全文获取类型
收费全文 | 466篇 |
免费 | 26篇 |
出版年
2023年 | 2篇 |
2022年 | 2篇 |
2021年 | 8篇 |
2020年 | 6篇 |
2019年 | 9篇 |
2018年 | 10篇 |
2017年 | 12篇 |
2016年 | 12篇 |
2015年 | 19篇 |
2014年 | 13篇 |
2013年 | 31篇 |
2012年 | 33篇 |
2011年 | 28篇 |
2010年 | 15篇 |
2009年 | 22篇 |
2008年 | 20篇 |
2007年 | 28篇 |
2006年 | 25篇 |
2005年 | 25篇 |
2004年 | 16篇 |
2003年 | 21篇 |
2002年 | 24篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 2篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1990年 | 11篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有492条查询结果,搜索用时 203 毫秒
141.
Sabatini N Di Giacomo V Rapino M Rana R Garaci G Giuseppe F Cataldi A 《Journal of cellular biochemistry》2005,95(3):611-619
The study of the ability of chemotherapeutic agents and/or ionizing radiation (IR) to induce cell death in tumor cells is essential for setting up new and more efficient therapies against human cancer. Since drug and ionizing radiation resistance is an impediment to successful chemotherapy against cancer, we wanted to check if etoposide/ionizing radiation combined treatment could have a synergic effect to improve cell death in K562, a well-known human erythroleukemia ionizing radiation resistant cell line. In this study, we examined the role played by JNK/SAPK, p53, and mitochondrial pathways in cell death response of K562 cells to etoposide and IR treatment. Our results let us suppose that the induction of cell death, already evident in 15 Gy exposed cells, mainly in 15 Gy plus etoposide, may be mediated by JNK/SAPK pathway. Moreover, p53 is a potential substrate for JNK and may act as a JNK target for etoposide and ionizing radiation. Thus further investigation on these and other molecular mechanisms underlying the cell death response following etoposide and ionizing radiation exposure could be useful to overcome resistance mechanisms in tumor cells. 相似文献
142.
Zhang M Moran M Round J Low TA Patel VP Tomassian T Hernandez JD Miceli MC 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(3):1479-1490
CD45 is dynamically repositioned within lipid rafts and the immune synapse during T cell activation, although the molecular consequences of CD45 repositioning remain unclear. In this study we examine the role of CD45 membrane compartmentalization in regulating murine T cell activation. We find that raft-localized CD45 antagonizes IL-2 production by opposing processive TCR signals, whereas raft-excluded CD45 promotes ERK-dependent polarized synaptic lipid raft clustering and IL-2 production. We propose that these dual CD45 activities ensure that only robust TCR signals proceed, whereas signals meeting threshold requirements are potentiated. Our findings highlight membrane compartmentalization as a key regulator of CD45 function and elucidate a novel signal transduction pathway by which raft-excluded CD45 positively regulates T cell activation. 相似文献
143.
144.
Effect of Cu,Zn superoxide dismutase on cholesterol metabolism in human hepatocarcinoma (HepG2) cells 总被引:1,自引:0,他引:1
Mondola P Serù R Santillo M Damiano S Bifulco M Laezza C Formisano P Rotilio G Ciriolo MR 《Biochemical and biophysical research communications》2002,295(3):603-609
The microsomal enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and the low density lipoprotein (LDL) receptor pathway carry out a key role on cholesterol homeostasis in eucaryotic cells. The HMG-CoA reductase is sensitive to oxidative inactivation and to phosphorylation by many kinases that are able to inactivate the protein and increase its susceptibility to proteolysis. We previously demonstrated that a calf thymus Cu,Zn SOD affects cholesterol metabolism. This protein binds with rat hepatocyte cell membrane by a specific surface membrane receptor. The involvement of Cu,Zn SOD in cholesterol metabolism is confirmed further by the presence of this antioxidant enzyme in circulating serum lipoproteins. We studied the effect of native human Cu,Zn SOD, metal-free SOD (apo SOD), and SOD-inactivated with hydrogen peroxide on cholesterol metabolism in human hepatocarcinoma HepG2 cells. Results showed that all forms of SODs used, at the concentration of 150 ng/ml, are able to affect cholesterol metabolism decreasing both HMG-CoA reductase activity and its protein levels; this inhibitory effect is accompanied by reduced cholesterol synthesis measured as [14C]acetate incorporation into [14C]cholesterol and by an increased [125I]LDL binding to HepG2 cells. Furthermore, the inhibitory effect of Cu,Zn SOD on cholesterol synthesis was completely abolished when the cells were incubated with Cu,Zn SOD in the presence of bisindoilmaleimide (BDM), an inhibitor of protein kinase C (PKC); moreover, we demonstrated that Cu,Zn SOD as well as apo SOD was able to increase PKC activity. Overall, data demonstrate that Cu,Zn SOD affects cholesterol metabolism independently from its dismutase activity and its metal content and that the inhibitory action on cholesterol synthesis is mediated by an activation of protein kinase C. 相似文献
145.
