全文获取类型
收费全文 | 25637篇 |
免费 | 2215篇 |
国内免费 | 2567篇 |
出版年
2024年 | 61篇 |
2023年 | 231篇 |
2022年 | 588篇 |
2021年 | 951篇 |
2020年 | 803篇 |
2019年 | 948篇 |
2018年 | 959篇 |
2017年 | 775篇 |
2016年 | 946篇 |
2015年 | 1496篇 |
2014年 | 1892篇 |
2013年 | 2025篇 |
2012年 | 2447篇 |
2011年 | 2269篇 |
2010年 | 1504篇 |
2009年 | 1345篇 |
2008年 | 1755篇 |
2007年 | 1528篇 |
2006年 | 1374篇 |
2005年 | 1147篇 |
2004年 | 1169篇 |
2003年 | 1063篇 |
2002年 | 934篇 |
2001年 | 388篇 |
2000年 | 282篇 |
1999年 | 248篇 |
1998年 | 230篇 |
1997年 | 151篇 |
1996年 | 144篇 |
1995年 | 144篇 |
1994年 | 105篇 |
1993年 | 85篇 |
1992年 | 66篇 |
1991年 | 48篇 |
1990年 | 33篇 |
1989年 | 48篇 |
1988年 | 29篇 |
1987年 | 29篇 |
1986年 | 28篇 |
1985年 | 26篇 |
1984年 | 8篇 |
1983年 | 10篇 |
1982年 | 20篇 |
1981年 | 6篇 |
1980年 | 6篇 |
1977年 | 5篇 |
1974年 | 5篇 |
1967年 | 4篇 |
1965年 | 4篇 |
1962年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
961.
Ning Sheng Yanyan Wang Ying Xie Sihan Chen Jun Lu Zifeng Zhang Mengqiu Li Qun Shan Dongmei Wu Guihong Zheng Yuanlin Zheng Shaohua Fan 《Journal of cellular physiology》2019,234(8):13001-13013
Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2), is a gene isolated from a human liver complementary DNA library. In this study, we found that LASS2 protein level was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage and LASS2-negative tumors showed significant association with longer disease-free survival (DFS) and overall survival (OS) in ovarian cancer patients. The heterogeneous expression of LASS2 had been exhibited in diverse ovarian cancer cells. A significantly lower messenger RNA (mRNA) and protein level of LASS2 was seen in 3AO cell compared with those in other types of ovarian cancer cells. Meanwhile, the mRNA and protein levels of LASS2 in ES-2 and NIH:OVCAR-3 cells were obviously higher. LASS2 overexpression in 3AO cell could promote migration, invasion, and metastasis abilities in vitro and in vivo, while LASS2 knockdown in ES-2 and NIH:OVCAR-3 cells had the opposite effects. The oncogenic capacity of LASS2 in ovarian cancer may be mediated by increased expression of YAP/TAZ. It is indicated that lowering the expression of LASS2 is likely to serve as an unprecedented approach for the treatment of ovarian cancer. 相似文献
962.
Chunhui Sun Qiaoqiao Diao Jun Lu Zifeng Zhang Dongmei Wu Xingqi Wang Jun Xie Guihong Zheng Qun Shan Shaohua Fan Bin Hu Yuanlin Zheng 《Journal of cellular physiology》2019,234(5):5926-5939
Autophagy is a vital negative factor regulating cellular senescence. Purple sweet potato color (PSPC), one type of flavonoid, has been demonstrated to suppress endothelial senescence and restore endothelial function in diabetic mice by inhibiting the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome. However, the roles of autophagy in the inflammatory response during endothelial senescence are unknown. Here, we found that PSPC augmented autophagy to restrict high-glucose-induced premature endothelial senescence. In addition, PSPC administration impaired endothelium aging in diabetic mice by increasing autophagy. Inhibition of autophagy accelerated endothelial senescence, while enhancement of autophagy delayed senescence. Moreover, deactivation of the NLRP3 inflammasome triggered by PSPC was autophagy-dependent. Autophagy receptor microtubule-associated protein 1 light chain 3 and p62 interacted with the inflammasome component NLRP3, suggesting that autophagosomes target the NLRP3 inflammasome and deliver it to the lysosome for degradation. Altogether, PSPC amplified cellular autophagy, subsequently attenuated NLRP3 inflammasome activity and finally delayed endothelial senescence to ameliorate cardiovascular complication. These results suggest a potential therapeutic target in senescence-related cardiovascular diseases. 相似文献
963.
