全文获取类型
收费全文 | 66751篇 |
免费 | 18310篇 |
国内免费 | 3473篇 |
出版年
2024年 | 58篇 |
2023年 | 532篇 |
2022年 | 1014篇 |
2021年 | 2526篇 |
2020年 | 3445篇 |
2019年 | 5242篇 |
2018年 | 5250篇 |
2017年 | 5108篇 |
2016年 | 5698篇 |
2015年 | 6396篇 |
2014年 | 6583篇 |
2013年 | 7167篇 |
2012年 | 5493篇 |
2011年 | 4805篇 |
2010年 | 5065篇 |
2009年 | 3578篇 |
2008年 | 2765篇 |
2007年 | 2168篇 |
2006年 | 1920篇 |
2005年 | 1733篇 |
2004年 | 1576篇 |
2003年 | 1396篇 |
2002年 | 1348篇 |
2001年 | 1097篇 |
2000年 | 1001篇 |
1999年 | 909篇 |
1998年 | 477篇 |
1997年 | 446篇 |
1996年 | 421篇 |
1995年 | 347篇 |
1994年 | 345篇 |
1993年 | 236篇 |
1992年 | 349篇 |
1991年 | 301篇 |
1990年 | 246篇 |
1989年 | 193篇 |
1988年 | 157篇 |
1987年 | 146篇 |
1986年 | 122篇 |
1985年 | 145篇 |
1984年 | 95篇 |
1983年 | 78篇 |
1982年 | 65篇 |
1981年 | 45篇 |
1980年 | 40篇 |
1979年 | 56篇 |
1978年 | 41篇 |
1977年 | 46篇 |
1975年 | 35篇 |
1974年 | 45篇 |
排序方式: 共有10000条查询结果,搜索用时 546 毫秒
961.
Shanping Wang Fei Liu Keai Sinn Tan Hooi‐Leng Ser Loh Teng‐Hern Tan Learn‐Han Lee Wen Tan 《Journal of cellular and molecular medicine》2020,24(1):722-736
Evidence demonstrates that M1 macrophage polarization promotes inflammatory disease. Here, we discovered that (R)‐salbutamol, a β2 receptor agonist, inhibits and reprograms the cellular metabolism of RAW264.7 macrophages. (R)‐salbutamol significantly inhibited LPS‐induced M1 macrophage polarization and downregulated expressions of typical M1 macrophage cytokines, including monocyte chemotactic protein‐1 (MCP‐1), interleukin‐1β (IL‐1β) and tumour necrosis factor α (TNF‐α). Also, (R)‐salbutamol significantly decreased the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and reactive oxygen species (ROS), while increasing the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio. In contrast, (S)‐salbutamol increased the production of NO and ROS. Bioenergetic profiles showed that (R)‐salbutamol significantly reduced aerobic glycolysis and enhanced mitochondrial respiration. Untargeted metabolomics analysis demonstrated that (R)‐salbutamol modulated metabolic pathways, of which three metabolic pathways, namely, (a) phenylalanine metabolism, (b) the pentose phosphate pathway and (c) glycerophospholipid metabolism were the most noticeably impacted pathways. The effects of (R)‐salbutamol on M1 polarization were inhibited by a specific β2 receptor antagonist, ICI‐118551. These findings demonstrated that (R)‐salbutamol inhibits the M1 phenotype by downregulating aerobic glycolysis and glycerophospholipid metabolism, which may propose (R)‐salbutamol as the major pharmacologically active component of racemic salbutamol for the treatment of inflammatory diseases and highlight the medicinal value of (R)‐salbutamol. 相似文献
962.
Lingbo Kong Biao Wang Xiaobin Yang Baorong He Dingjun Hao Liang Yan 《Journal of cellular and molecular medicine》2020,24(6):3271-3281
In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently, the bone resorption gradually occupies a dominant status. During this imbalance process, osteoclast is unique cell linage act the bone resorptive biological activity, which is a highly differentiated ultimate cell derived from monocyte/macrophage. The erosive function of osteoclasts is that they have to adhere the bone matrix and migrate along it, in which adhesive cytoskeleton recombination of osteoclast is essential. In that, the podosome is a membrane binding microdomain organelle, based on dynamic actin, which forms a cytoskeleton superstructure connected with the plasma membrane. Otherwise, as the main adhesive protein, integrin regulates the formation of podosome and cytoskeleton, which collaborates with the various molecules including: c-Cbl, p130Cas, c-Src and Pyk2, through several signalling cascades cross talking, including: M-CSF and RANKL. In our current study, we discuss the role of integrin and associated molecules in osteoclastogenesis cytoskeletal, especially podosomes, regulation and relevant signalling cascades cross talking. 相似文献
963.
