全文获取类型
收费全文 | 3810篇 |
免费 | 380篇 |
国内免费 | 275篇 |
专业分类
4465篇 |
出版年
2024年 | 8篇 |
2023年 | 33篇 |
2022年 | 69篇 |
2021年 | 151篇 |
2020年 | 100篇 |
2019年 | 148篇 |
2018年 | 146篇 |
2017年 | 121篇 |
2016年 | 165篇 |
2015年 | 264篇 |
2014年 | 275篇 |
2013年 | 292篇 |
2012年 | 364篇 |
2011年 | 320篇 |
2010年 | 209篇 |
2009年 | 187篇 |
2008年 | 230篇 |
2007年 | 199篇 |
2006年 | 162篇 |
2005年 | 137篇 |
2004年 | 138篇 |
2003年 | 125篇 |
2002年 | 117篇 |
2001年 | 66篇 |
2000年 | 52篇 |
1999年 | 53篇 |
1998年 | 26篇 |
1997年 | 20篇 |
1996年 | 24篇 |
1995年 | 16篇 |
1994年 | 20篇 |
1993年 | 20篇 |
1992年 | 22篇 |
1991年 | 14篇 |
1990年 | 17篇 |
1989年 | 9篇 |
1988年 | 13篇 |
1987年 | 10篇 |
1986年 | 16篇 |
1985年 | 6篇 |
1984年 | 12篇 |
1983年 | 11篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 4篇 |
1978年 | 6篇 |
1976年 | 8篇 |
1975年 | 10篇 |
1974年 | 9篇 |
排序方式: 共有4465条查询结果,搜索用时 0 毫秒
921.
Hepatitis B virus X protein activates the p38 mitogen-activated protein kinase pathway in dedifferentiated hepatocytes 总被引:12,自引:0,他引:12 下载免费PDF全文
Hepatitis B virus X protein (pX) is implicated in hepatocarcinogenesis by an unknown mechanism. Employing a cellular model linked to pX-mediated transformation, we investigated the role of the previously reported Stat3 activation by pX in hepatocyte transformation. Our model is composed of a differentiated hepatocyte (AML12) 3pX-1 cell line that undergoes pX-dependent transformation and a dedifferentiated hepatocyte (AML12) 4pX-1 cell line that does not exhibit transformation by pX. We report that pX-dependent Stat3 activation occurs only in non-pX-transforming 4pX-1 cells and conclude that Stat3 activation is not linked to pX-mediated transformation. Maximum Stat3 transactivation requires Ser727 phosphorylation, mediated by mitogenic pathway activation. Employing dominant negative mutants and inhibitors of mitogenic pathways, we demonstrate that maximum, pX-dependent Stat3 transactivation is inhibited by the p38 mitogen-activated protein kinase (MAPK)-specific inhibitor SB 203580. Using transient-transreporter and in vitro kinase assays, we demonstrate for the first time that pX activates the p38 MAPK pathway only in 4pX-1 cells. pX-mediated Stat3 and p38 MAPK activation is Ca(2+) and c-Src dependent, in agreement with the established cellular action of pX. Importantly, pX-dependent activation of p38 MAPK inactivates Cdc25C by phosphorylation of Ser216, thus initiating activation of the G(2)/M checkpoint, resulting in 4pX-1 cell growth retardation. Interestingly, pX expression in the less differentiated hepatocyte 4pX-1 cells activates signaling pathways known to be active in regenerating hepatocytes. These results suggest that pX expression in the infected liver effects distinct mitogenic pathway activation in less differentiated versus differentiated hepatocytes. 相似文献
922.
利用SRAP和SSR分子标记检测分析29份棉花种质遗传完整性 总被引:13,自引:2,他引:13
利用SRAP和SSR分子标记检测29份棉花种质遗传完整性。结果表明,无论每一份不同更新发芽率水平繁殖后代的种质之间,还是每一份不同繁殖世代数种质之间,其等位基因频率差异不显著,也没有检测到稀有等位基因缺失的情况。本试验表明不同更新发芽率水平和繁殖世代数差异没有对棉花这种常异花授粉作物种质遗传完整性变化产生影响。 相似文献
923.
Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance. 相似文献
924.
925.
