfunction and neuronal necroptosis in male C57BL/6J mice in vivo and HT-22 cell lines in vitro. The behavioural testing results of the present study indicate that ketamine ameliorated TNF-α-induced neurological dysfunction. Moreover, immunohistochemical staining results showed that TNF-α-induced brain dysfunction was caused by necroptosis and microglial activation, which could be attenuated by ketamine pre-treatment inhibiting reactive oxygen species production and mixed lineage kinase domain-like phosphorylation in hippocampal neurons. Therefore, we concluded that ketamine may have neuroprotective effects as a potent inhibitor of necroptosis, which provides a new theoretical and experimental basis for the application of ketamine in TNF-α-induced necroptosis-associated diseases. 相似文献