全文获取类型
收费全文 | 708篇 |
免费 | 72篇 |
专业分类
780篇 |
出版年
2024年 | 3篇 |
2023年 | 3篇 |
2022年 | 12篇 |
2021年 | 19篇 |
2020年 | 8篇 |
2019年 | 12篇 |
2018年 | 13篇 |
2017年 | 13篇 |
2016年 | 16篇 |
2015年 | 38篇 |
2014年 | 30篇 |
2013年 | 32篇 |
2012年 | 51篇 |
2011年 | 47篇 |
2010年 | 29篇 |
2009年 | 35篇 |
2008年 | 41篇 |
2007年 | 37篇 |
2006年 | 40篇 |
2005年 | 31篇 |
2004年 | 19篇 |
2003年 | 12篇 |
2002年 | 21篇 |
2001年 | 19篇 |
2000年 | 8篇 |
1999年 | 18篇 |
1998年 | 5篇 |
1996年 | 5篇 |
1994年 | 3篇 |
1992年 | 12篇 |
1991年 | 10篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 6篇 |
1987年 | 10篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 12篇 |
1983年 | 3篇 |
1981年 | 9篇 |
1980年 | 8篇 |
1979年 | 7篇 |
1977年 | 4篇 |
1976年 | 6篇 |
1972年 | 4篇 |
1971年 | 4篇 |
1970年 | 6篇 |
1969年 | 5篇 |
1967年 | 5篇 |
1966年 | 3篇 |
排序方式: 共有780条查询结果,搜索用时 18 毫秒
21.
22.
Laura Remacha David Pirman Christopher E. Mahoney Javier Coloma Bruna Calsina Maria Currás-Freixes Rocío Letón Rafael Torres-Pérez Susan Richter Guillermo Pita Belén Herráez Giovanni Cianchetta Emiliano Honrado Lorena Maestre Miguel Urioste Javier Aller Óscar García-Uriarte María Ángeles Gálvez Alberto Cascón 《American journal of human genetics》2019,104(5):1008-1010
23.
24.
25.
K R Luehrsen S Davidson Y J Lee R Rouhani A Soleimani T Raich C A Cain E J Collarini D T Yamanishi J Pearson K Magee M R Madlansacay V Bodepudi D Davoudzadeh P A Schueler W Mahoney 《The journal of histochemistry and cytochemistry》2000,48(1):133-145
Oligonucleotides that carry a detectable label can be used to probe for mRNA targets in in situ hybridization experiments. Oligonucleotide probes (OPs) have several advantages over cDNA probes and riboprobes. These include the easy synthesis of large quantities of probe, superior penetration of probe into cells and tissues, and the ability to design gene- or allele-specific probes. One significant disadvantage of OPs is poor sensitivity, in part due to the constraints of adding and subsequently detecting multiple labels per oligonucleotide. In this study, we compared OPs labeled with multiple detectable haptens (such as biotin, digoxigenin, or fluorescein) to those directly conjugated with horseradish peroxidase (HRP). We used branching phosphoramidites to add from two to 64 haptens per OP and show that in cells, 16-32 haptens per OP give the best detection sensitivity for mRNA targets. OPs were also made by directly conjugating the same oligonucleotide sequences to HRP. In general, the HRP-conjugated OPs were more sensitive than the multihapten versions of the same sequence. Both probe designs work well both on cells and on formaldehyde-fixed, paraffin-embedded tissues. We also show that a cocktail of OPs further increases sensitivity and that OPs can be designed to detect specific members of a gene family. This work demonstrates that multihapten-labeled and HRP-conjugated OPs are sensitive and specific and can make superior in situ hybridization probes for both research and diagnostic applications. 相似文献
26.
Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling 总被引:1,自引:0,他引:1
Apoptotic cells are swiftly engulfed by phagocytes and degraded inside phagosomes. Phagosome maturation requires phosphatidylinositol 3-phosphate [PtdIns(3)P], yet how PtdIns(3)P triggers phagosome maturation remains largely unknown. Through a genomewide PtdIns(3)P effector screen in the nematode Caenorhabditis elegans , we identified LST-4/SNX9, SNX-1, and SNX-6, three BAR domain-containing sorting nexins, that act in two parallel pathways to drive PtdIns(3)P-mediated degradation of apoptotic cells. We found that these proteins were enriched on phagosomal surfaces through association with PtdIns(3)P and through specific protein-protein interaction, and they promoted the fusion of early endosomes and lysosomes to phagosomes, events essential for phagosome maturation. Specifically, LST-4 interacts with DYN-1 (dynamin), an essential phagosome maturation initiator, to strengthen DYN-1's association to phagosomal surfaces, and facilitates the maintenance of the RAB-7 GTPase on phagosomal surfaces. Furthermore, both LST-4 and SNX-1 promote the extension of phagosomal tubules to facilitate the docking and fusion of intracellular vesicles. Our findings identify the critical and differential functions of two groups of sorting nexins in phagosome maturation and reveal a signaling cascade initiated by phagocytic receptor CED-1, mediated by PtdIns(3)P, and executed through these sorting nexins to degrade apoptotic cells. 相似文献
27.
Marlys Hammond David G. Washburn Tram H. Hoang Sharada Manns James S. Frazee Hiroko Nakamura Jaclyn R. Patterson Walter Trizna Charlene Wu Leonard M. Azzarano Rakesh Nagilla Melanie Nord Rebecca Trejo Martha S. Head Baoguang Zhao Angela M. Smallwood Kendra Hightower Nicholas J. Laping Christine G. Schnackenberg Scott K. Thompson 《Bioorganic & medicinal chemistry letters》2009,19(15):4441-4445
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing. 相似文献
28.
