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Unlicensed personnel administering medications to older persons living at home: a challenge for social and care services
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Nahrendorf M Spindler M Hu K Bauer L Ritter O Nordbeck P Quaschning T Hiller KH Wallis J Ertl G Bauer WR Neubauer S 《Cardiovascular research》2005,65(2):419-427
OBJECTIVE: Creatine kinase (CK) is responsible for the transport of high-energy phosphates in excitable tissue and is of central importance in myocardial energy homeostasis. Significant changes in myocardial energetics have been reported in mice lacking the various CK isoenzymes. Our hypothesis was that ablation of CK isoenzymes leads to cardiac hypertrophy, impaired function, and aggravation of left ventricular remodeling post-myocardial infarction. METHODS: CK-deficient mice (CK KO) were examined by cardiac magnetic resonance imaging (MRI) to determine left ventricular volumes, ejection fraction, and mass: ten wild-type (WT), 6 mitochondrial CK KO (Mito-CK-/-), 10 cytosolic CK KO (M-CK-/-), and 10 mice with combined KO (M/Mito-CK-/-). RESULTS: While ejection fraction was similar in all groups, there was significant LV dilatation with a approximately 30% increase in LV end-diastolic volumes in Mito-CK-/- and in M/Mito-CK-/-. Compared to WT, there was a striking 73% and 64% increase of LV mass in Mito-CK-/- and in M/Mito-CK-/- mice, respectively, but no significant increase of LV mass (+33%; p=n.s.) in M-CK-/-. Furthermore, significant re-expression of beta-MHC, a marker of myocardial hypertrophy, was found in all CK-deficient hearts. LV remodeling was investigated by MRI in hearts of 7 WT and 10 M/Mito-CK-/- mice 4 weeks postmyocardial infarction (MI). Four weeks post-LAD ligation (MI size approximately 32%), WT and M/Mito-CK-/- showed a similar degree of cardiac dysfunction, dilatation, and hypertrophy. CONCLUSION: Mito-CK-/- and M/Mito-CK-/- mice show significant LV dilatation and marked LV hypertrophy, but LV remodeling post-MI is not aggravated. CK ablation leads to substantial adaptational changes in heart. 相似文献
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Andrea E. Prota Katja Bargsten J. Fernando Diaz May Marsh Carmen Cuevas Marc Liniger Christian Neuhaus Jose M. Andreu Karl-Heinz Altmann Michel O. Steinmetz 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(38):13817-13821
The recent success of antibody–drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.Microtubule-targeting agents such as the taxanes and the vinca alkaloids represent a successful class of anticancer drugs (1). Vinblastine, for example, is a microtubule-destabilizing agent (MDA) that is widely used in combination therapy for the treatment of childhood and adult malignancies (2). The broad clinical application of MDAs, however, is hampered by their severe adverse effects (3). This problem has been very recently addressed by the use of antibody–drug conjugate (ADC) approaches, which have revived interest in the development of highly potent MDAs for therapeutic use (4–6).For several important MDAs, the molecular mechanism of action on tubulin and microtubules has so far remained elusive. Rhizoxin, for example, is a potent MDA that has been investigated in phase 2 clinical trials, but for reasons poorly understood, it has demonstrated only very limited clinical efficacy (7). At the molecular level, it is well established that rhizoxin interferes with the binding of vinblastine to tubulin; however, the exact location of its binding site has been a matter of debate (8–10). Interestingly, biochemical and mutagenesis data suggest that the structurally unrelated MDA maytansine (9, 11), which is part of an ADC that was recently approved by the FDA for the treatment of advanced breast cancer (11, 12), and the phase 1 drug PM060184 (13, 14) (Fig. 1A) share a common tubulin-binding site with rhizoxin (9, 13, 14). These two latter drugs have also been reported to interfere with the binding of vinblastine; however, as for rhizoxin, the exact binding sites and modes of action of maytansine and PM060184 have not been elucidated (9, 14–16).Open in a separate windowFig. 1.Structure of the tubulin–rhizoxin F complex. (A) Chemical structures of rhizoxin F, maytansine, and PM060184. (B) Overall view of the T2R-TTL–rhizoxin F complex. Tubulin (gray), RB3 (light green), and TTL (violet) are shown in ribbon representation; the MDA rhizoxin F (orange) and GDP (cyan) are depicted in spheres representation. As a reference, the vinblastine structure (yellow, PDB ID no. 1Z2B) is superimposed onto the T2R complex. (C) Overall view of the tubulin–rhizoxin F interaction in two different orientations. The tubulin dimer with bound ligand (α-tubulin-2 and β-tubulin-2 of the T2R-TTL–rhizoxin F complex) is shown in surface representation. The vinblastine structure is superimposed onto the β-tubulin chain to highlight the distinct binding site of rhizoxin F. All ligands are in sphere representation and are colored in orange (rhizoxin F), cyan (GDP), and yellow (vinblastine). (D) Close-up view of the interaction observed between rhizoxin F (orange sticks) and β-tubulin (gray ribbon). Interacting residues of β-tubulin are shown in stick representation and are labeled.To establish the exact tubulin-binding site of rhizoxin, maytansine, and PM060184 and to clarify their specific interactions with the protein, we have investigated the structures of the corresponding ligand–tubulin complexes by X-ray crystallography. Our data reveal a new tubulin-binding site and pharmacophore for small molecules, and binding to this site is associated with a distinct molecular mechanism for the inhibition of microtubule formation. 相似文献
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Bruce A. Perkins MD Nima Soleymanlou PhD Julio Rosenstock MD Jay S. Skyler MD Lori M. Laffel MD Karl-Heinz Liesenfeld Dietmar Neubacher Matthew M. Riggs PhD Curtis K. Johnston PharmD Rena J. Eudy-Byrne PhD Ahmed Elmokadem PhD Jyothis T. George MD Jan Marquard MD Valerie Nock PhD 《Diabetes, obesity & metabolism》2020,22(3):427-433