全文获取类型
收费全文 | 20285篇 |
免费 | 1813篇 |
国内免费 | 2325篇 |
出版年
2024年 | 46篇 |
2023年 | 262篇 |
2022年 | 636篇 |
2021年 | 1023篇 |
2020年 | 806篇 |
2019年 | 949篇 |
2018年 | 873篇 |
2017年 | 685篇 |
2016年 | 882篇 |
2015年 | 1302篇 |
2014年 | 1552篇 |
2013年 | 1656篇 |
2012年 | 2031篇 |
2011年 | 1743篇 |
2010年 | 1111篇 |
2009年 | 1021篇 |
2008年 | 1146篇 |
2007年 | 1006篇 |
2006年 | 918篇 |
2005年 | 749篇 |
2004年 | 645篇 |
2003年 | 593篇 |
2002年 | 461篇 |
2001年 | 350篇 |
2000年 | 284篇 |
1999年 | 257篇 |
1998年 | 195篇 |
1997年 | 151篇 |
1996年 | 138篇 |
1995年 | 124篇 |
1994年 | 137篇 |
1993年 | 87篇 |
1992年 | 93篇 |
1991年 | 89篇 |
1990年 | 53篇 |
1989年 | 57篇 |
1988年 | 37篇 |
1987年 | 44篇 |
1986年 | 31篇 |
1985年 | 35篇 |
1984年 | 20篇 |
1983年 | 14篇 |
1982年 | 15篇 |
1981年 | 15篇 |
1980年 | 9篇 |
1978年 | 10篇 |
1976年 | 10篇 |
1975年 | 11篇 |
1973年 | 8篇 |
1970年 | 7篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
Ferroptosis, a form of regulated cell death, plays an important role in acute kidney injury (AKI). Previous studies have shown that prolyl hydroxylase domain protein (PHD) inhibitors that activate HIF signaling provide strong protection against AKI, which is characterized by marked cell death. However, the relationship between PHD inhibition/HIF signaling and ferroptosis in AKI has not been elucidated. Here, we review recent studies to explore the issue. First, we will review the literature concerning the functions of HIF in promoting mitophagy, suppressing mitochondrial respiration and modulating redox homeostasis. Second, we will describe the current understanding of ferroptosis and its role in AKI, particularly from the perspective of mitochondrial dysfunction. Finally, we will discuss the possibility that mitochondria link PHD inhibition/HIF signaling and ferroptosis in AKI. In conclusion, we propose that HIF may protect renal cells against ferroptosis in AKI by reducing mitochondrial oxidative stress and damage.Subject terms: Cell biology, Kidney diseases 相似文献
992.
Liping Meng Hui Lin Xingxiao Huang Jingfan Weng Fang Peng Shengjie Wu 《Cell death & disease》2022,13(1)
N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.Subject terms: Cardiomyopathies, Endocrine system and metabolic diseases 相似文献
993.
994.
Xiaoshen Wang Xuzichao Li Yongjian Ma Jiaqi He Xiang Liu Guimei Yu Hang Yin Heng Zhang 《Nucleic acids research》2022,50(1):512
Mobile genetic elements such as phages and plasmids have evolved anti-CRISPR proteins (Acrs) to suppress CRISPR-Cas adaptive immune systems. Recently, several phage and non-phage derived Acrs including AcrIIA17 and AcrIIA18 have been reported to inhibit Cas9 through modulation of sgRNA. Here, we show that AcrIIA17 and AcrIIA18 inactivate Cas9 through distinct mechanisms. AcrIIA17 inhibits Cas9 activity through interference with Cas9-sgRNA binary complex formation. In contrast, AcrIIA18 induces the truncation of sgRNA in a Cas9-dependent manner, generating a shortened sgRNA incapable of triggering Cas9 activity. The crystal structure of AcrIIA18, combined with mutagenesis studies, reveals a crucial role of the N-terminal β-hairpin in AcrIIA18 for sgRNA cleavage. The enzymatic inhibition mechanism of AcrIIA18 is different from those of the other reported type II Acrs. Our results add new insights into the mechanistic understanding of CRISPR-Cas9 inhibition by Acrs, and also provide valuable information in the designs of tools for conditional manipulation of CRISPR-Cas9. 相似文献
995.
