全文获取类型
收费全文 | 17010篇 |
免费 | 1516篇 |
国内免费 | 2088篇 |
出版年
2024年 | 37篇 |
2023年 | 268篇 |
2022年 | 573篇 |
2021年 | 969篇 |
2020年 | 738篇 |
2019年 | 893篇 |
2018年 | 836篇 |
2017年 | 600篇 |
2016年 | 798篇 |
2015年 | 1145篇 |
2014年 | 1384篇 |
2013年 | 1399篇 |
2012年 | 1705篇 |
2011年 | 1564篇 |
2010年 | 1018篇 |
2009年 | 824篇 |
2008年 | 905篇 |
2007年 | 804篇 |
2006年 | 680篇 |
2005年 | 607篇 |
2004年 | 428篇 |
2003年 | 350篇 |
2002年 | 334篇 |
2001年 | 224篇 |
2000年 | 194篇 |
1999年 | 190篇 |
1998年 | 137篇 |
1997年 | 124篇 |
1996年 | 124篇 |
1995年 | 101篇 |
1994年 | 93篇 |
1993年 | 67篇 |
1992年 | 88篇 |
1991年 | 59篇 |
1990年 | 58篇 |
1989年 | 53篇 |
1988年 | 39篇 |
1987年 | 28篇 |
1986年 | 30篇 |
1985年 | 29篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 15篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 11篇 |
1978年 | 6篇 |
1976年 | 9篇 |
1975年 | 10篇 |
1974年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
831.
New CRISPR-based genome editing technologies are developed to continually drive advances in life sciences, which, however, are predominantly derived from systems of Type II CRISPR-Cas9 and Type V CRISPR-Cas12a for eukaryotes. Here we report a novel CRISPR-n(nickase)Cas3 genome editing tool established upon a Type I-F system. We demonstrate that nCas3 variants can be created by alanine-substituting any catalytic residue of the Cas3 helicase domain. While nCas3 overproduction via plasmid shows severe cytotoxicity, an in situ nCas3 introduces targeted double-strand breaks, facilitating genome editing without visible cell killing. By harnessing this CRISPR-nCas3 in situ gene insertion, nucleotide substitution and deletion of genes or genomic DNA stretches can be consistently accomplished with near-100% efficiencies, including simultaneous removal of two large genomic fragments. Our work describes the first establishment of a CRISPR-nCas3-based genome editing technology, thereby offering a simple, yet useful approach to convert the naturally most abundantly occurring Type I systems into advanced genome editing tools to facilitate high-throughput prokaryotic engineering. 相似文献
832.
833.
Chong Zhang Xiang-Yu Wang Peng Zhang Tao-Chen He Jia-Hao Han Rui Zhang Jing Lin Jie Fan Lu Lu Wen-Wei Zhu Hu-Liang Jia Ju-Bo Zhang Jin-Hong Chen 《Cell death & disease》2022,13(1)
Tumor metastasis is a hallmark of cancer. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated pre-metastatic niche formation during colorectal cancer (CRC) liver metastasis remain incompletely understood. Here we identified HSPC111 was the leading upregulated gene in hepatic stellate cells (HSCs) incubated with CRC cell-derived exosomes. In xenograft mouse model, CRC cell-derived exosomal HSPC111 facilitated pre-metastatic niche formation and CRC liver metastases (CRLM). Consistently, CRC patients with liver metastasis had higher level of HSPC111 in serum exosomes, primary tumors and cancer-associated fibroblasts (CAFs) in liver metastasis than those without. Mechanistically, HSPC111 altered lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulated the level of acetyl-CoA. The accumulation of acetyl-CoA further promoted CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforced exosomal HSPC111 excretion from CRC cells and promoted liver metastasis. These results uncovered that CRC cell-derived exosomal HSPC111 promotes pre-metastatic niche formation and CRLM via reprogramming lipid metabolism in CAFs, and implicate HSPC111 may be a potential therapeutic target for preventing CRLM.Subject terms: Cancer metabolism, Metastasis, Epithelial-mesenchymal transition 相似文献
834.
Sheng Zhang Xueqiang Peng Shuo Yang Xinyu Li Mingyao Huang Shibo Wei Jiaxing Liu Guangpeng He Hongyu Zheng Liang Yang Hangyu Li Qing Fan 《Cell death & disease》2022,13(2)
Autophagy is a conserved method of quality control in which cytoplasmic contents are degraded via lysosomes. Lipophagy, a form of selective autophagy and a novel type of lipid metabolism, has recently received much attention. Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). Although much remains unknown, lipophagy appears to play a significant role in many organisms, cell types, metabolic states, and diseases. It participates in the regulation of intracellular lipid storage, intracellular free lipid levels (e.g., fatty acids), and energy balance. However, it remains unclear how intracellular lipids regulate autophagy. Impaired lipophagy can cause cells to become sensitive to death stimuli and may be responsible for the onset of a variety of diseases, including nonalcoholic fatty liver disease and metabolic syndrome. Like autophagy, the role of lipophagy in cancer is poorly understood, although analysis of specific autophagy receptors has helped to expand the diversity of chemotherapeutic targets. These studies have stimulated increasing interest in the role of lipophagy in the pathogenesis and treatment of cancer and other human diseases.Subject terms: Autophagy, Mechanisms of disease 相似文献
835.
Sile Liu Weiyuan Wang Yue Ning Hongmei Zheng Yuting Zhan Haihua Wang Yang Yang Jiadi Luo Qiuyuan Wen Hongjing Zang Jinwu Peng Jian Ma Songqing Fan 《Cell death & disease》2022,13(2)
Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.Subject terms: Drug development, Growth factor signalling, Oncogenesis 相似文献
836.
837.
838.
Although superhydrophobic materials have attracted much research interest in anti-icing,some controversy still exists.In this research,we report a cost-effective method used to verify the contribution of area fraction to ice adhesion strength.We tried to partially-embed siliea nanopnarticles into microscale fabrics of a commercial polyamide mesh.Then,the area fraction could be determined by altering the mesh size.Generally,the ice adhesion strength decreases as the area fraction decreases.An ice adhesion strength of~1.9 kPa and a delayed freezing time of~1048 s can be obtained.We attribute the low ice adhesion strength to the combination of superhydro-phobicity and stress concentration.The superhydrophobicity prohibits the water from penetrating into the voids of the meshes,and the small actual contact area leads to stress concentration which promotes interfacial crack propagation.Moreover,our superhydrophobic mesh simultaneously exhibis a micro-nano hierarchical structure and a partally-cmbedded structure.Therefore,the as-prepared superhydrophobic mesh retained the ieephobicity after 20 icingldeicing cycles,and maintained its superhydrophobicity even afier 60 sandpaper-abrasion cycles and a 220"C thermal treatment. 相似文献
839.
840.