Rosalba M. Farnesi Marinella Marinelli Simonetta Tei Daniela Vagnetti 《Journal of morphology》1981,170(2):195-205
The muscular system in the posterior sucker of Branchiobdella pentodonta Whit. has circular, longitudinal and radial fibers. In the anterior sucker, which has circular and longitudinal fibers, the muscle system is scarce. Concentric fibers are found around the mouth. In both suckers the glandular elements form voluminous complexes secreting mucus for attachment to the substrate. Suckers show neuromuscular junctions and three distinct types of neuroglandular junctions: one with typical neurosecretory granules, one with larger neurosecretory granules produced by cells located at the origin of the segmental nerves, and one with presynaptic vesicles. The second type is peculiar to the posterior sucker. A comparison is made between suckers of Branchiobdella and those of leeches. 相似文献
146.
147.
148.
Felipe Montecinos-Franjola Nicholas G. James Luis Concha-Marambio Juan E. Brunet Rosalba Lagos Octavio Monasterio David M. Jameson 《Biochimica et Biophysica Acta - Proteins and Proteomics》2014,1844(7):1193-1200
Cell division protein FtsZ cooperatively self-assembles into straight filaments when bound to GTP. A set of conformational changes that are linked to FtsZ GTPase activity are involved in the transition from straight to curved filaments that eventually disassemble. In this work, we characterized the fluorescence of single Trp mutants as a reporter of the predicted conformational changes between the GDP- and GTP-states of Escherichia coli FtsZ. Steady-state fluorescence characterization showed the Trp senses different environments and displays low solvent accessibility. Time-resolved fluorescence data indicated that the main conformational changes in FtsZ occur at the interaction surface between the N and C domains, but also minor rearrangements were detected in the bulk of the N domain. Surprisingly, despite its location near the bottom protofilament interface at the C domain, the Trp 275 fluorescence lifetime did not report changes between the GDP and GTP states. The equilibrium unfolding of FtsZ features an intermediate that is stabilized by the nucleotide bound in the N-domain as well as by quaternary protein–protein interactions. In this context, we characterized the unfolding of the Trp mutants using time-resolved fluorescence and phasor plot analysis. A novel picture of the structural transition from the native state in the absence of denaturant, to the solvent-exposed unfolded state is presented. Taken together our results show that conformational changes between the GDP and GTP states of FtsZ, such as those observed in FtsZ unfolding, are restricted to the interaction surface between the N and C domains. 相似文献
149.
Filippo Pietrantonio Claudia Maggi Maria Di Bartolomeo Maria Grazia Facciorusso Federica Perrone Adele Testi Roberto Iacovelli Rosalba Miceli Ilaria Bossi Giorgia Leone Massimo Milione Giuseppe Pelosi Filippo de Braud 《PloS one》2014,9(4)
Introduction
Although cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations.Patients and Methods
We evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number – defined as mean of 3 to 5 fusion signals in ≥10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease.Results
No ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885).Conclusion
Gain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy. 相似文献150.
Placebo analgesia is mediated by both opioid and nonopioid mechanisms, but so far nothing is known about the nonopioid component. Here we show that the specific CB1 cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant or SR141716) blocks nonopioid placebo analgesic responses but has no effect on opioid placebo responses. These findings suggest that the endocannabinoid system has a pivotal role in placebo analgesia in some circumstances when the opioid system is not involved. 相似文献