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991.
992.
The purpose of this study was to determine the mechanisms responsible for transport of raloxifene and its hydrophilic conjugates. Human intestinal Caco-2 cell culture model and Caco-2 cell lysate were used for the studies. The results indicated that absorptive permeability (PAB) of raloxifene was lower than its secretory permeability (PAB). As the concentration increased, the efflux ratio (PBA/PAB) decreased, but PBA increased. PAB was also increased in the presence of verapamil and cyclosporine A, two P-glycoprotein inhibitors. Raloxifene was extensively metabolized into sulfated and glucuronidated conjugates. The extent of metabolism or clearance was decreased as the concentration increased from 3.4 (96%) to 30 (22%) microM. Multidrug resistance-related protein inhibitors MK-571 (C26H26ClN2O3S2) and leukotriene C4 significantly decreased (maximal 80%) apical efflux of both conjugates. They also significantly decreased (maximal 85%) basolateral efflux of glucuronides but not sulfates. On the other hand, organic anion transporter (OAT) inhibitor estrone sulfate and estrone glucuronide significantly decreased (maximal 50%) the efflux of sulfate from both sides but had variable effects on glucuronide efflux. Inhibition of conjugate efflux with the OAT inhibitor estrone sulfate was concentration dependent, which resulted in increased transport of intact raloxifene (maximal 90%). This increase in raloxifene transport was also observed in the presence of another OAT inhibitor estrone glucuronide (70%). In conclusion, this is the first report that inhibition of an efflux transporter responsible for the transport of metabolites can result in increase in the transport of the intact compound. It also provides additional explanation why raloxifene has low bioavailability but a long half-life. 相似文献
993.
994.
995.
Evaluation of four DNA extraction methods for the detection of Mycobacterium avium subsp. paratuberculosis by polymerase chain reaction 总被引:1,自引:0,他引:1
Chui LW King R Lu P Manninen K Sim J 《Diagnostic microbiology and infectious disease》2004,48(1):39-45
Polymerase chain reaction (PCR) has been widely used due to its high specificity, sensitivity, and rapid turn-around time. However, inhibitory factors may be co-extracted with the target nucleic acid that will hinder the performance of PCR. In this study, DNA extraction methods for Mycobacterium avium subsp. paratuberculosis were evaluated including rapid lysis, organic extraction, silica-based and magnetic particle-based (MagaZorb) technologies on bacterial cells, and spiked bovine feces. Efficiency of the extraction was determined by PCR end point titration with primers targeting the insertion sequence, IS900. Results of the end point titrations are identical for bacterial cells and spiked feces. Inhibition was observed in PCR with DNA isolated from spiked feces, and a 1/100 dilution was able to alleviate this problem with DNA extracted by MagaZorb. A 1/1000 dilution was required for the other three methods. MagaZorb proved to be more efficient at removing inhibitory factors and required the least labor and completion time. Further evaluation is required for its utilization in other clinical specimens. 相似文献
996.
Jeong TC Chang HW Lee ES Jeon TW Jeong HG Holsapple MP 《Journal of toxicology and environmental health. Part A》2004,67(23-24):1955-1970
Studies demonstrated that cocaine-induced immunosuppression is mediated by metabolites of cocaine. Although SKF 525-A inhibited cocaine N-demethylation in liver S9 fractions isolated from female B6C3F1 mice, our study showed that pretreatment of mice with SKF 525-A potentiated cocaine-induced suppression of the antibody response to sheep red blood cells. An increase in formaldehyde generation was subsequently shown following incubation of cocaine with the S9 fractions prepared from SKF 525-A-treated mice, indicating the possibility of cytochrome P-450 (CYP) induction. Therefore, the inductive effects of SKF 525-A on CYP enzyme activities and proteins were investigated in female B6C3F1 mice to elucidate the potentiation of cocaine-induced immunosuppression by SKF 525-A. When SKF 525-A was administered at 10, 20, or 40 mg/kg/d intraperitoneally for 7 consecutive days, both ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase activities were induced dose-dependently. Furthermore, the induction of enzymatic activity was time dependent. Meanwhile, when the type of isozyme induced by SKF 525-A was analyzed by Western immunoblotting with monospecific anti-CYP 1A and anti-CYP 2B antibodies, only the CYP 2B appeared to be induced. From in vitro inhibition studies with monoclonal antibodies, it was confirmed that the induced activity of ethoxyresorufin O-deethylase by SKF 525-A was due to increased levels of CYP 2B proteins. Our present results provide an explanation for the potentiation of cocaine-induced immunosuppression by repeated exposure to SKF 525-A. Our results also indicate that ethoxyresorufin O-deethylase, a selective substrate for CYP 1A, may also be catalyzed by CYP 2B. 相似文献
997.
