全文获取类型
收费全文 | 7398篇 |
免费 | 556篇 |
国内免费 | 551篇 |
专业分类
8505篇 |
出版年
2024年 | 10篇 |
2023年 | 105篇 |
2022年 | 256篇 |
2021年 | 447篇 |
2020年 | 254篇 |
2019年 | 323篇 |
2018年 | 287篇 |
2017年 | 243篇 |
2016年 | 315篇 |
2015年 | 435篇 |
2014年 | 533篇 |
2013年 | 549篇 |
2012年 | 664篇 |
2011年 | 564篇 |
2010年 | 332篇 |
2009年 | 351篇 |
2008年 | 379篇 |
2007年 | 305篇 |
2006年 | 283篇 |
2005年 | 209篇 |
2004年 | 219篇 |
2003年 | 214篇 |
2002年 | 136篇 |
2001年 | 136篇 |
2000年 | 128篇 |
1999年 | 143篇 |
1998年 | 83篇 |
1997年 | 70篇 |
1996年 | 81篇 |
1995年 | 70篇 |
1994年 | 61篇 |
1993年 | 31篇 |
1992年 | 62篇 |
1991年 | 43篇 |
1990年 | 40篇 |
1989年 | 22篇 |
1988年 | 24篇 |
1987年 | 28篇 |
1986年 | 16篇 |
1985年 | 33篇 |
1984年 | 8篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
排序方式: 共有8505条查询结果,搜索用时 15 毫秒
991.
992.
Shi W Li L Shi X Zheng F Zeng J Jiang X Gong F Zhou M Li Z 《Immunology and cell biology》2006,84(4):366-373
The killing of tumour cells that are resistant to soluble TNF-alpha (sTNF-alpha) by the membrane-bound form of TNF-alpha (mTNF-alpha) suggests that different intracellular signalling pathways are involved. We found that mTNF-alpha induced apoptosis in HL-60 cells and failed to cause degradation of inhibitor of kappa B alpha (IkappaB-alpha) and translocation and activation of nuclear factor kappa B (NF-kappaB), whereas sTNF-alpha failed to induce apoptosis, but lowered cytoplasmic inhibitor of kappa B alpha, induced translocation of NF-kappaB to the nucleus and experimentally increased activity of the regulated luciferase. Furthermore, mTNF-alpha upregulated the expression of TNF receptor associated factor (TRAF) 1 and failed to induce TRAF1 and TRAF2 membrane translocation, but led to cytoplasmic colocalization. In contrast, sTNF-alpha stimulated the expression of TRAF1 and TRAF2, recruiting both molecules onto the cell membrane poststimulation. These results suggest that the increased susceptibility of HL-60 cells to mTNF-alpha may be due to the failure of TRAF2 membrane translocation caused by the upregulation of TRAF1 expression and formation of a TRAF1/TRAF2 complex in the cytoplasm, thereby inhibiting NF-kappaB activation and inducing apoptosis. 相似文献
993.
Hypoglycemic activity of polysaccharide, with antioxidation, isolated from cultured Cordyceps mycelia 总被引:8,自引:0,他引:8
S.P. Li G.H. Zhang Q. Zeng Z.G. Huang Y.T. Wang T.T.X. Dong K.W.K. Tsim 《Phytomedicine》2006,13(6):428-433
Cordyceps sinensis, a well-known traditional Chinese medicine, possesses anti-tumor, immunostimulant and antioxidant activities; however, the identities of active components have not been determined. In our previous study using antioxidant activity-guided fractionation [Li et al., 2003. A polysaccharide isolated from Cordyceps sinensis, a traditional Chinese medicine, protects PC12 cells against hydrogen peroxide-induced injury. Life Sci. 73, 2503-2513], a polysaccharide of molecular weight approximately 210kDa was isolated from cultured Cordyceps mycelia by ion-exchange and sizing chromatography. The isolated polysaccharide, named CSP-1, which has strong anti-oxidation activity, contains glucose, mannose and galactose in the ratio of 1:0.6:0.75. In the present study, we demonstrated the hypoglycemic effect of CSP-1 on normal and alloxan-diabetic mice and streptozotocin (STZ)-diabetic rats. The basal glucose level did not differ significantly among the normal mice. CSP-1 (at 200 and 400mg/kg body wt./day for 7 days, p.o.), however, significantly reduced the blood glucose level by 12.0+/-3.2% and 22.5+/-4.7% in normal mice, respectively (p<0.05). When administered at a dose of higher than 200mg/kg body wt. daily for 7 days, CSP-1 produced a significant drop in blood glucose level in both STZ-induced diabetic rats and alloxan-induced diabetic mice. The serum insulin levels in diabetic animals were also increased by administration of CSP-1 (p<0.05). CSP-1 with hypoglycemic properties increased circulating insulin level in diabetic animals, which suggests that CSP-1 may stimulate pancreatic release of insulin and/or reduce insulin metabolism. 相似文献
994.
Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa 总被引:1,自引:0,他引:1
Sadikot RT Zeng H Joo M Everhart MB Sherrill TP Li B Cheng DS Yull FE Christman JW Blackwell TS 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(8):4923-4930
We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappaB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappaB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappaB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappaB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappaB. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappaB up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappaB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappaB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa. 相似文献
995.
Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803 总被引:3,自引:0,他引:3
Ling H Zhang LY Su Q Song Y Luo ZY Zhou XT Zeng X He J Tan H Yuan JP 《Cellular & molecular biology letters》2006,11(3):408-423
Diallyl disulfide (DADS) is a major constituent of garlic. Previously, we found that DADS both inhibited proliferation in
human gastric cancer cells in vitro and in vivo, and induced G2/M arrest. In this study, we investigated whether this differentiation effect was induced by DADS in human
gastric cancer MGC803 cells, and whether it was related to an alteration in ERK activity. The results showed that the growth
of MGC803 cells was inhibited by DADS. Cells treated with DADS displayed a lower nucleocytoplasmic ratio and tended to form
gland and intercellular conjunction structures. The ConA-mediated cell agglutination ratio and cells’ ALP specific activity
decreased. In MGC803 cells, dye transfer was limited to a few cells neighbouring the dye-injected cell and to a depth of 1–2
layers beneath the scrape site. However, after treatment with DADS, the LY (Lucifer Yellow) was transferred to several cells
immediately neighbouring the microinjected cell and to a depth of 2–4 cell layers from the scrape site. This indicated that
DADS induced differentiation in MGC803 cells. Western blot analysis revealed that although DADS did not influence the quantity
of ERK1/2 protein expressed, it did decrease its phosphorylation in a concentration-dependent manner, compared with the controls.
At 30 mg·L−1, DADS inhibited the activation of ERK1/2 in 15–30 min. These results suggested that the DADS-induced differentiation of MGC803
cells involved an alteration of the ERK1/2 signaling pathway. 相似文献
996.
Human kallikrein 10, a predictive marker for breast cancer 总被引:3,自引:0,他引:3
Our laboratory is involved in identifying genes that can be used as early diagnostic or prognostic markers in breast cancer. We previously identified a gene (NES1) that is expressed in normal but not in transformed mammary epithelial cells (MECs). NES1 is located on chromosome 19q13.4 within the kallikrein locus and thus was designated as human kallikrein 10 (hK10), although we have been unable to detect any protease activity. Importantly, hK10 expression is decreased in a majority of breast cancer cell lines. Transfection of hK10 into hK10-negative breast cancer cells reduces the tumorigenicity. Using methylation-specific PCR and subsequent sequencing, we demonstrate a strong correlation between hypermethylation of hK10 and loss of mRNA expression. Further analysis showed that essentially 100% of normal breast specimens had hK10 expression, whereas 46% of ductal carcinoma in situ (DCIS) and the majority of infiltrating ductal carcinoma (IDC) samples lacked the hK10 mRNA. Importantly, hK10-negative DCIS diagnosed at the time of biopsy were subsequently diagnosed as IDC at the time of definitive surgery. It has been shown that hK10 protein expression is regulated by steroids. In addition to breast cancers, hK10 is downregulated in cervical cancer, prostate cancer and acute lymphocytic leukemia, whereas it is upregulated in ovarian cancers. These results point to the paradoxical role of hK10 in human cancers and underscore the importance of further studies of this kallikrein. 相似文献
997.
