全文获取类型
收费全文 | 25158篇 |
免费 | 15526篇 |
国内免费 | 2篇 |
出版年
2024年 | 1篇 |
2023年 | 12篇 |
2022年 | 89篇 |
2021年 | 393篇 |
2020年 | 2183篇 |
2019年 | 3716篇 |
2018年 | 3819篇 |
2017年 | 4095篇 |
2016年 | 4083篇 |
2015年 | 3982篇 |
2014年 | 3618篇 |
2013年 | 4045篇 |
2012年 | 1714篇 |
2011年 | 1429篇 |
2010年 | 2994篇 |
2009年 | 1762篇 |
2008年 | 639篇 |
2007年 | 230篇 |
2006年 | 231篇 |
2005年 | 275篇 |
2004年 | 255篇 |
2003年 | 247篇 |
2002年 | 242篇 |
2001年 | 246篇 |
2000年 | 181篇 |
1999年 | 132篇 |
1998年 | 9篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 7篇 |
1994年 | 13篇 |
1993年 | 6篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1889年 | 1篇 |
1882年 | 1篇 |
1881年 | 1篇 |
1873年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
181.
182.
Deciphering protein‐protein interactions (PPIs) is fundamental for understanding signal transduction pathways in plants. The split firefly luciferase (Fluc) complementation (SLC) assay has been widely used for analyzing PPIs. However, concern has risen about the bulky halves of Fluc interfering with the functions of their fusion partners. Nano luciferase (Nluc) is the smallest substitute for Fluc with improved stability and luminescence. Here, we developed a dual‐use system enabling the detection of PPIs through the Nluc‐based SLC and co‐immunoprecipitation assays. This was realized by coexpression of two proteins under investigation in fusion with the HA‐ or FLAG‐tagged Nluc halves, respectively. We validated the robustness of this system by reproducing multiple previously documented PPIs in protoplasts or Agrobacterium‐transformed plants. We next applied this system to evaluate the homodimerization of Arabidopsis CERK1, a coreceptor of fungal elicitor chitin, and its heterodimerization with other homologs in the absence or presence of chitin. Moreover, split fragments of Nluc were fused to two cytosolic ends of Arabidopsis calcium channels CNGC2 and CNGC4 to help sense the allosteric change induced by the bacterial elicitor flg22. Collectively, these results demonstrate the usefulness of the Nluc‐based SLC assay for probing constitutive or inducible PPIs and protein allostery in plant cells. 相似文献
183.
184.
185.
186.
Helen E. Driessen Magda S. Fontes Leonie van Stuijvenberg Maike A. Brans Marie‐Jose Goumans Marc A. Vos Toon A. van Veen 《Journal of cellular and molecular medicine》2020,24(15):8417-8429
In the diseased and remodelled heart, increased activity and expression of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide‐3‐related‐peptide (AC3I)) together with eplerenone treatment (AC3I‐Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I‐Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT‐Epler) and mice with only CaMKII inhibition (AC3I‐No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro‐fibrotic TGF‐β/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro‐fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis. 相似文献
187.
Kaitlyn M. Price Karen G. Wigg Yu Feng Kirsten Blokland Margaret Wilkinson Gengming He Elizabeth N. Kerr Tasha‐Cate Carter Sharon L. Guger Maureen W. Lovett Lisa J. Strug Cathy L. Barr 《Genes, Brain & Behavior》2020,19(6)
Reading disabilities (RD) are the most common neurocognitive disorder, affecting 5% to 17% of children in North America. These children often have comorbid neurodevelopmental/psychiatric disorders, such as attention deficit/hyperactivity disorder (ADHD). The genetics of RD and their overlap with other disorders is incompletely understood. To contribute to this, we performed a genome‐wide association study (GWAS) for word reading. Then, using summary statistics from neurodevelopmental/psychiatric disorders, we computed polygenic risk scores (PRS) and used them to predict reading ability in our samples. This enabled us to test the shared aetiology between RD and other disorders. The GWAS consisted of 5.3 million single nucleotide polymorphisms (SNPs) and two samples; a family‐based sample recruited for reading difficulties in Toronto (n = 624) and a population‐based sample recruited in Philadelphia [Philadelphia Neurodevelopmental Cohort (PNC)] (n = 4430). The Toronto sample SNP‐based analysis identified suggestive SNPs (P ~ 5 × 10?7) in the ARHGAP23 gene, which is implicated in neuronal migration/axon pathfinding. The PNC gene‐based analysis identified significant associations (P < 2.72 × 10?6) for LINC00935 and CCNT1, located in the region of the KANSL2/CCNT1/LINC00935/SNORA2B/SNORA34/MIR4701/ADCY6 genes on chromosome 12q, with near significant SNP‐based analysis. PRS identified significant overlap between word reading and intelligence (R2 = 0.18, P = 7.25 × 10?181), word reading and educational attainment (R2 = 0.07, P = 4.91 × 10?48) and word reading and ADHD (R2 = 0.02, P = 8.70 × 10?6; threshold for significance = 7.14 × 10?3). Overlap was also found between RD and autism spectrum disorder (ASD) as top‐ranked genes were previously implicated in autism by rare and copy number variant analyses. These findings support shared risk between word reading, cognitive measures, educational outcomes and neurodevelopmental disorders, including ASD. 相似文献
188.