Simon Borna Ales Drobek Jarmila Kralova Daniela Glatzova Iva Splichalova Matej Fabisik Jana Pokorna Tereza Skopcova Pavla Angelisova Veronika Kanderova Julia Starkova Petr Stanek Orest V. Matveichuk Nataliia Pavliuchenko Katarzyna Kwiatkowska Majd B. Protty Michael G. Tomlinson Meritxell Alberich‐Jorda Vladimir Korinek Tomas Brdicka 《Journal of cellular and molecular medicine》2020,24(2):1980-1992
WW domain binding protein 1‐like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6‐RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non‐haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4‐family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l‐deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis. 相似文献
964.
Yun Ge Man Huang Yao Wu Ning Dong Yong‐Ming Yao 《Journal of cellular and molecular medicine》2020,24(2):2027-2039
Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are required to limit immune‐induced pathology and to maintain homeostasis during the early‐phase of sepsis. This study aimed to investigate the role of interleukin (IL)‐38, a newly described member of the IL‐1 cytokine family, in mediated immune response of CD4+CD25+ Tregs in sepsis. Here, we provide evidence that expressions of IL‐38 and its receptor were detected in murine CD4+CD25+ Tregs. Stimulation of CD4+CD25+ Tregs with LPS markedly up‐regulated the expression of IL‐38. Treatment with rmIL‐38 dramatically enhanced the immunosuppressive activity of CD4+CD25+ Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti–IL‐38 antibody was administered. Administration of rmIL‐38 improved the survival rate of CLP mice. In addition, CD4+CD25+ Tregs depletion before the onset of sepsis obviously abolished IL‐38–mediated protective response. These findings suggest that IL‐38 enhances the immunosuppressive activity of CD4+CD25+ Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis. 相似文献
965.
Jun Bian Zhenjian Zhuo Jinhong Zhu Zhonghua Yang Zhang Jiao Yong Li Jiwen Cheng Haixia Zhou Suhong Li Li Li Jing He Yanfei Liu 《Journal of cellular and molecular medicine》2020,24(16):9280-9286
Neuroblastoma ranks as the most commonly seen and deadly solid tumour in infancy. The aberrant activity of m6A‐RNA methyltransferase METTL3 is involved in human cancers. Therefore, functional genetic variants in the METTL3 gene may contribute to neuroblastoma risk. In the current nine‐centre case‐control study, we aimed to analyse the association between the METTL3 gene single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility. We genotyped four METTL3 gene SNPs (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G, and rs1263801 G>C) in 968 neuroblastoma patients and 1814 controls in China. We found significant associations between these SNPs and neuroblastoma risk in neither single‐locus nor combined analyses. Interestingly, in the stratified analysis, we observed a significant risk association with rs1061027 AA in subgroups of children ≤ 18 months of age (adjusted OR = 1.87, 95% CI = 1.03‐3.41, P = .040) and females (adjusted OR = 1.86, 95% CI = 1.07‐3.24, P = .028). Overall, we identified a significant association between METTL3 gene rs1061027 C>A polymorphism and neuroblastoma risk in children ≤18 months of age and females. Our findings provide novel insights into the genetic determinants of neuroblastoma. 相似文献
966.
Juan Wang Min Han Su‐xia Han Cuiju Zhi Suli Gao Yao Li 《Journal of cellular and molecular medicine》2020,24(2):1795-1803
Atrial fibrosis is an important factor in the initiation and maintenance of atrial fibrillation (AF); therefore, understanding the pathogenesis of atrial fibrosis may reveal promising therapeutic targets for AF. In this study, we successfully established a rapid atrial pacing canine model and found that the inducibility and duration of AF were significantly reduced by the overexpression of c‐Ski, suggesting that this approach may have therapeutic effects. c‐Ski was found to be down‐regulated in the atrial tissues of the rapid atrial pacing canine model. We artificially up‐regulated c‐Ski expression with a c‐Ski–overexpressing adenovirus. Haematoxylin and eosin, Masson's trichrome and picrosirius red staining showed that c‐Ski overexpression alleviated atrial fibrosis. Furthermore, we found that the expression levels of collagen III and α‐SMA were higher in the groups of dogs subjected to right‐atrial pacing, and this increase was attenuated by c‐Ski overexpression. In addition, c‐Ski overexpression decreased the phosphorylation of smad2, smad3 and p38 MAPK (p38α and p38β) as well as the expression of TGF‐β1 in atrial tissues, as shown by a comparison of the right‐atrial pacing + c‐Ski‐overexpression group to the control group with right‐atrial pacing only. These results suggest that c‐Ski overexpression improves atrial remodelling in a rapid atrial pacing canine model by suppressing TGF‐β1–Smad signalling and p38 MAPK activation. 相似文献
967.
