全文获取类型
收费全文 | 21344篇 |
免费 | 2006篇 |
国内免费 | 2341篇 |
出版年
2024年 | 59篇 |
2023年 | 303篇 |
2022年 | 688篇 |
2021年 | 1128篇 |
2020年 | 779篇 |
2019年 | 991篇 |
2018年 | 889篇 |
2017年 | 704篇 |
2016年 | 919篇 |
2015年 | 1383篇 |
2014年 | 1590篇 |
2013年 | 1742篇 |
2012年 | 2023篇 |
2011年 | 1790篇 |
2010年 | 1155篇 |
2009年 | 1033篇 |
2008年 | 1161篇 |
2007年 | 1052篇 |
2006年 | 965篇 |
2005年 | 862篇 |
2004年 | 720篇 |
2003年 | 710篇 |
2002年 | 627篇 |
2001年 | 415篇 |
2000年 | 336篇 |
1999年 | 306篇 |
1998年 | 172篇 |
1997年 | 166篇 |
1996年 | 146篇 |
1995年 | 92篇 |
1994年 | 133篇 |
1993年 | 84篇 |
1992年 | 94篇 |
1991年 | 74篇 |
1990年 | 69篇 |
1989年 | 56篇 |
1988年 | 49篇 |
1987年 | 35篇 |
1986年 | 36篇 |
1985年 | 45篇 |
1984年 | 21篇 |
1983年 | 22篇 |
1982年 | 21篇 |
1981年 | 14篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1976年 | 3篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1971年 | 3篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Denghui Wei Weixiang Zhan Ying Gao Liyan Huang Run Gong Wen Wang Ruhua Zhang Yuanzhong Wu Song Gao Tiebang Kang 《Cell research》2021,31(2):157-177
Exosomes are generated within the multivesicular endosomes (MVEs) as intraluminal vesicles (ILVs) and secreted during the fusion of MVEs with the cell membrane. The mechanisms of exosome biogenesis remain poorly explored. Here we identify that RAB31 marks and controls an ESCRT-independent exosome pathway. Active RAB31, phosphorylated by epidermal growth factor receptor (EGFR), engages flotillin proteins in lipid raft microdomains to drive EGFR entry into MVEs to form ILVs, which is independent of the ESCRT (endosomal sorting complex required for transport) machinery. Active RAB31 interacts with the SPFH domain and drives ILV formation via the Flotillin domain of flotillin proteins. Meanwhile, RAB31 recruits GTPase-activating protein TBC1D2B to inactivate RAB7, thereby preventing the fusion of MVEs with lysosomes and enabling the secretion of ILVs as exosomes. These findings establish that RAB31 has dual functions in the biogenesis of exosomes: driving ILVs formation and suppressing MVEs degradation, providing an exquisite framework to better understand exosome biogenesis.Subject terms: Small GTPases, Endosomes, Multivesicular bodies, Lysosomes, ESCRT 相似文献
993.
994.
995.
996.
Xinxin Wang Xin Ma Gaobo Wei Weirui Ma Zhen Zhang Xuepeng Chen Lei Gao Zhenbo Liu Yue Yuan Lizhi Yi Jun Wang Toshinobu Tokumoto Junjiu Huang Dahua Chen Jian Zhang Jiang Liu 《基因组蛋白质组与生物信息学报(英文版)》2021,19(1):48-63
DNA methylation is a prevalent epigenetic modification in vertebrates, and it has been shown to be involved the regulation of gene expression and embryo development. However, it remains unclear how DNA methylation regulates sexual development, especially in species without sex chromosomes. To determine this, we utilized zebrafish to investigate DNA methylation reprogramming during juvenile germ cell development and adult female-to-male sex transition.We reveal that primordial germ cells(PGCs) undergo significant DNA methylation reprogramming during germ cell development, and the methylome of PGCs is reset to an oocyte/ovary-like pattern at 9 days post fertilization(9 dpf). When DNA methyltransferase(DNMT) activity in juveniles was blocked after 9 dpf, the zebrafish developed into females. We also show that Tet3 is involved in PGC development. Notably, we find that DNA methylome reprogramming during adult zebrafish sex transition is similar to the reprogramming during the sex differentiation from 9 dpf PGCs to sperm. Furthermore, inhibiting DNMT activity can prevent the female-to-male sex transition, suggesting that methylation reprogramming is required for zebrafish sex transition. In summary, DNA methylation plays important roles in zebrafish germ cell development and sexual plasticity. 相似文献
997.
