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981.
Pingping Dong Shufeng Dai Lin Tian 《Journal of receptor and signal transduction research》2018,38(1):83-88
This study aimed to investigate the anti-cervical cancer effects of everolimus (Eve) and paclitaxel (Pac) when used alone or in combination. Human cervical cancer cells HeLa and SiHa were divided into four group: Blank control group (control), everolimus group (Eve), paclitaxel group (Pac) and combined therapy group (Eve?+?Pac). The cell viability was detected by CCK-8 assay and the cell cloning ability was detected by clonegenic assay. Flow cytometry was used to detect cell apoptosis. Meanwhile, the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR) and their phosphorylated proteins were studied by western blot. The HeLa and SiHa cells proliferation and cloning ability were significantly inhibited in drug treatment groups compared with control group (p?.05), and the Eve?+?Pac combinatorial therapy showed the better results than single treatment with Eve or Pac. Combination of Eve and Pac has synergistic effect on the induction of apoptosis in cervical cancer cells. In addition, the protein ratios in HeLa and SiHa cell treated with the Eve?+?Pac combination were significantly lower than that of cervical cancer cells treated with either Eve or Pac cell alone. Our study suggested that Eve?+?Pac provide a novel therapeutic strategy for cervical cancer. 相似文献
982.
Chunyan Feng Bin Lou Jibin Dong Zhiqiang Li Yunqin Chen Yue Li Xuemei Zhang Xian-Cheng Jiang Tingbo Ding 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(8):834-843
Levels of polyunsaturated phosphatidylcholine (PC) influence plasma membrane structure and function. Phosphatidylcholine (PC) is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation/reacylation remodeling via Lands' cycle (non-Kennedy pathway). The reacylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT), which adds a polyunsaturated fatty acid at the sn-2 position. Four LPCAT isoforms have been described to date, among which we found LPCAT3 to be the major isoform in adipose tissue, but its exact role in adipogenesis is unclear. In this study, we aimed to investigate whether LPCAT3 activity affects 3T3L1 cell adipogenic differentiation potential and its underline mechanism. Lentivirus-mediated LPCAT3 shRNA expression stably knocked down LPCAT3 in 3T3L1 preadipocytes and LPCAT3 deficiency dramatically reduced the levels of cellular polyunsaturated PCs. Importantly, we found that this deficiency activated the β-catenin dependent Wnt signaling pathway, which suppressed the expression of adipogenesis-related genes, thereby inhibiting 3T3L1 preadipocyte differentiation and lipid accumulation. Moreover, three different Wnt/β-catenin pathway inhibitors reversed the effect of LPCAP3 deficiency, suggesting that Wnt/β-catenin pathway activation is one of the causes for the observed phenotypes. To the best of our knowledge, we show here for the first time that PC remodeling is an important regulator of adipocyte differentiation. 相似文献
983.
984.
985.
Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan 下载免费PDF全文
Shruti Bhide Adriana S. Trujillo Maureen T. O'Connor Grant H. Young Diane E. Cryderman Sahaana Chandran Mastaneh Nikravesh Lori L. Wallrath Girish C. Melkani 《Aging cell》2018,17(3)
Mutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies. 相似文献
986.
The genetic component of human longevity: New insights from the analysis of pathway‐based SNP‐SNP interactions 下载免费PDF全文
Serena Dato Mette Soerensen Francesco De Rango Giuseppina Rose Kaare Christensen Lene Christiansen Giuseppe Passarino 《Aging cell》2018,17(3)
In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA, PTPN1, PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity. 相似文献
987.
Gian-Luca McLelland 《Autophagy》2018,14(9):1658-1660
Mitochondrial damage triggers mitochondrial quality control pathways, which act to ensure the health of the mitochondrial network. The turnover of damaged mitochondria by mitophagy is initiated by the Parkinson disease-linked genes PRKN and PINK1, and we recently investigated the role that interorganellar contact sites between the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM) play in this pathway. In this punctum, we summarize our findings that show that the ER-OMM tether MFN2 acts as a suppressor of mitophagy through its ability to link the OMM to the ER, potentially limiting the accessibility of other ubiquitination substrates to PINK1 and PRKN. PINK1, PRKN and the AAA-ATPase VCP disrupt contact between mitochondria and the ER via MFN2 ubiquitination, retrotranslocation and turnover from the mitochondrial membrane. Our study provides insight into the role of OMM remodeling in mitophagy. 相似文献
988.