Mechanistic study of the anti‐cancer effect of Gynostemma pentaphyllum saponins in the ApcMin/+ mouse model 下载免费PDF全文
William Chi‐Shing Tai Wing‐Yan Wong Magnolia Muk‐Lan Lee Brandon Dow Chan Cheng Lu Wen‐Luan Wendy Hsiao 《Proteomics》2016,16(10):1557-1569
Gynostemma pentaphyllum saponins (GpS) have been shown to have anti‐cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the ApcMin/+ colorectal cancer (CRC) mouse model to investigate the anti‐cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in ApcMin/+ mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf‐1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin‐1 (Prdx1) and peroxiredoxin‐2 (Prdx2), and the downregulation of Raf‐1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti‐cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5‐fluorouracil (5‐FU) and found that GpS could enhance the anti‐cancer efficacy of 5‐FU, further suppressing the number of polyps in ApcMin/+ mice. Our findings highlight the potential of GpS as an anti‐cancer agent, the potential mechanisms of its anti‐cancer activities, and its effect as an adjuvant of 5‐FU in the chemotherapy of CRC. 相似文献
926.
927.
Diallyl trisulfide inhibits migration,invasion and angiogenesis of human colon cancer HT‐29 cells and umbilical vein endothelial cells,and suppresses murine xenograft tumour growth 下载免费PDF全文
Kuang‐Chi Lai Shu‐Chun Hsu Jai‐Sing Yang Chien‐Chih Yu Jin‐Cherng Lein Jing‐Gung Chung 《Journal of cellular and molecular medicine》2015,19(2):474-484
Angiogenesis inhibitors are beneficial for the prevention and treatment of angiogenesis‐dependent diseases including cancer. We examined the cytotoxic, anti‐metastatic, anti‐cancer and anti‐angiogenic effects of diallyl trisulfide (DATS). In HT29 cells, DATS inhibited migration and invasion through the inhibition of focal adhesion kinase (FAK), extracellular signal‐regulated kinase, c‐Jun N‐terminal kinase and p38 which was associated with inhibition of matrix metalloproteinases‐2, ‐7 and ‐9 and VEGF. In human umbilical vein endothelial cells (HUVEC), DATS inhibited the migration and angiogenesis through FAK, Src and Ras. DATS also inhibited the secretion of VEGF. The capillary‐like tube structure formation and migration by HUVEC was inhibited by DATS. The chicken egg chorioallantoic membrane (CAM) assay indicated that DATS treatment inhibited ex‐vivo angiogenesis. We investigated the anti‐tumour effects of DATS against human colon cancer xenografts in BALB/cnu/nu mice and its anti‐angiogenic activity in vivo. In this in‐vivo study, DATS also inhibited the tumour growth, tumour weight and angiogenesis (decreased the levels of haemoglobin) in HT29 cells. In conclusion, the present results suggest that the inhibition of angiogenesis may be an important mechanism in colon cancer chemotherapy by DATS. 相似文献
928.
Circularization of the HIV-1 RNA genome 总被引:2,自引:0,他引:2
929.
The implementation of the consensus on the management of Helicobacter pylori and barriers to consensus 下载免费PDF全文
Hsiu‐Chi Cheng Jyh‐Ming Liou Jiing‐Chyuan Luo Cheng‐Tang Chiu Ming‐Shiang Wu Yi‐Chia Lee Chun‐Ying Wu Deng‐Chyang Wu Ping‐I Hsu Chun‐Chao Chang Wei‐Lun Chang Jaw‐Town Lin Bor‐Shyang Sheu 《Helicobacter》2018,23(5)
Background
A consensus on the management of Helicobacter pylori has been developed. We aimed to assess whether dissemination through continuing medical education (CME) could enhance the adoption of this consensus among clinicians and to explore potential barriers to acceptance.Materials and methods
Four CME courses were held to disseminate the consensus. Adoption surveys were performed to evaluate participants’ behavior in the past and their commitment to adopt the consensus in future clinical practice after CME. The gaps and barriers to adoption were also surveyed.Results
A total of 240 physicians had attended the CME courses and received surveys with the 22 statements/substatements of the consensus. Before CME, adoption was good in six, fair in ten, and poor in six. After CME, 21 statements had either an initial >90% adoption or improvement to good or fair (P < 0.001), but one still had poor even though it showed improvement (P = 0.02). Although commitment was good or fair after CME, there was a >20% gap between “commitment” and “no barrier” to adoption for 11 statements, ten of which had a main barrier of financial incentives. Among the statements with fair or poor commitment after CME, less commitment to adoption and more barriers related to financial incentives were pronounced in clinicians serving in regional/district hospitals or clinics compared to those serving in medical centers.Conclusions
Continuing medical education may improve the adoption of the H. pylori consensus. The financial incentives were shown to be a main barrier to adoption of the consensus and should be improved. 相似文献930.
Ekouevi DK Stringer E Coetzee D Tih P Creek T Stinson K Westfall AO Welty T Chintu N Chi BH Wilfert C Shaffer N Stringer J Dabis F 《PloS one》2012,7(1):e29823