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Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.  相似文献   
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Molluscs, comprising one of the most successful phyla, lack clear evidence of adaptive immunity and yet thrive in the oceans, which are rich in viruses. There are thought to be nearly 120,000 species of Mollusca, most living in marine habitats. Despite the extraordinary abundance of viruses in oceans, molluscs often have very long life spans (10 to 100 years). Thus, their innate immunity must be highly effective at countering viral infections. Antiviral compounds are a crucial component of molluscan defenses against viruses and have diverse mechanisms of action against a wide variety of viruses, including many that are human pathogens. Antiviral compounds found in abalone, oyster, mussels, and other cultured molluscs are available in large supply, providing good opportunities for future research and development. However, most members of the phylum Mollusca have not been examined for the presence of antiviral compounds. The enormous diversity and adaptations of molluscs imply a potential source of novel antiviral compounds for future drug discovery.  相似文献   
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Species interactions are integral drivers of community structure and can change from competitive to facilitative with increasing environmental stress. In subtidal marine ecosystems, however, interactions along physical stress gradients have seldom been tested. We observed seaweed canopy interactions across depth and latitudinal gradients to test whether light and temperature stress structured interaction patterns. We also quantified interspecific and intraspecific interactions among nine subtidal canopy seaweed species across three continents to examine the general nature of interactions in subtidal systems under low consumer pressure. We reveal that positive and neutral interactions are widespread throughout global seaweed communities and the nature of interactions can change from competitive to facilitative with increasing light stress in shallow marine systems. These findings provide support for the stress gradient hypothesis within subtidal seaweed communities and highlight the importance of canopy interactions for the maintenance of subtidal marine habitats experiencing environmental stress.  相似文献   
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BackgroundDespite evidence about the "modern epidemic" of overdiagnosis, and expanding disease definitions that medicalize more people, data are lacking on public views about these issues. Our objective was to measure public perceptions about overdiagnosis and views about financial ties of panels setting disease definitions.MethodsWe conducted a 15 minute Computer Assisted Telephone Interview with a randomly selected community sample of 500 Australians in January 2014. We iteratively developed and piloted a questionnaire, with a convenience sample (n=20), then with participants recruited by a research company (n=20). Questions included whether respondents had been informed about overdiagnosis; opinions on informing people; and views about financial ties among panels writing disease definitions.FindingsOur sample was generally representative, but included a higher proportion of females and seniors, typical of similar surveys. American Association for Public Opinion Research response rate was 20% and cooperation rate was 44%. Only 10% (95% CI 8%–13%) of people reported ever being told about overdiagnosis by a doctor. 18% (95% CI 11%–28%) of men who reported having prostate cancer screening, and 10% (95% CI 6%–15%) of women who reported having mammography said they were told about overdiagnosis. 93% (95% CI 90%–95%) agreed along with screening benefits, people should be informed about overdiagnosis. On panels setting disease definitions, 78% (95% CI 74%–82%) felt ties to pharmaceutical companies inappropriate, and 91% (95% CI 82%–100%) believed panels should have a minority or no members with ties. Limitations included questionnaire novelty and complexity.ConclusionsA small minority of Australians surveyed, including those reporting being screened for prostate or breast cancer, reported being informed of overdiagnosis; most believed people should be informed; and a majority felt it inappropriate that doctors with ties to pharmaceutical companies write disease definitions. Results suggest strategies to better inform people about overdiagnosis, and review disease definition processes, have significant public sympathy.  相似文献   
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Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.  相似文献   
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Sandvig K  Llorente A 《Molecular & cellular proteomics : MCP》2012,11(7):M111.012914-M111.012914-11
Cancer biomarkers are invaluable tools for cancer detection, prognosis, and treatment. Recently, microvesicles have appeared as a novel source for cancer biomarkers. We present here the results from a proteomic analysis of microvesicles released to the extracellular environment by the metastatic prostate cancer cell line PC-3. Using nanocapillary liquid chromatography-tandem mass spectrometry 266 proteins were identified with two or more peptide sequences. Further analysis showed that 16% of the proteins were classified as extracellular and that intracellular proteins were annotated in a variety of locations. Concerning biological processes, the proteins found in PC-3 cell-released microvesicles are mainly involved in transport, cell organization and biogenesis, metabolic process, response to stimulus, and regulation of biological processes. Several of the proteins identified (tetraspanins, annexins, Rab proteins, integrins, heat shock proteins, cytoskeletal proteins, 14-3-3 proteins) have previously been found in microvesicles isolated from other sources. However, some of the proteins seem to be more specific to the vesicular population released by the metastatic prostate cancer PC-3 cell line. Among these proteins are the tetraspanin protein CD151 and the glycoprotein CUB domain-containing protein 1. Interestingly, our results show these proteins are promising biomarkers for prostate cancer and therefore candidates for clinical validation studies in biological fluids.  相似文献   
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