全文获取类型
收费全文 | 1019篇 |
免费 | 78篇 |
国内免费 | 1篇 |
出版年
2024年 | 1篇 |
2023年 | 9篇 |
2022年 | 5篇 |
2021年 | 24篇 |
2020年 | 22篇 |
2019年 | 19篇 |
2018年 | 37篇 |
2017年 | 26篇 |
2016年 | 29篇 |
2015年 | 71篇 |
2014年 | 59篇 |
2013年 | 76篇 |
2012年 | 97篇 |
2011年 | 85篇 |
2010年 | 66篇 |
2009年 | 49篇 |
2008年 | 68篇 |
2007年 | 68篇 |
2006年 | 47篇 |
2005年 | 44篇 |
2004年 | 37篇 |
2003年 | 37篇 |
2002年 | 23篇 |
2001年 | 3篇 |
2000年 | 5篇 |
1999年 | 8篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 8篇 |
1995年 | 9篇 |
1994年 | 8篇 |
1993年 | 5篇 |
1992年 | 12篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有1098条查询结果,搜索用时 265 毫秒
21.
?sa Segerstolpe Sander Granneman Petra Bj?rk Flavia de Lima Alves Juri Rappsilber Charlotta Andersson Martin H?gbom David Tollervey Lars Wieslander 《Nucleic acids research》2013,41(2):1178-1190
Ribosomal subunit biogenesis in eukaryotes is a complex multistep process. Mrd1 is an essential and conserved small (40S) ribosomal subunit synthesis factor that is required for early cleavages in the 35S pre-ribosomal RNA (rRNA). Yeast Mrd1 contains five RNA-binding domains (RBDs), all of which are necessary for optimal function of the protein. Proteomic data showed that Mrd1 is part of the early pre-ribosomal complexes, and deletion of individual RBDs perturbs the pre-ribosomal structure. In vivo ultraviolet cross-linking showed that Mrd1 binds to the pre-rRNA at two sites within the 18S region, in helix 27 (h27) and helix 28. The major binding site lies in h27, and mutational analyses shows that this interaction requires the RBD1-3 region of Mrd1. RBD2 plays the dominant role in h27 binding, but other RBDs also contribute directly. h27 and helix 28 are located close to the sequences that form the central pseudoknot, a key structural feature of the mature 40S subunit. We speculate that the modular structure of Mrd1 coordinates pseudoknot formation with pre-rRNA processing and subunit assembly. 相似文献
22.
Flavia M. Gonçalves Alisson Martins-Oliveira Riccardo Lacchini Vanessa A. Belo Jose G. Speciali Fabíola Dach Jose E. Tanus-Santos 《Gene》2013
Matrix metalloproteinases (MMP) are involved in the disruption of blood–brain barrier (BBB) during migraine attacks. In the present study, we hypothesized that two functional polymorphisms (C− 1306T and C− 735T) in MMP-2 gene and MMP-2 haplotypes are associated with migraine and modify MMP-2 and tissue inhibitor of MMP (TIMP)-2 levels in migraine. Genotypes for MMP-2 polymorphisms were determined by real time-PCR using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by gelatin zymography and ELISA, respectively, in 148 healthy women without history of migraine and in 204 women with migraine (153 without aura; MWA, and 51 with aura; MA). Patients with MA had higher plasma MMP-2 concentrations and MMP-2/TIMP-2 ratios than patients with MWA and controls (P < 0.05). While MMP-2 genotype and haplotype distributions for the polymorphisms were similar among the groups (P > 0.05), we found that the CC genotype for C− 735T polymorphism and the CC haplotype were associated with higher plasma MMP-2 concentrations in MA group (P < 0.05). Our findings may help to understand the role of MMP-2 and its genetic variants in the pathophysiology of migraine and to identify a particular group of migraine patients with increased MMP-2 levels that would benefit from the use of MMP inhibitors. 相似文献
23.
Paula Clemente Susana Peralta Alberto Cruz-Bermudez Lucía Echevarría Flavia Fontanesi Antoni Barrientos Miguel A. Fernandez-Moreno Rafael Garesse 《The Journal of biological chemistry》2013,288(12):8321-8331
Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency. 相似文献
24.
Sun Wook Cho Flavia Q. Pirih Amy J. Koh Megan Michalski Matthew R. Eber Kathryn Ritchie Benjamin Sinder Seojin Oh Saja A. Al-Dujaili JoonHo Lee Ken Kozloff Theodora Danciu Thomas J. Wronski Laurie K. McCauley 《The Journal of biological chemistry》2013,288(10):6814-6825
Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6+/+ and IL-6−/− mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6−/− compared with IL-6+/+ bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6−/− earlier than IL-6+/+ marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6−/− marrow. In the skeletal system, although intermittent PTH administration to IL-6+/+ and IL-6−/− mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system. 相似文献
25.
Camila Arantes Hartmann Vilma Regina Martins Flavia Regina Souza Lima 《FEBS letters》2013,587(2):238-244
Prion protein (PrPC) has neuroprotective functions and herein we demonstrate that astrocytes from PrPC-over-expressing mice are more resistant to induced cell death than wild-type astrocytes. The Stress-Inducible-Protein 1 (STI1), a PrPC ligand, prevents cell death in both wild-type and PrPC-over-expressing astrocytes through the activation of protein-kinase-A. Cultured embryonic astrocytes and brain extracts from PrPC-over-expressing mice show higher glial fibrillary acidic protein expression and reduced vimentin and nestin levels when compared to wild-type astrocytes, suggesting faster astrocyte maturation in the former mice. Our data indicate that PrPC levels modulate astrocyte development, and that PrPC–STI1 interaction contributes to protect against astrocyte death. 相似文献
26.
27.
Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil. 相似文献
28.
29.