全文获取类型
收费全文 | 13059篇 |
免费 | 1071篇 |
国内免费 | 1383篇 |
专业分类
15513篇 |
出版年
2024年 | 55篇 |
2023年 | 231篇 |
2022年 | 550篇 |
2021年 | 866篇 |
2020年 | 539篇 |
2019年 | 665篇 |
2018年 | 673篇 |
2017年 | 442篇 |
2016年 | 601篇 |
2015年 | 924篇 |
2014年 | 1087篇 |
2013年 | 1058篇 |
2012年 | 1272篇 |
2011年 | 1152篇 |
2010年 | 709篇 |
2009年 | 636篇 |
2008年 | 686篇 |
2007年 | 576篇 |
2006年 | 454篇 |
2005年 | 360篇 |
2004年 | 315篇 |
2003年 | 333篇 |
2002年 | 255篇 |
2001年 | 160篇 |
2000年 | 125篇 |
1999年 | 151篇 |
1998年 | 86篇 |
1997年 | 85篇 |
1996年 | 77篇 |
1995年 | 59篇 |
1994年 | 47篇 |
1993年 | 34篇 |
1992年 | 52篇 |
1991年 | 29篇 |
1990年 | 32篇 |
1989年 | 40篇 |
1988年 | 18篇 |
1987年 | 10篇 |
1986年 | 10篇 |
1985年 | 23篇 |
1984年 | 6篇 |
1983年 | 9篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1972年 | 2篇 |
1970年 | 3篇 |
1967年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
41.
Ruijun Liu Ruili Liu Zhiyi Guo Jianghao Ren Jia Huang Qingquan Luo Qiang Tan 《Cell death & disease》2022,13(8)
In view of the important roles played by Kinetochore proteins in mitosis, we believed that they may contribute to the development and progression of human cancers, which has been reported recently elsewhere. Kinetochore-associated 1 (KNTC1) participates in the segregation of sister chromatids during mitosis, the effects of which on non-small-cell lung cancer (NSCLC) remain unclear. Here, we sought to identify the biological significance of KNTC1 in NSCLC. KNTC1 protein expression in NSCLC tissues was investigated by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was utilized to establish KNTC1 silence NSCLC cell lines. The effects of KNTC1 depletion on NSCLC cell proliferation, migration, apoptosis, and tumor formation were analyzed by MTT assay, wound-healing assay, transwell assay, flow cytometry assay, and in nude mouse models in vivo. After KNTC1 reduction, NSCLC cell viability, proliferation, migration, and invasion were restrained. A xenograft tumor model was also provided to demonstrate the inhibited tumorigenesis in NSCLC. In addition, the downstream mechanism analysis indicated that KNTC1 depletion was positively associated with PSMB8. The findings of the present study suggested that KNTC1 may have a pivotal role in mediating NSCLC progression and may act as a novel therapeutic target for NSCLC.Subject terms: Non-small-cell lung cancer, Cell migration 相似文献
42.
43.
44.
Yu Shang Li Li Tengfei Zhang Qingping Luo Qingzhong Yu Zhe Zeng Lintao Li Miaomiao Jia Guoyi Tang Sanlin Fan Qin Lu Wenting Zhang Yuhan Xue Hongling Wang Wei Liu Hongcai Wang Rongrong Zhang Chan Ding Huabin Shao Guoyuan Wen 《PLoS pathogens》2022,18(6)
The development of thermostable vaccines can relieve the bottleneck of existing vaccines caused by thermal instability and subsequent poor efficacy, which is one of the predominant reasons for the millions of deaths caused by vaccine-preventable diseases. Research into the mechanism of viral thermostability may provide strategies for developing thermostable vaccines. Using Newcastle disease virus (NDV) as model, we identified the negative surface charge of attachment glycoprotein as a novel determinant of viral thermostability. It prevented the temperature-induced aggregation of glycoprotein and subsequent detachment from virion surface. Then structural stability of virion surface was improved and virus could bind to and infect cells efficiently after heat-treatment. Employing the approach of surface charge engineering, thermal stability of NDV and influenza A virus (IAV) vaccines was successfully improved. The increase in the level of vaccine thermal stability was determined by the value-added in the negative surface charge of the attachment glycoprotein. The engineered live and inactivated vaccines could be used efficiently after storage at 37°C for at least 10 and 60 days, respectively. Thus, our results revealed a novel surface-charge-mediated link between HN protein and NDV thermostability, which could be used to design thermal stable NDV and IAV vaccines rationally. 相似文献
45.
46.
47.
Junru Feng Hui Lu Wenhao Ma Wenjing Tian Zhuan Lu Hongying Yang Yongping Cai Pengfei Cai Yuchen Sun Zilong Zhou Jiaqian Feng Jiazhong Deng Ying Shu Kun Qu Weidong Jia Ping Gao Huafeng Zhang 《蛋白质与细胞》2022,13(11):825
Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13238-022-00906-6. 相似文献
48.
49.
Xiaofeng Nian Li Li Xusheng Ma Xiurong Li Wenhui Li Nianzhang Zhang John Asekhaen Ohiolei Le Li Guodong Dai Yanhong Liu Hongbin Yan Baoquan Fu Sa Xiao Wanzhong Jia 《PLoS neglected tropical diseases》2022,16(5)
Almost all Echinococcus multilocularis (Em) infections occur in the liver of the intermediate host, causing a lethal zoonotic helminthic disease, alveolar echinococcosis (AE). However, the long non-coding RNAs (lncRNAs) expression profiles of the host and the potential regulatory function of lncRNA during Em infection are poorly understood. In this study, the profiles of lncRNAs and mRNAs in the liver of mice at different time points after Em infection were explored by microarray. Thirty-one differentially expressed mRNAs (DEMs) and 68 differentially expressed lncRNAs (DELs) were found continuously dysregulated. These DEMs were notably enriched in “antigen processing and presentation”, “Th1 and Th2 cell differentiation” and “Th17 cell differentiation” pathways. The potential predicted function of DELs revealed that most DELs might influence Th17 cell differentiation and TGF-β/Smad pathway of host by trans-regulating SMAD3, STAT1, and early growth response (EGR) genes. At 30 days post-infection (dpi), up-regulated DEMs were enriched in Toll-like and RIG-I-like receptor signaling pathways, which were validated by qRT-PCR, Western blotting and downstream cytokines detection. Furthermore, flow cytometric analysis and serum levels of the corresponding cytokines confirmed the changes in cell-mediated immunity in host during Em infection that showed Th1 and Th17-type CD4+ T-cells were predominant at the early infection stage whereas Th2-type CD4+ T-cells were significantly higher at the middle/late stage. Collectively, our study revealed the potential regulatory functions of lncRNAs in modulating host Th cell subsets and provide novel clues in understanding the influence of Em infection on host innate and adaptive immune response. 相似文献
50.