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91.
Volkow ND Fowler JS Wang GJ Telang F Logan J Wong C Ma J Pradhan K Benveniste H Swanson JM 《PloS one》2008,3(4):e2017
The use of stimulants (methylphenidate and amphetamine) as cognitive enhancers by the general public is increasing and is controversial. It is still unclear how they work or why they improve performance in some individuals but impair it in others. To test the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby reduce cerebral activity by increasing efficiency, we measured the effects of methylphenidate on brain glucose utilization in healthy adults. We measured brain glucose metabolism (using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose) in 23 healthy adults who were tested at baseline and while performing an accuracy-controlled cognitive task (numerical calculations) given with and without methylphenidate (20 mg, oral). Sixteen subjects underwent a fourth scan with methylphenidate but without cognitive stimulation. Compared to placebo methylphenidate significantly reduced the amount of glucose utilized by the brain when performing the cognitive task but methylphenidate did not affect brain metabolism when given without cognitive stimulation. Whole brain metabolism when the cognitive task was given with placebo increased 21% whereas with methylphenidate it increased 11% (50% less). This reflected both a decrease in magnitude of activation and in the regions activated by the task. Methylphenidate's reduction of the metabolic increases in regions from the default network (implicated in mind-wandering) was associated with improvement in performance only in subjects who activated these regions when the cognitive task was given with placebo. These results corroborate prior findings that stimulant medications reduced the magnitude of regional activation to a task and in addition document a "focusing" of the activation. This effect may be beneficial when neuronal resources are diverted (i.e., mind-wandering) or impaired (i.e., attention deficit hyperactivity disorder), but it could be detrimental when brain activity is already optimally focused. This would explain why methylphenidate has beneficial effects in some individuals and contexts and detrimental effects in others. 相似文献
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Zhou H Li W Wang SP Mendoza V Rosa R Hubert J Herath K McLaughlin T Rohm RJ Lassman ME Wong KK Johns DG Previs SF Hubbard BK Roddy TP 《Journal of lipid research》2012,53(6):1223-1231
Stable isotope tracer studies of apoprotein flux in rodent models present difficulties as they require working with small volumes of plasma. We demonstrate the ability to measure apoprotein flux by administering either (2)H- or (18)O-labeled water to mice and then subjecting samples to LC-MS/MS analyses; we were able to simultaneously determine the labeling of several proteolytic peptides representing multiple apoproteins. Consistent with relative differences reported in the literature regarding apoprotein flux in humans, we found that the fractional synthetic rate of apoB is greater than apoA1 in mice. In addition, the method is suitable for quantifying acute changes in protein flux: we observed a stimulation of apoB production in mice following an intravenous injection of Intralipid and a decrease in apoB production in mice treated with an inhibitor of microsomal triglyceride transfer protein. In summary, we demonstrate a high-throughput method for studying apoprotein kinetics in rodent models. Although notable differences exist between lipoprotein profiles that are observed in rodents and humans, we expect that the method reported here has merit in studies of dyslipidemia as i) rodent models can be used to probe target engagement in cases where one aims to modulate apoprotein production and ii) the approach should be adaptable to studies in humans. 相似文献
95.
T.M. Wong 《Life sciences》1983,33(3):255-259
ADH at doses 20 μU/100 g and 100 μU/100 g or 20 μU/100 g and 200 μU/100 g was injected intravenously into pentobarbital and alcohol anaesthetized rats loaded with either water or isotonic solution consisting of NaCl, glucose and ethanol. At the dose of 20 μU/100 g ADH retained water in both water and NaCl loaded animals. At high doses 100 μU/100 g in NaCl loaded rats and 200 μU/100 g in water loaded rats, ADH retained water and increased the renal excretion of Na+. That the natriuretic effect of ADH at the dose 20 μU/100 g was enhanced in NaCl loaded rats suggests that ADH is probably important in the regulation of Na+ content in the body when it is loaded with NaCl. 相似文献
96.
We aimed to find out relations among nonphotochemical quenching (NPQ), gross photosynthetic rate (P G), and photoinhibition during photosynthetic light induction in three woody species (one pioneer tree and two understory shrubs) and four ferns adapted to different light regimes. Pot-grown plants received 100% and/or 10% sunlight according to their light-adaptation capabilities. After at least four months of light acclimation, CO2 exchange and chlorophyll fluorescence were measured simultaneously in the laboratory. We found that during light induction the formation and relaxation of the transient NPQ was closely related to light intensity, light-adaption capability of species, and P G. NPQ with all treatments increased rapidly within the first 1–2 min of the light induction. Thereafter, only species with high P G and electron transport rate (ETR), i.e., one pioneer tree and one mild shade-adapted fern, showed NPQ relaxing rapidly to a low steady-state level within 6–8 min under PPFD of 100 μmol(photon) m?2 s?1 and ambient CO2 concentration. Leaves with low P Gand ETR, regardless of species characteristics or inhibition by low CO2 concentration, showed slow or none NPQ relaxation up to 20 min after the start of low light induction. In contrast, NPQ increased slowly to a steady state (one pioneer tree) or it did not reach the steady state (the others) from 2 to 30 min under PPFD of 2,000 μmol m?2 s?1. Under high excess of light energy, species adapted to or plants acclimated to high light exhibited high NPQ at the initial 1 or 2 min, and showed low photoinhibition after 30 min of light induction. The value of fastest-developing NPQ can be quickly and easily obtained and might be useful for physiological studies. 相似文献
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Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase 总被引:1,自引:0,他引:1
Li T Wen H Brayton C Das P Smithson LA Fauq A Fan X Crain BJ Price DL Golde TE Eberhart CG Wong PC 《The Journal of biological chemistry》2007,282(44):32264-32273
Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer. 相似文献
99.
Nitric oxide inhibits larval settlement in Amphibalanus amphitrite cyprids by repressing muscle locomotion and molting 下载免费PDF全文
Nitric oxide (NO) is a universal signaling molecule and plays a negative role in the metamorphosis of many biphasic organisms. Recently, the NO/cGMP (cyclic guanosine monophosphate) signaling pathway was reported to repress larval settlement in the barnacle Amphibalanus amphitrite. To understand the underlying molecular mechanism, we analyzed changes in the proteome of A. amphitrite cyprids in response to different concentrations of the NO donor sodium nitroprusside (SNP; 62.5, 250, and 1000 μM) using a label‐free proteomics method. Compared with the control, the expression of 106 proteins differed in all three treatments. These differentially expressed proteins were assigned to 13 pathways based on KEGG pathway enrichment analysis. SNP treatment stimulated the expression of heat shock proteins and arginine kinase, which are functionally related to NO synthases, increased the expression levels of glutathione transferases for detoxification, and activated the iron‐mediated fatty acid degradation pathway and the citrate cycle through ferritin. Moreover, NO repressed the level of myosins and cuticular proteins, which indicated that NO might inhibit larval settlement in A. amphitrite by modulating the process of muscle locomotion and molting. 相似文献
100.
Chen H Hayashi G Lai OY Dilthey A Kuebler PJ Wong TV Martin MP Fernandez Vina MA McVean G Wabl M Leslie KS Maurer T Martin JN Deeks SG Carrington M Bowcock AM Nixon DF Liao W 《PLoS genetics》2012,8(2):e1002514
An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. 相似文献