Michael Meyer Maya Ben‐Yehuda Greenwald Theresa Rauschendorfer Catharina Snger Marko Jukic Haruka Iizuka Fumimasa Kubo Lin Chen David M. Ornitz Sabine Werner 《Journal of cellular and molecular medicine》2020,24(2):1774-1785
Fibroblast growth factors (FGFs) are key regulators of tissue development, homeostasis and repair, and abnormal FGF signalling is associated with various human diseases. In human and murine epidermis, FGF receptor 3 (FGFR3) activation causes benign skin tumours, but the consequences of FGFR3 deficiency in this tissue have not been determined. Here, we show that FGFR3 in keratinocytes is dispensable for mouse skin development, homeostasis and wound repair. However, the defect in the epidermal barrier and the resulting inflammatory skin disease that develops in mice lacking FGFR1 and FGFR2 in keratinocytes were further aggravated upon additional loss of FGFR3. This caused fibroblast activation and fibrosis in the FGFR1/FGFR2 double‐knockout mice and even more in mice lacking all three FGFRs, revealing functional redundancy of FGFR3 with FGFR1 and FGFR2 for maintaining the epidermal barrier. Taken together, our study demonstrates that FGFR1, FGFR2 and FGFR3 act together to maintain epidermal integrity and cutaneous homeostasis, with FGFR2 being the dominant receptor. 相似文献
968.
Bo‐fang Zhang Hong Jiang Jing Chen Qi Hu Shuo Yang Xiao‐pei Liu Gen Liu 《Journal of cellular and molecular medicine》2020,24(1):1099-1115
Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, and novel therapeutic targets still need to be investigated to alleviate myocardial injury and the ensuing maladaptive cardiac remodelling. Accumulating studies have indicated that lncRNA H19 might exert a crucial regulatory effect on cardiovascular disease. In this study, we aimed to explore the biological function and molecular mechanism of H19 in MI. To investigate the biological functions of H19, miRNA‐22‐3p and KDM3A, gain‐ and loss‐of‐function experiments were performed. In addition, bioinformatics analysis, dual‐luciferase reporter assays, RNA immunoprecipitation (RIP) assays, RNA pull‐down assays, quantitative RT‐PCR and Western blot analyses as well as rescue experiments were conducted to reveal an underlying competitive endogenous RNA (ceRNA) mechanism. We found that H19 was significantly down‐regulated after MI. Functionally, enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation. However, H19 knockdown resulted in the opposite effects. Bioinformatics analysis and dual‐luciferase assays revealed that, mechanistically, miR‐22‐3p was a direct target of H19, which was also confirmed by RIP and RNA pull‐down assays in primary cardiomyocytes. In addition, bioinformatics analysis and dual‐luciferase reporter assays also demonstrated that miRNA‐22‐3p directly targeted the KDM3A gene. Moreover, subsequent rescue experiments further verified that H19 regulated the expression of KDM3A to ameliorate MI‐induced myocardial injury in a miR‐22‐3p‐dependent manner. The present study revealed the critical role of the lncRNAH19/miR‐22‐3p/KDM3A pathway in MI. These findings suggest that H19 may act as a potential biomarker and therapeutic target for MI. 相似文献
969.
Dafeng Yang Zhousheng Yang Lei Chen Dabin Kuang Yang Zou Jie Li Xu Deng Songyuan Luo Jianfang Luo Jun He Miao Yan Guixia He Yang Deng Rong Li Qiong Yuan Yangzhao Zhou Pei Jiang Shenglan Tan 《Journal of cellular and molecular medicine》2020,24(10):5911-5925
Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4-positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E-deficient (Apoe−/−) mice. Yet, those protective effects are abrogated by using NOS inhibitor L-NAME in Apoe−/− mice received DMY. Mechanistically, DMY decreases microRNA-21 (miR-21) and increases its target gene dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR-21 in Apoe−/− mice or miR-21 overexpression in cultured HUVECs abrogates those DMY-mediated protective effects. These data demonstrate that endothelial miR-21-inhibited DDAH1-ADMA-eNOS-NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management. 相似文献
970.