Acute kidney injury (AKI), caused by various stimuli including ischemia reperfusion, nephrotoxic insult, and sepsis, is characterized by abrupt decline of kidney function. Till now, the molecular mechanisms for AKI have not been fully explored and the effective therapies are still lacking. Noncoding RNAs (ncRNAs), a group of biomolecules function at RNA level, are involved in a wide range of physiopathological processes including AKI. MicroRNAs (miRNAs) are the most extensively studied ncRNAs in AKI. Evidence indicated that miRNAs are altered significantly in various types of AKI. Gain-and-loss-of-function studies demonstrated that miRNAs, such as miR-24, miR-126, miR-494, and miR-687, may bind to the 3′-untranslated region of their target genes to regulate inflammation, programmed cell death, and cell cycle in the injury and repair stages of AKI, indicating their therapeutic potential in AKI. In contrast, functions of long noncoding RNAs and circular RNAs in AKI are hot topics but still largely unknown. Additionally, ncRNAs packaged in exosome can be detected in circulation and urine, they may serve as specific biomarkers for AKI. This review summarized the alteration and functional role of ncRNAs and their therapeutic potential in AKI. 相似文献
964.
Sun-Hong Hwang Sunhoe Bang Kyung Shin Kang Deborah Kang Jongkyeong Chung 《Biochemical and biophysical research communications》2019,508(1):308-313
Wnt signaling pathway plays critical roles in body axes patterning, cell fate specification, cell proliferation, cell migration, stem cell maintenance, cancer development and etc. Deregulation of this pathway can be causative of cancer, metabolic disease and neurodegenerative disease such as Parkinson`s disease. Among the core components of Wnt signaling pathway, we discovered that Dishevelled (Dsh) interacts with ULK1 and is phosphorylated by ULK1. Unexpectedly, the knockdown of ULK1 elicited a marked increase in Wnt/β-catenin signaling. Multiple ULK1 phosphorylation sites existed on Dsh and many of them were located on the PDZ-DEP region. By using evolutionarily well conserved Drosophila Dsh, we found that S239, S247 and S254 in the PDZ-DEP region are involved in phosphorylation of Dsh by ULK1. Among these, S247 and S254 were conserved in human Dsh. When phospho-mimetic mutants (2D and 2E Dsh mutants) of these conserved residues were generated and expressed in the eyes of the fruit flies, the activity of Dsh was significantly decreased compared to wild type Dsh. Through additional alanine scanning, we further identified that S239, S247, S254, S266, S376, S554 and S555 on full length Dsh were phosphorylated by ULK1. In regards to the S266A mutation located in the PDZ domain among these phosphorylated residues, our results suggested that Dsh forms an SDS-resistant high molecular weight complex with β-catenin and TCF in the nucleus in an S266 phosphorylation-dependent manner. Based on these results, we propose that ULK1 plays a pivotal role in the regulation of Wnt/β-catenin signaling pathway by phosphorylating Dsh. 相似文献
965.
[目的]探究慢生型花生根瘤菌III型分泌系统在花生-根瘤菌互作的功能。[方法]本研究采用同源重组和三亲本接合转移的方法,构建Bradyrhizobium sp.MZ5的III型分泌系统调节基因ttsI突变体;荧光定量PCR检测添加大豆苷元(Daidzein)和染料木黄酮(Genistein)诱导物后野生型和突变株转录水平上ttsI的表达量变化及其差异;蛭石结瘤实验分析ttsI基因突变对花生结瘤能力的影响。[结果]在转录水平上,大豆苷元和染料木黄酮对MZ5的III型分泌系统调节基因ttsI的表达具有显著的抑制作用(P<0.05)。在MZ5△ttsI突变体中ttsI基因的表达量都明显下调,与野生型菌株的相比都达到极显著水平(P<0.001)。蛭石结瘤实验表明,与野生型菌株相比,MZ5△ttsI突变体在不同花生品种的结瘤数和地上部干重都显著性降低。根瘤石蜡切片表明,MZ5△ttsI突变体在根瘤内的含菌量少于野生型菌株。[结论]Bradyrhizobium sp.MZ5菌株中的III型分泌系统在花生-根瘤菌互作中对结瘤有积极的促进作用。 相似文献
966.