The ischemia-reperfusion (I/R) induced skin lesion has been identified as primary cause of pressure ulcer. Better understanding of the mechanism is required for new therapy development. Leucine rich repeat containing protein 19 (LRRC19) is a recently discovered transmembrane protein containing leucine-rich repeats and plays a role in immune response. To investigate the role of LRRC19 in pressure ulcers, mouse ulcer model was established with two cycles of I/R. The expression of LRRC19 was assessed during injury. siRNA mediated LRRC19 downregulation was applied to investigate the disease severity, immune cell infiltration and pro-inflammatory cytokines production. The primary skin fibroblasts were stimulated with IL-1β to dissect the molecular mechanism. LRRC19 was readily induced in I/R induced lesion site in a pattern mimicking the disease progress as measured by wound area. Knockdown of LRRC19 by siRNA significantly alleviated the disease severity and attenuated immune cell infiltration and pro-inflammatory cytokines production. In primary skin fibroblast model, siRNA knockdown of LRRC19 suppressed IL-1β mediated NFκB activation and its downstream cytokines production. LRRC19 was a novel factor for I/R-induced tissue damage by promoting NFκB dependent pro-inflammatory response. Our results supported that LRRC19 could be a potential therapeutic target for pressure ulcers. 相似文献
989.
Jianling Xia Ming Zeng Hua Zhu Xiangjian Chen Zhiliang Weng Shi Li 《Journal of cellular and molecular medicine》2018,22(1):4-15
Bladder cancer (BC) is one of the most common cancers worldwide with a high progression rate and poor prognosis. The Hippo signalling pathway is a conserved pathway that plays a crucial role in cellular proliferation, differentiation and apoptosis. Furthermore, dysregulation and/or malfunction of the Hippo pathway is common in various human tumours, including BC. In this review, an overview of the Hippo pathway in BC and other cancers is presented. We focus on recent data regarding the Hippo pathway, its network and the regulation of the downstream co‐effectors YAP1/TAZ. The core components of the Hippo pathway, which induce BC stemness acquisition, metastasis and chemoresistance, will be emphasized. Additional research on the Hippo pathway will advance our understanding of the mechanism of BC as well as the development and progression of other cancers and may be exploited therapeutically. 相似文献
990.
Cinzia Antognelli Rodolfo Cecchetti Francesca Riuzzi Matthew J. Peirce Vincenzo N. Talesa 《Journal of cellular and molecular medicine》2018,22(5):2865-2883
Metastasis is the primary cause of death in prostate cancer (PCa) patients. Effective therapeutic intervention in metastatic PCa is undermined by our poor understanding of its molecular aetiology. Defining the mechanisms underlying PCa metastasis may lead to insights into how to decrease morbidity and mortality in this disease. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). Hydroimidazolone (MG‐H1) and argpyrimidine (AP) are AGEs originating from MG‐mediated post‐translational modification of proteins at arginine residues. AP is involved in the control of epithelial to mesenchymal transition (EMT), a crucial determinant of cancer metastasis and invasion, whose regulation mechanisms in malignant cells are still emerging. Here, we uncover a novel mechanism linking Glo1 to the maintenance of the metastatic phenotype of PCa cells by controlling EMT by engaging the tumour suppressor miR‐101, MG‐H1‐AP and TGF‐β1/Smad signalling. Moreover, circulating levels of Glo1, miR‐101, MG‐H1‐AP and TGF‐β1 in patients with metastatic compared with non‐metastatic PCa support our in vitro results, demonstrating their clinical relevance. We suggest that Glo1, together with miR‐101, might be potential therapeutic targets for metastatic PCa, possibly by metformin administration. 相似文献