Chemical genetics is an emerging research field that utilises biologically active small molecules to study biological functions of genes and their products. The direct regulation of the protein function by the biologically active small molecules can alternate the gene mutagenesis studies utilised in conventional genetics. Like conventional genetics, chemical genetics can be divided into two concepts - 'forward' and 'reverse' chemical genetics. These approaches of chemical genetics have a tremendous impact on both functional genomics and drug development. This review focuses on the two ways in which chemical genetics can be used for therapeutic target mining and their practical application in drug development, particularly, in angiogenesis-related diseases. 相似文献
998.
Lee KY You HJ Jeong HG Kang JS Kim HM Rhee SD Jeon YJ 《International immunopharmacology》2004,4(8):1029-1038
In our previous studies, we showed that PCSC, a polysaccharide isolated from Poria cocos, activated macrophages to induce the translocation of NF-kappaB/Rel into nucleus and DNA binding to its cognate site in the promoter of iNOS gene [Int. Immunopharmacol. 3 (2003) 1353]. In the present study, we investigated the role of p38 kinase pathway and membrane receptors (CD14, Toll-like receptor 4 (TLR4), and CR3) in mediating nitric oxide (NO) production and NF-kappaB/Rel activation induced by PCSC. Treament of RAW 264.7 cells with PCSC resulted in significant activation of p38. The specific p38 inhibitor SB203580 abrogated the PCSC-induced NF-kappaB/Rel activation and NO generation, whereas the selective mitogen-activated protein kinase/extracellular signal-regulated kinase 1 (MEK-1) inhibitor PD98059 did not affect the NF-kappaB/Rel and NO induction. Treatment of RAW 264.7 cells with anti-CD14 Ab, anti-TLR4 Ab, and anti-CR3 Absignificantly blocked PCSC-induced NO production activation. In conclusion, we demonstrate that PCSC induces NF-kappaB/Rel activation and iNOS expression through the CD14, TLR4, and CR3 membrane receptor and p38 kinase which is critically involved in the signal transduction leading to NF-kappaB/Rel activation in murine macrophages. 相似文献
999.
1000.
A Single-Power Alternating Current (SPAC) instrument was used to measure the low-impedance acupoints around Ho-Ku (LI-4), Yang-Hsi (LI-5), Yang-Ch'ih (TB-4), Yang-Ku (SI-5), T'ai-Yuan (Lu-9), Ta-Lung (EH-7) and Shen-Men (He-7). A four-electrode instrument was used to measure the subcutaneous impedance at these low-impedance acupoints and adjacent control points on 12 healthy people. The mean subcutaneous impedance at the acupoints was 49.8+/-8.4 omega, significantly lower than the impedance of 53.5+/-omega 9.3 omega for the control points (P < 0.005). Of the seven acupoints, five (71%) had significantly lower impedances than the mean impedance for the adjacent control points. Seven of the 14 control points had significantly higher impedances than the adjacent acupoints, with most control points (93%) having higher impedances than adjacent acupoints. In conclusion, subcutaneous impedance is lower at the low-impedance points as measured with the SPAC two-electrode method. One interpretation of these results is that more interstitial fluid lies beneath the low-impedance acupoints. 相似文献