996.
997.
Xue Song Hexin Wen Lugen Zuo Zhijun Geng Jing Nian Luyao Wang Yifan Jiang Jing Tao Zihan Zhu Xiaopei Wu Zhikun Wang Xiaofeng Zhang Liang Yu Hao Zhao Ping Xiang Jing Li Lin Shen Jianguo Hu 《Journal of cellular and molecular medicine》2022,26(1):216
Intestinal barrier dysfunction and intestinal inflammation interact in the progression of Crohn''s disease (CD). A recent study indicated that Epac‐2 protected the intestinal barrier and had anti‐inflammatory effects. The present study examined the function of Epac‐2 in CD‐like colitis. Interleukin‐10 gene knockout (Il‐10 −/−) mice exhibit significant spontaneous enteritis and were used as the CD model. These mice were treated with Epac‐2 agonists (Me‐cAMP) or Epac‐2 antagonists (HJC‐0350) or were fed normally (control), and colitis and intestinal barrier structure and function were compared. A Caco‐2 and RAW 264.7 cell co‐culture system were used to analyse the effects of Epac‐2 on the cross‐talk between intestinal epithelial cells and inflammatory cells. Epac‐2 activation significantly ameliorated colitis in mice, which was indicated by reductions in the colitis inflammation score, the expression of inflammatory factors and intestinal permeability. Epac‐2 activation also decreased Caco‐2 cell permeability in an LPS‐induced cell co‐culture system. Epac‐2 activation significantly suppressed nuclear factor (NF)‐κB/mitogen‐activated protein kinase (MAPK) signalling in vivo and in vitro. Epac‐2 may be a therapeutic target for CD based on its anti‐inflammatory functions and protective effects on the intestinal barrier. 相似文献
998.
Fang E. He Zhang Wanli Yin Chongyang Wang Yuanli Liu Yanze Li Linlin Wang Yue Wu Runze Zhang Chendan Zou Tianjun Song Cedric Matunda Chaoxia Zou Xu Gao 《Cell death & disease》2022,13(1)
Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI.Subject terms: RNA-binding proteins, Infertility 相似文献
999.
EIF1A encodes a translation initiation factor in eukaryocyte and aberrant expression of EIF1A is deemed to be associated with dysfunctions in intracranial diseases. The goal of this research was to explore the impacts of EIF1A on progression of human pituitary adenoma (PA). We employed immunohistochemistry to assess the expression of EIF1A in PA and para-carcinoma tissues. After constructing EIF1A-knockdown cell models via lentivirus infection, we examined cell proliferation through CCK-8 assay and Celigo cell counting assay. Flow cytometry was utilized to detect cell apoptosis and the migration ability of experimental cells was estimated using wound-healing assay and Transwell assay. The activity of the apoptosis-related factor, Caspase 3, was also examined via Caspase 3 activity assay. Lastly, in vivo xenograft mouse models were established to verify findings derived from in vitro cell models. Our results affirmed upregulation of EIF1A in PA cells and revealed that depletion of EIF1A could seriously limit cell proliferation and weaken the capacity of cell migration, and also enhance apoptosis of tumor cells. Mechanistically, degradation in cell growth mediated by EIF1A knockdown may involve in activation of MAPK signaling but inactivation of PI3K/AKT signaling pathway. This study indicates EIF1A plays a prominent role in facilitating tumor cell proliferation and migration which may further contribute to PA progression.Key words: EIF1A, Pituitary adenoma, Cell proliferation, Cell migration, MAPK 相似文献
1000.
Xue Deng Xing Sun Wenkai Yue Yongjia Duan Rirong Hu Kai Zhang Jiangxia Ni Jihong Cui Qiangqiang Wang Yelin Chen Ang Li Yanshan Fang 《The Journal of cell biology》2022,221(1)
The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy–endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43–mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation. 相似文献