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91.
92.
Newly synthesized canalicular ectoenzymes and a cell adhesion molecule (cCAM105) have been shown to traffic from the Golgi to the basolateral plasma membrane, from where they transcytose to the apical bile canalicular domain. It has been proposed that all canalicular proteins are targeted via this indirect route in hepatocytes. We studied the membrane targeting of rat canalicular proteins by in vivo [(35)S]methionine metabolic labeling followed by preparation of highly purified Golgi membranes and canalicular (CMVs) and sinusoidal/basolateral (SMVs) membrane vesicles and subsequent immunoprecipitation. In particular, we compared membrane targeting of newly synthesized canalicular ABC (ATP-binding cassette) transporters MDR1, MDR2, and SPGP (sister of P-glycoprotein) with that of cCAM105. Significant differences were observed in metabolic pulse-chase labeling experiments with regard to membrane targeting of these apical proteins. After a chase time of 15 min, cCAM105 appeared exclusively in SMVs, peaked at 1 h, and progressively declined thereafter. In CMVs, cCAM105 was first detected after 1 h and subsequently increased for 3 h. This findings confirm the transcytotic targeting of cCAM105 reported in earlier studies. In contrast, at no time point investigated were MDR1, MDR2, and SPGP detected in SMVs. In CMVs, MDR1 and MDR2 appeared after 30 min, whereas SPGP appeared after 2 h of labeling. In Golgi membranes, each of the ABC transporters peaked at 30 min and was virtually absent thereafter. These data suggest rapid, direct targeting of newly synthesized MDR1 and MDR2 from the Golgi to the bile canaliculus and transient sequestering of SPGP in an intracellular pool en route from the Golgi to the apical plasma membrane. This study provides biochemical evidence for direct targeting of newly synthesized apical ABC transporters from the Golgi to the bile canaliculus in vivo.  相似文献   
93.
Memory in viral quasispecies   总被引:7,自引:0,他引:7       下载免费PDF全文
Biological adaptive systems share some common features: variation among their constituent elements and continuity of core information. Some of them, such as the immune system, are endowed with memory of past events. In this study we provide direct evidence that evolving viral quasispecies possess a molecular memory in the form of minority components that populate their mutant spectra. The experiments have involved foot-and-mouth disease virus populations with known evolutionary histories. The composition and behavior of the viral population in response to a selective constraint were influenced by past evolutionary history in a way that could not be predicted from examination of consensus nucleotide sequences of the viral populations. The molecular memory of the viral quasispecies influenced both the nature and the intensity of the response of the virus to a selective constraint.  相似文献   
94.
Nine cultivars of common bean were grown in the presence of a natural microflora without exogenous rhizobial inoculation. Nodules were harvested 30 days post planting (early flowering stage) and the presence of trehalose determined. Amounts present varied according to cultivar and were between 0.20 and 1.63 mg g−1 nodule dry weight. Rhizobial strains were isolated from the nodules of three selected cultivars (Canario 101, Flor de Mayo Bajio and Flor de Mayo 38). Trehalose levels in nodules produced after either mixed strain reinfection, or after axenic homologous reinfection or after axenic cross‐reinfection could be manipulated by applying drought stress. Mixed reinfection nodules from stressed plants accumulated between two and six times the trehalose concentration found in non‐stressed control plants. After axenic cross‐reinfection up to 48‐fold increases in nodule trehalose content were recorded during drought stress. Those cultivars exhibiting high nodule trehalose levels and/or a high degree of trehalose stimulation in response to drought stress also exhibited a high leaf relative water content and were also the most drought resistant. During drought stress nodule trehalase levels rose only slightly.  相似文献   
95.
Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors. The main effects of nicotine associated with smoking are nicotinic receptor activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction.  相似文献   
96.