Xuefei Zhu Jingwei Xue Xing Jiang Yamin Gong Congwen Gao Ting Cao Qian Li Lulu Bai Yuwei Li Gaixia Xu Bin Peng Xingzhi Xu 《Nucleic acids research》2022,50(3):1517
Expression of the E3 ligase TRIM21 is increased in a broad spectrum of cancers; however, the functionally relevant molecular pathway targeted by TRIM21 overexpression remains largely unknown. Here, we show that TRIM21 directly interacts with and ubiquitinates CLASPIN, a mediator for ATR-dependent CHK1 activation. TRIM21-mediated K63-linked ubiquitination of CLASPIN counteracts the K6-linked ubiquitination of CLASPIN which is essential for its interaction with TIPIN and subsequent chromatin loading. We further show that overexpression of TRIM21, but not a TRIM21 catalytically inactive mutant, compromises CHK1 activation, leading to replication fork instability and tumorigenesis. Our findings demonstrate that TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination, providing a potential target for cancer therapy. 相似文献
998.
999.
Xiaoman Li Liang Wang Jialin Hao Qingfeng Zhu Min Guo Changjing Wu Sihui Li Qiqiang Guo Qiuhong Ren Ning Bai Fei Yi Bo Jiang Wenyu Zhang Yanling Feng Hongde Xu Han Jiang Xiaoyue Zhai Guohua Zhang Hong-long Ji Xuesong Yang Dan Zhang Jianhua Fu Jianjun Chang Xiaoyu Song Liu Cao 《International journal of biological sciences》2022,18(3):1107
The lamellar body (LB), a concentric structure loaded with surfactant proteins and phospholipids, is an organelle specific to type 2 alveolar epithelial cells (AT2). However, the origin of LBs has not been fully elucidated. We have previously reported that autophagy regulates Weibel-Palade bodies (WPBs) formation, and here we demonstrated that autophagy is involved in LB maturation, another lysosome-related organelle. We found that during development, LBs were transformed from autophagic vacuoles containing cytoplasmic contents such as glycogen. Fusion between LBs and autophagosomes was observed in wild-type neonate mice. Moreover, the markers of autophagic activity, microtubule-associated protein 1 light chain 3B (LC3B), largely co-localized on the limiting membrane of the LB. Both autophagy-related gene 7 (Atg7) global knockout and conditional Atg7 knockdown in AT2 cells in mice led to defects in LB maturation and surfactant protein B production. Additionally, changes in autophagic activity altered LB formation and surfactant protein B production. Taken together, these results suggest that autophagy plays a critical role in the regulation of LB formation during development and the maintenance of LB homeostasis during adulthood. 相似文献
1000.
Bolong Yi Hao Li Heng Cai Xin Lou Mingjun Yu Zhen Li 《Journal of cellular and molecular medicine》2022,26(2):475
At present, growing evidence indicates that long non‐coding RNAs (lncRNAs) participate in the progression of glioma. The function of LOXL1‐AS1 in vasculogenic mimicry (VM) in glioma remains unclear. First, the expressions of TIAR, the lncRNA LOXL1‐AS1, miR‐374b‐5p and MMP14 were examined by qRT‐PCR and Western blot in both, glioma tissues and glioma cell lines. Proliferation, migration, invasion and tube formation assays were conducted to evaluate the roles of TIAR, LOXL1‐AS1, miR‐374b‐5p and MMP14 in malignant cellular behaviours in glioma cells. A nude mouse xenograft model and dual staining for CD34 and PAS were used to assess whether VM was affected by TIAR, LOXL1‐AS1 or miR‐374b‐5p in vivo. In this study, low levels of TIAR and high levels of LOXL1‐AS1 were found in glioma cells and tissues. TIAR downregulated the expression of LOXL1‐AS1 by destabilizing it. LOXL1‐AS1 acted like a miRNA sponge towards miR‐374b‐5p so that downregulation of the former greatly inhibited cell proliferation, migration, invasion and VM. Additionally, miR‐374b‐5p overexpression repressed malignant biological behaviours and VM in glioma by modifying MMP14. In summary, we demonstrated that TIAR combined with LOXL1‐AS1 modulates VM in glioma via the miR‐374b‐5p/MMP14 axis, revealing novel targets for glioma therapy. 相似文献