Lesley J Gál I Mahoney DJ Cordell MR Rugg MS Hyman R Day AJ Mikecz K 《The Journal of biological chemistry》2004,279(24):25745-25754
Interactions between CD44 and hyaluronan are implicated in the primary adhesion of lymphocytes to endothelium at inflammatory locations. Here we show that preincubation of hyaluronan with full-length recombinant TSG-6 or its Link module domain (Link_TSG6) enhances or induces the binding of hyaluronan to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. These effects are blocked by CD44-specific antibodies and are absent in CD44-negative cells. Enhancement of CD44-mediated interactions of lymphoid cells with hyaluronan by TSG-6 proteins was seen under conditions of flow at shear forces that occur in post-capillary venules. Increases in the number of rolling cells were observed on substrates comprising TSG-6-hyaluronan complexes as compared with a substrate containing hyaluronan alone. In ligand competition experiments, cell surface-bound TSG-6-hyaluronan complexes were more potent than hyaluronan alone in inhibiting cell adhesion to immobilized hyaluronan. Link_TSG6 mutants with impaired hyaluronan binding function had a reduced ability to modulate ligand binding by cell surface CD44. However, some mutants that exhibited close to wild-type hyaluronan binding were found to have either reduced or increased activity, suggesting that some amino acid residues outside of the hyaluronan binding site might be involved in protein self-association, potentially leading to the formation of cross-linked hyaluronan fibers. In turn, cross-linked hyaluronan could increase the binding avidity of CD44 by inducing receptor clustering. The ability of TSG-6 to modulate the interaction of hyaluronan with CD44 has important implications for CD44-mediated cell activity at sites of inflammation, where TSG-6 is expressed. 相似文献
29.
Tammy Sobolik-Delmaire Dawn Katafiasz Sarah A. Keim My G. Mahoney 《Cell communication & adhesion》2007,14(2):99-109
Desmosomes are prominent cell-cell adhesive junctions found in a variety of epithelial tissues, including the oral epithelium. The transmembrane core of the desmosome is composed of the desmosomal cadherins that interact extracellularly to mediate cell-cell adhesion. The cytoplasmic domain of desmosomal cadherins interact with plaque proteins that in turn interact with the keratin intermediate filament cytoskeleton. Plakophilin 1 is a major desmosomal plaque component that functions to recruit intermediate filaments to sites of cell-cell contact via interactions with desmoplakin. Decreased assembly of desmosomes has been reported in several epithelial cancers. We examined plakophilin-1 expression in an esophageal squamous cell carcinoma tissue microarray and found that plakophilin-1 expression inversely correlates with tumor grade. In addition, we sought to investigate the effect of plakophilin-1 expression on desmosome assembly and cell motility in oral squamous cell carcinoma cell lines. Cell lines expressing altered levels of plakophilin-1 were generated and the ability of these cells to recruit desmoplakin to sites of cell-cell contact was examined. Our results show that decreased expression of plakophilin-1 results in decreased desmosome assembly and increased cell motility and invasion. These data lead us to propose that loss of plakophilin-1 expression during head and neck squamous cell carcinoma (HNSCC) progression may contribute to an invasive phenotype. 相似文献
30.
Jaclyn S. Long Yuko Fujiwara Joanne Edwards Claire L. Tannahill Gabor Tigyi Susan Pyne Nigel J. Pyne 《The Journal of biological chemistry》2010,285(46):35957-35966
We demonstrate here that the bioactive lipid sphingosine 1-phosphate (S1P) uses sphingosine 1-phosphate receptor 4 (S1P4) and human epidermal growth factor receptor 2 (HER2) to stimulate the extracellular signal regulated protein kinase 1/2 (ERK-1/2) pathway in MDA-MB-453 cells. This was based on several lines of evidence. First, the S1P stimulation of ERK-1/2 was abolished by JTE013, which we show here is an S1P2/4 antagonist and reduced by siRNA knockdown of S1P4. Second, the S1P-stimulated activation of ERK-1/2 was almost completely abolished by a HER2 inhibitor (ErbB2 inhibitor II) and reduced by siRNA knockdown of HER2 expression. Third, phyto-S1P, which is an S1P4 agonist, stimulated ERK-1/2 activation in an S1P4- and HER2-dependent manner. Fourth, FTY720 phosphate, which is an agonist at S1P1,3,4,5 but not S1P2 stimulated activation of ERK-1/2. Fifth, S1P stimulated the tyrosine phosphorylation of HER2, which was reduced by JTE013. HER2 which is an orphan receptor tyrosine kinase is the preferred dimerization partner of the EGF receptor. However, EGF-stimulated activation of ERK-1/2 was not affected by siRNA knockdown of HER2 or by ErbB2 (epidermal growth factor receptor 2 (or HER2)) inhibitor II in MDA-MB-453 cells. Moreover, S1P-stimulated activation of ERK-1/2 does not require an EGF receptor. Thus, S1P and EGF function in a mutually exclusive manner. In conclusion, the magnitude of the signaling gain on the ERK-1/2 pathway produced in response to S1P can be increased by HER2 in MDA-MB-453 cells. The linkage of S1P with an oncogene suggests that S1P and specifically S1P4 may have an important role in breast cancer progression. 相似文献