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1.
Serving as one of our primary environmental inputs, vision is the most sophisticated sensory system in humans. Here, we present recent findings derived from energetics, genetics and physiology that provide a more advanced understanding of color perception in mammals. Energetics of cistrans isomerization of 11-cis-retinal accounts for color perception in the narrow region of the electromagnetic spectrum and how human eyes can absorb light in the near infrared (IR) range. Structural homology models of visual pigments reveal complex interactions of the protein moieties with the light sensitive chromophore 11-cis-retinal and that certain color blinding mutations impair secondary structural elements of these G protein-coupled receptors (GPCRs). Finally, we identify unsolved critical aspects of color tuning that require future investigation.  相似文献   
2.
We have recently demonstrated that exposure to barium for a short time (≤4 days) and at a low level (5 µM = 687 µg/L) promotes invasion of human nontumorigenic HaCaT cells, which have characteristics similar to those of normal keratinocytes, suggesting that exposure to barium for a short time enhances malignant characteristics. Here we examined the effect of exposure to low level of barium for a long time, a condition mimicking the exposure to barium through well water, on malignant characteristics of HaCaT keratinocytes. Constitutive invasion activity, focal adhesion kinase (FAK) protein expression and activity, and matrix metalloproteinase 14 (MMP14) protein expression in primary cultured normal human epidermal keratinocytes, HaCaT keratinocytes, and HSC5 and A431 human squamous cell carcinoma cells were augmented following an increase in malignancy grade of the cells. Constitutive invasion activity, FAK phosphorylation, and MMP14 expression levels of HaCaT keratinocytes after treatment with 5 µM barium for 4 months were significantly higher than those of control untreated HaCaT keratinocytes. Taken together, our results suggest that exposure to a low level of barium for a long time enhances constitutive malignant characteristics of HaCaT keratinocytes via regulatory molecules (FAK and MMP14) for invasion. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 161–167, 2015.  相似文献   
3.
As some breast cancer‐related deaths can be attributed to the metastasis of cancer stem cells, chemotherapeutic agents targeting breast cancer stem cells are of interest as a potential treatment. Flavonoids that exhibit cytotoxicity on breast cancer stem cells have rarely been observed. Thus, the objective of this study was to measure potential cytotoxic effects of 42 different flavonoids on the human breast cancer stem‐like cell line, MCF7‐SC. The relationship between flavonoid structural properties and cytotoxicity has not been reported previously; therefore, we determined quantitative structure–activity relationships using both comparative molecular field analysis and comparative molecular similarity analysis. Further biological experiments including Western blot analysis, flow cytometry, and immunofluorescence microscopy were also conducted on the most cytotoxic 8‐chloroflavanone.  相似文献   
4.
The erythropoietin‐producing hepatocellular carcinoma receptor B4 is a receptor tyrosine kinase whose expression is preserved in various malignancies, including colon, gastric, and breast carcinoma. Hepatocellular carcinoma receptor B4 presence in tumor cells and involvement in cancer suppression makes it a potential therapeutic target for activating compounds. Moreover, modulators of its activity also have a strong potential to be used in diagnosis and therapy monitoring. We used virtual ligand screening to identify novel hepatocellular carcinoma receptor B4 kinase modulators for experimental testing. Three independent assay platforms confirmed that dinitrophenyl‐L‐arginine is likely to affect the kinase activity of hepatocellular carcinoma receptor B4. An enzyme‐coupled spectrophotometric assay has been used to examine this possibility and may prove to be useful for assessing other novel kinase modulator candidates. Overall, our observations suggest that dinitrophenyl‐L‐arginine has an activating effect on hepatocellular carcinoma receptor B4 and, therefore, more efficient derivatives may have therapeutic effects in tumors where hepatocellular carcinoma receptor B4 exhibits antimalignant properties. The hepatocellular carcinoma receptor B4‐activating effect is discussed with respect to previously described mechanisms, using predicted and experimental structures for docked ligands. As a novel kinase activity modulator, dinitrophenyl‐L‐arginine may provide new insights into molecular mechanisms by which kinases are activated or regulated, and may serve as a lead compound for the generation of novel hepatocellular carcinoma receptor B4‐activating therapeutic compounds.  相似文献   
5.
A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke.  相似文献   
6.
In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2‐hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase‐2 (MMP‐2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP‐2 along with potent anticancer activity against four tumor cell lines. Structure–activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V‐FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent.  相似文献   
7.
Selective inhibitors of kinases that regulate the cell cycle, such as cyclin‐dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7‐trisubstituted pyrazolo[4,3‐d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i , which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT‐116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti‐angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis‐like activity in endothelial cells offers possible therapeutic potential.  相似文献   
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9.
BackgroundThe incidence of leptomeningeal carcinomatosis (LMC) has increased in patients with metastatic non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of icotinib in the treatment of LMC.MethodsTwenty-one NSCLC patients diagnosed with LMC and treated with icotinib were retrospectively reviewed.ResultsAn exon 21 point mutation and an exon 19 deletion of EGFR were found in 10 and 11 patients, respectively. A standard dose of icotinib (125 mg/day, three times a day) was prescribed to 16 patients without previous icotinib therapy. A double dose of icotinib was prescribed to five patients who developed LMC during icotinib therapy with a standard dose. Eighteen of 20 patients showed improvement of dizziness and headache. Seventeen of 21 patients had an improved Eastern Cooperative Oncology Group performance status (ECOG PS) score after icotinib treatment. The median overall survival of the patients after the diagnosis of LMC was 10.1 months (95% confidence interval (CI): 8.4–12.0 months). Univariate analysis showed that the ECOG PS score, parenchymal brain metastasis, and previous icotinib administration were significantly associated with patient survival. Multivariate analysis also demonstrated that the ECOG PS score was an independent predictor for survival.ConclusionOur results suggest that icotinib is effective for the treatment of LMC from NSCLC with an EGFR mutation, especially for patients with a good ECOG PS score.  相似文献   
10.
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