Mu‐Wen Nie Ye‐Chen Han Zhu‐Jun Shen Hong‐Zhi Xie 《Journal of cellular and molecular medicine》2020,24(14):7915-7927
Sepsis is the most common cause of death in intensive care units. This study investigated the circular RNA (circRNA) and mRNA expression profiles and functional networks of the aortic tissue in sepsis. We established a lipopolysaccharide (LPS)‐induced rat sepsis model. High‐throughput sequencing was performed on the aorta tissue to identify differentially expressed (DE) circRNAs and mRNAs, which were validated by real‐time quantitative polymerase chain reaction (RT‐qPCR). Bioinformatic analysis was carried out and coding and non‐coding co‐expression (CNC) and competing endogenous RNA (ceRNA) regulatory networks were constructed to investigate the mechanisms. In total, 373 up‐regulated and 428 down‐regulated circRNAs and 2063 up‐regulated and 2903 down‐regulated mRNAs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of mRNAs showed that the down‐regulated genes were mainly enriched in the process of energy generation. CNC and ceRNA regulatory networks were constructed with seven DE circRNAs. The results of functional enrichment analysis of CNC target genes revealed the important role of circRNAs in inflammatory response. The ceRNA network also highlighted the significant enrichment in calcium signalling pathway. Significant alterations in circRNAs and mRNAs were observed in the aortic tissue of septic rats. In addition, CNC and ceRNA networks were established. 相似文献
189.
Rong‐rong Zhu Qian Chen Zhi‐bo Liu Han‐guang Ruan Qi‐cai Wu Xue‐liang Zhou 《Journal of cellular and molecular medicine》2020,24(14):7907-7914
Increased expression and activity of cardiac and circulating cathepsin D and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23‐kD prolactin (PRL) to 16‐kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY‐411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt‐1, reduced Hes1, phosphorylated Stat3 (p‐Stat3), VEGFA and PDGFB, and promoted cleavage of 23k‐D PRL to 16‐kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt‐1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM. 相似文献
190.
Hai‐Fan Yu Lian‐Wen Zheng Zhan‐Qing Yang Yu‐Si Wang Ji‐Cheng Huang Shu Liu Zhan‐Peng Yue Bin Guo 《Journal of cellular and molecular medicine》2020,24(12):7023-7033
Serpinb6b is a novel member of Serpinb family and found in germ and somatic cells of mouse gonads, but its physiological function in uterine decidualization remains unclear. The present study revealed that abundant Serpinb6b was noted in decidual cells, and advanced the proliferation and differentiation of stromal cells, indicating a creative role of Serpinb6b in uterine decidualization. Further analysis found that Serpinb6b modulated the expression of Mmp2 and Mmp9. Meanwhile, Serpinb6b was identified as a target of Bmp2 regulation in stromal differentiation. Treatment with rBmp2 resulted in an accumulation of intracellular cAMP level whose function in this differentiation program was mediated by Serpinb6b. Addition of PKA inhibitor H89 impeded the Bmp2 induction of Serpinb6b, whereas 8‐Br‐cAMP rescued the defect of Serpinb6b expression elicited by Bmp2 knock‐down. Attenuation of Serpinb6b greatly reduced the induction of constitutive Wnt4 activation on stromal cell differentiation. By contrast, overexpression of Serpinb6b prevented this inhibition of differentiation process by Wnt4 siRNA. Moreover, blockage of Wnt4 abrogated the up‐regulation of cAMP on Serpinb6b. Collectively, Serpinb6b mediates uterine decidualization via Mmp2/9 in response to Bmp2/cAMP/PKA/Wnt4 pathway. 相似文献