Extramedullary hematopoiesis has been shown to contribute to the pathogenesis of a variety of diseases including cardiovascular diseases. In this process, the spleen is seeded with mobilized bone marrow cells that augment its hematopoietic ability. It is unclear whether these immigrant cells that are produced/reprogrammed in spleen are similar or different from those found in the bone marrow. To begin to understand this, we investigated the relative potency of adult splenocytes per se to repopulate bone marrow of lethally-irradiated mice and its functional consequences in atherosclerosis. The splenocytes were harvested from GFP donor mice and transplanted into myeloablated wild type recipient mice without the inclusion of any bone marrow helper cells. We found that adult splenocytes repopulated bone marrow of myeloablated mice and the transplanted cells differentiated into a full repertoire of myeloid cell lineages. The level of monocytes/macrophages in the bone marrow of recipient mice was dependent on the cell origin, i.e., the donor splenocytes gave rise to significantly more monocytes/macrophages than the donor bone marrow cells. This occurred despite a significantly lower number of hematopoietic stem cells being present in the donor splenocytes when compared with donor bone marrow cells. Atherosclerosis studies revealed that donor splenocytes displayed a similar level of atherogenic and atheroprotective activities to those of donor bone marrow cells. Cell culture studies showed that the phenotype of macrophages derived from spleen is different from those of bone marrow. Together, these results demonstrate that splenocytes can seed bone marrow of myeloablated mice and modulate atherosclerosis. In addition, our study shows the potential of splenocytes for therapeutic interventions in inflammatory disease.  相似文献   
97.
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above-mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 μM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 μM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 μM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 μM) and MRP2 induction by GNT (only at 10 μM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements.  相似文献   
98.
Thevetia peruviana is a small tree that produces several compounds with pharmaceutical application, among which peruvoside could be highlighted. However, these compounds are produced in low concentration in the plant, making it important to develop strategies such as plant cell culture and elicitation to obtain higher quantities of the desired product. In this work, cell suspension cultures of T. peruviana were established in four different culture media: Murashige–Skoog (MS), half Murashige–Skoog (half MS), Schenk–Hildebrandt (SH), and Gamborg (B5) to study their effect on cell growth. Cell growth kinetics were studied in SH medium, and the extracellular peruvoside production during the culture time was determined. The best culture medium for the establishment of cell suspension cultures was MS with a growth index of 3.17 ± 0.2 g g−1 inoculum. The cell growth kinetics showed the four characteristic growth phases of a cell culture (lag, exponential, stationary, and death), and during none of these phases was it possible to observe peruvoside production. The elicitor effect of methyl-jasmonate (MeJ) was studied in cell suspension cultures established in SH medium. The effect of MeJ concentration and the time in which it should be applied were determined. The best results were obtained at a concentration of 100 mg l−1 of MeJ applied at the beginning of the culture, which induced a peruvoside production of 8.93 mg l−1 medium. The current results are the first report of an in vitro peruvoside production system.  相似文献   
99.
The ligand binding domain of the LDL receptor (LDLR) contains seven structurally homologous repeats. The fifth repeat (LR5) is considered to be the main module responsible for the binding of lipoproteins LDL and β‐VLDL. LR5, like the other homologous repeats, is around 40‐residue long and contains three disulfide bonds and a conserved cluster of negatively charged residues surrounding a hexacoordinated calcium ion. The calcium coordinating cage is formed by the backbone oxygens of W193 and D198, and side‐chain atoms of D196, D200, D206, and E207. The functionality of LDLR is closely associated with the presence of calcium. Magnesium ions are to some extent similar to calcium ions. However, they appear to be involved in different physiological events and their concentrations in extracellular and intracellular compartments are regulated by different mechanisms. Whether magnesium ions can play a role in the complex cycle of LDLR internalization and recycling is not known. We report here a detailed study of the interaction between LR5 and these two cations combining ITC, emission fluorescence, high resolution NMR, and MD simulations, at extracellular and endosomal pHs. Our results indicate that the conformational stability and internal dynamics of LR5 are strongly modulated by the specific bound cation. It appears that the difference in binding affinity for these cations is somewhat compensated by their different concentrations in late LDL‐associated endosomes. While the mildly acidic and calcium‐depleted environment in late endosomes has been proposed to contribute significantly to LDL release, the presence of magnesium might assist in efficient LDLR recycling. Proteins 2010. © 2009 Wiley‐Liss, Inc.  相似文献   
100.
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