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91.
Hommelgaard AM Roepstorff K Vilhardt F Torgersen ML Sandvig K van Deurs B 《Traffic (Copenhagen, Denmark)》2005,6(9):720-724
The role of caveolae in endocytosis is hotly debated. Here, we argue that most caveolae are stable microdomains at the cell surface. Only a small fraction of caveolae is constitutively internalized, leading to a quantitatively minor uptake of ligands and receptors. In addition, we suggest that a more pronounced downregulation of caveolae from the plasma membrane can occur, presumably stimulated by receptor cross-linking and clustering in caveolae. Finally, we propose that future studies dealing with internalization of caveolae should actually document such internalization and include kinetic data. 相似文献
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Maria Brandal Berstad Anette WeyergangKristian Berg 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Photochemical internalization (PCI) is a modality for cytosolic release of drugs trapped in endocytic vesicles. The method is based upon photosensitizers localized in the membranes of endocytic vesicles which create membrane rupture upon light exposure by generating reactive oxygen species (ROS), predominantly singlet oxygen (1O2).Methods
The human epidermal growth factor receptor 2 (HER2)-targeted immunotoxin (IT), trastuzumab–saporin, was evaluated in combination with PCI using TPCS2a (Amphinex®), a new photosensitizer approved for clinical use.Results
PCI synergistically enhanced the cytotoxicity of trastuzumab–saporin on trastuzumab-resistant HER2+ Zr-75-1 cells. The PCI effect was only observed when the IT was administered prior to the photochemical treatment (“light after” strategy), while administration of a non-targeted drug may equally well be performed after light exposure. Mechanistic studies showed reduced ligand-induced HER2 phosphorylation and receptor-mediated endocytosis after TPCS2a-PDT. Photochemical disruption of the cytoplasmic domain of HER2 was found to be induced by 1O2 generated both by photosensitizer located in the endocytic vesicles and in the outer leaflet of the plasma membrane.Conclusions
Administration of the HER2-targeted toxin prior to light exposure is a prerequisite for successful PCI-mediated delivery of HER2-targeted toxins.General significance
PCI of HER2-targeted toxins is demonstrated as a highly effective treatment modality which may overcome trastuzumab resistance. The mechanistic studies of the lack of PCI effect of the “light first” procedure is of outermost importance when designing a clinical PCI treatment protocol for delivery of HER2-targeted therapies. 相似文献97.
Hamaia SW Pugh N Raynal N Némoz B Stone R Gullberg D Bihan D Farndale RW 《The Journal of biological chemistry》2012,287(31):26019-26028
Integrins are well characterized cell surface receptors for extracellular matrix proteins. Mapping integrin-binding sites within the fibrillar collagens identified GFOGER as a high affinity site recognized by α2β1, but with lower affinity for α1β1. Here, to identify specific ligands for α1β1, we examined binding of the recombinant human α1 I domain, the rat pheochromocytoma cell line (PC12), and the rat glioma Rugli cell line to our collagen Toolkit II and III peptides using solid-phase and real-time label-free adhesion assays. We observed Mg(2+)-dependent binding of the α1 I domain to the peptides in the following rank order: III-7 (GLOGEN), II-28 (GFOGER), II-7 and II-8 (GLOGER), II-18 (GAOGER), III-4 (GROGER). PC12 cells showed a similar profile. Using antibody blockade, we confirmed that binding of PC12 cells to peptide III-7 was mediated by integrin α1β1. We also identified a new α1β1-binding activity within peptide II-27. The sequence GVOGEA bound weakly to PC12 cells and strongly to activated Rugli cells or to an activated α1 I domain, but not to the α2 I domain or to C2C12 cells expressing α2β1 or α11β1. Thus, GVOGEA is specific for α1β1. Although recognized by both α2β1 and α11β1, GLOGEN is a better ligand for α1β1 compared with GFOGER. Finally, using biosensor assays, we show that although GLOGEN is able to compete for the α1 I domain from collagen IV (IC(50) ~3 μm), GFOGER is much less potent (IC(50) ~90 μm), as shown previously. These data confirm the selectivity of GFOGER for α2β1 and establish GLOGEN as a high affinity site for α1β1. 相似文献
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Background
Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies and has a high mortality rate due to late detection and lack of efficient treatments. Identifying novel drug targets for this indication may open the way for new treatment strategies. Comparison of gene expression profiles of NSCLC and normal adjacent tissue (NAT) allowed to determine that 5-alpha-reductase type I (SRD5A1) was up-regulated in NSCLC compared to NAT. This raised the question whether SRD5A1 was involved in sustained proliferation and survival of NSCLC. 相似文献100.
Anette Stauch Hans-Peter Duerr Jean-Claude Dujardin Manu Vanaerschot Shyam Sundar Martin Eichner 《PLoS neglected tropical diseases》2012,6(12)