A broad-spectrum dye-decolorizing bacterium, strain DN322, was isolated from activated sludge of a textile printing wastewater treatment plant. The strain was characterized and identified as a member of Aeromonas hydrophila based on Gram staining, morphology characters, biochemical tests, and nearly complete sequence analysis of 16S rRNA gene and the gyrase subunit beta gene (gyrB). Strain DN322 decolorized a variety of synthetic dyes, including triphenylmethane, azo, and anthraquinone dyes. For color removal, the most suitable pH and temperature were pH 5.0–10.0 and 25–37°C, respectively. Triphenylmethane dye, e.g., Crystal Violet, Basic Fuchsin, Brilliant Green, and Malachite Green (50 mg l−1) were decolorized more than 90% within 10 h under aerobic culture condition and Crystal Violet could be used as sole carbon source and energy source for cell growth. The color removal of triphenylmethane dyes was due to a soluble cytosolic enzyme, and the enzyme was an NADH/NADPH-dependent oxygenase; For azo and anthraquinone dyes, e.g., Acid Amaranth, Great Red GR, Reactive Red KE-3B, and Reactive Brilliant Blue K-GR (50 mg l−1) could be decolorized more than 85% within 36 h under anoxic condition. This strain may be useful for bioremediation applications. 相似文献
998.
999.
Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling
Wang Y Du D Fang L Yang G Zhang C Zeng R Ullrich A Lottspeich F Chen Z 《The EMBO journal》2006,25(21):5058-5070
The conserved polarity complex, comprising the partitioning-defective (Par) proteins Par3 and Par6, and the atypical protein kinase C, functions in various cell-polarization events and asymmetric cell divisions. However, little is known about whether and how external stimuli-induced signals may regulate Par3 function in epithelial cell polarity. Here, we found that Par3 was tyrosine phosphorylated through phosphoproteomic profiling of pervanadate-induced phosphotyrosine proteins. We also demonstrated that the tyrosine phosphorylation event induced by multiple growth factors including epidermal growth factor (EGF) was dependent on activation of Src family kinase (SFK) members c-Src and c-Yes. The tyrosine residue 1127 (Y1127) of Par3 was identified as the major EGF-induced phosphorylation site. Moreover, we found that Y1127 phosphorylation reduced the association of Par3 with LIM kinase 2 (LIMK2), thus enabling LIMK2 to regulate cofilin phosphorylation dynamics. Substitution of Y1127 for phenylalanine impaired the EGF-induced Par3 and LIMK2 dissociation and delayed epithelial tight junction (TJ) assembly considerably. Collectively, these data suggest a novel, phosphotyrosine-dependent fine-tuning mechanism of Par3 in epithelial TJ assembly controlled by the EGF receptor-SFK signaling pathway. 相似文献
1000.
To examine the role of the C-terminal domain in the chaperone function of trigger factor (TF), a number of truncation mutants were constructed, namely: TF419, TF389, TF380, TF360, TF344, and TF251, in which the C-terminal 13, 43, 52, 72, 88 residues or the entire C-domain were deleted, respectively. Co-expression of mutant chicken adenylate kinase (AK) with TF and the C-terminal truncation mutants was achieved using a plasmid pBVAT that allows expression of TF and AK from a single plasmid. The results show that truncation of the C-terminus of TF has only minor effect on its ability to assist AK refolding in vivo. Further, ribosome-binding experiments indicate that C-terminal truncation mutants can still bind to the ribosome and the presence of the C-terminus may in fact lower the affinity of TF for the ribosome in vivo. This indicates that the C-domain of trigger factor may not be essential for the ribosome-associated molecular chaperone function of TF. However, the purified TF C-terminal truncation mutants had a dramatically reduced ability to assist rabbit muscle GAPDH refolding in vitro and a reduced tendency to dimerize. This shows that the structural integrity of the C-terminus contributes to both the chaperone function of TF and the stability of the dimeric form. 相似文献