基于高通量测序的乐安江冬季细菌群落特征分析 总被引:1,自引:0,他引:1
【目的】分析乐安江从上游至下游水体细菌群落结构组成变化,揭示细菌群落结构组成变化的影响因素。【方法】分析不同河段水体中C、N、P、Cu、Zn、As和Pb等化学指标。对水体DNA的16S rRNA基因进行高通量测序确定细菌群落特征。基于Bray-Curtis距离的采样点非度量多维尺度(NMDS)分析和聚类分析研究乐安江水体细菌群落结构差异,基于冗余分析(RDA)研究环境因子与细菌群落的关系。【结果】乐安江水体中C、N、P、Cu、Zn、As和Pb等化学指标含量中下游偏高。中游河水受德兴铜矿废水影响,细菌群落多样性降低,下游受农业、生活废水影响,细菌群落丰富度和多样性升高。水体中优势菌群为β-变形菌纲(Beta-proteobacteria,53.03%)、放线菌门(Actinobacteria,20.24%)和拟杆菌门(Bacteroidetes,14.75%)。中游受德兴铜矿废水影响,Beta-proteobacteria丰度增大,而Actinobacteria丰度减小;下游受微生物间捕食影响,Bacteroidetes丰度下降。在细菌群落与环境因子的关系中,DO是解释乐安江细菌群落结构变化的最佳环境因子。【结论】乐安江中游德兴铜矿废水和中下游农业、生活废水明显改变了水体细菌群落结构组成,使水体细菌群落特征从上游到下游发生显著变化。本研究为揭示人类活动对乐安江水生态环境的影响提供了参考性数据。 相似文献
967.
Kyung Eun Kim Eun Ae Jeong Hyun Joo Shin Jong Youl Lee Eun Bee Choi Hyeong Seok An Kyung-Ah Park Zhen Jin Dong Kun Lee Tamas L. Horvath Gu Seob Roh 《Biochemical and biophysical research communications》2019,508(1):123-129
Hypothalamic inflammation has been known as a contributor to high-fat diet (HFD)-induced insulin resistance and obesity. Myeloid-specific sirtuin 1 (SIRT1) deletion aggravates insulin resistance and hypothalamic inflammation in HFD-fed mice. Neurogranin, a calmodulin-binding protein, is expressed in the hypothalamus. However, the effects of myeloid SIRT1 deletion on hypothalamic neurogranin has not been fully clarified. To investigate the effect of myeloid SIRT1 deletion on food intake and hypothalamic neurogranin expression, mice were fed a HFD for 20 weeks. Myeloid SIRT1 knockout (KO) mice exhibited higher food intake, weight gain, and lower expression of anorexigenic proopiomelanocortin in the arcuate nucleus than WT mice. In particular, KO mice had lower ventromedial hypothalamus (VMH)-specific neurogranin expression. However, SIRT1 deletion reduced HFD-induced hypothalamic neurogranin. Furthermore, hypothalamic phosphorylated AMPK and parvalbumin protein levels were also lower in HFD-fed KO mice than in HFD-fed WT mice. Thus, these findings suggest that myeloid SIRT1 deletion affects food intake through VMH-specific neurogranin-mediated AMPK signaling and hypothalamic inflammation in mice fed a HFD. 相似文献
968.
Epigenetic modifications can extend over long genomic regions to form domain-level chromatin states that play critical roles in gene regulation. The molecular mechanism for the establishment and maintenance of these states is not fully understood and remains challenging to study with existing experimental techniques. Here, we took a data-driven approach and parameterized an information-theoretic model to infer the formation mechanism of domain-level chromatin states from genome-wide epigenetic modification profiles. This model reproduces statistical correlations among histone modifications and identifies well-known states. Importantly, it predicts drastically different mechanisms and kinetic pathways for the formation of euchromatin and heterochromatin. In particular, long, strong enhancer and promoter states grow gradually from short but stable regulatory elements via a multistep process. On the other hand, the formation of heterochromatin states is highly cooperative, and no intermediate states are found along the transition path. This cooperativity can arise from a chromatin looping-mediated spreading of histone methylation mark and supports collapsed, globular three-dimensional conformations rather than regular fibril structures for heterochromatin. We further validated these predictions using changes of epigenetic profiles along cell differentiation. Our study demonstrates that information-theoretic models can go beyond statistical analysis to derive insightful kinetic information that is otherwise difficult to access. 相似文献
969.
Estrogen inhibits osteoclasts formation and bone resorption via microRNA-27a targeting PPARγ and APC
Lei Guo Kaizhe Chen Jun Yuan Ping Huang Xing Xu Changwei Li Niandong Qian Jin Qi Zhiliang Shao Lianfu Deng Chuan He Jiping Xu 《Journal of cellular physiology》2019,234(1):581-594
Inhibition of osteoclasts formation and bone resorption by estrogen is very important in the etiology of postmenopausal osteoporosis. The mechanisms of this process are still not fully understood. Recent studies implicated an important role of microRNAs in estrogen-mediated responses in various cellular processes, including cell differentiation and proliferation. Thus, we hypothesized that these regulatory molecules might be implicated in the process of estrogen-decreased osteoclasts formation and bone resorption. Western blot, quantitative real-time polymerase chain reaction, tartrate-resistant acid phosphatase staining, pit formation assay and luciferase assay were used to investigate the role of microRNAs in estrogen-inhibited osteoclast differentiation and bone resorption. We found that estrogen could directly suppress receptor activator of nuclear factor B ligand/macrophage colony-stimulating factor-induced differentiation of bone marrow-derived macrophages into osteoclasts in the absence of stromal cell. MicroRNA-27a was significantly increased during the process of estrogen-decreased osteoclast differentiation. Overexpressing of microRNA-27a remarkably enhanced the inhibitory effect of estrogen on osteoclast differentiation and bone resorption, whereas which were alleviated by microRNA-27a depletion. Mechanistic studies showed that microRNA-27a inhibited peroxisome proliferator-activated receptor gamma (PPARγ) and adenomatous polyposis coli (APC) expression in osteoclasts through a microRNA-27a binding site within the 3′-untranslational region of PPARγ and APC. PPARγ and APC respectively contributed to microRNA-27a-decreased osteoclast differentiation and bone resorption. Taken together, these results showed that microRNA-27a may play a significant role in the process of estrogen-inhibited osteoclast differentiation and function. 相似文献
970.
Qiang‐Qiang Xiong Tian‐Hua Shen Lei Zhong Chang‐Lan Zhu Xiao‐Song Peng Xiao‐Peng He Jun‐Ru Fu Lin‐Juan Ouyang Jian‐Min Bian Li‐Fang Hu Xiao‐Tang Sun Jie Xu Hui‐Ying Zhou Hao‐Hua He Xiao‐Rong Chen 《Physiologia plantarum》2019,167(4):564-584
Abrupt drought–flood alternation (T1) is a meteorological disaster that frequently occurs during summer in southern China and the Yangtze river basin, often causing a significant loss of rice production. In this study, the response mechanism of yield decline under abrupt drought–flood alternation stress at the panicle differentiation stage was analyzed by looking at the metabolome, proteome as well as yield and physiological and biochemical indexes. The results showed that drought and flood stress caused a decrease in the yield of rice at the panicle differentiation stage, and abrupt drought–flood alternation stress created a synergistic effect for the reduction of yield. The main reason for the decrease of yield per plant under abrupt drought–flood alternation was the decrease of seed setting rate. Compared with CK0 (no drought and no flood), the net photosynthetic rate and soluble sugar content of T1 decreased significantly and its hydrogen peroxidase, superoxide dismutase, peroxidase activity increased significantly. The identified differential metabolites and differentially expressed proteins indicated that photosynthesis metabolism, energy metabolism pathway and reactive oxygen species response have changed strongly under abrupt drought–flood alteration stress, which are factors that leads to the rice grain yield reduction. 相似文献