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141.
Barnea M Haviv L Gutman R Chapnik N Madar Z Froy O 《Biochimica et biophysica acta》2012,1822(11):1796-1806
Metformin is a commonly-used treatment for type 2 diabetes, whose mechanism of action has been linked, in part, to activation of AMP-activated protein kinase (AMPK). However, little is known regarding its effect on circadian rhythms. Our aim was to evaluate the effect of metformin administration on metabolism, locomotor activity and circadian rhythms. We tested the effect of metformin treatment in the liver and muscle of young lean, healthy mice, as obesity and diabetes disrupt circadian rhythms. Metformin led to increased leptin and decreased glucagon levels. The effect of metformin on liver and muscle metabolism was similar leading to AMPK activation either by liver kinase B1 (LKB1) and/or other kinases in the muscle. AMPK activation resulted in the inhibition of acetyl CoA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis. Metformin also led to the activation of liver casein kinase I α (CKIα) and muscle CKIε, known modulators of the positive loop of the circadian clock. This effect was mainly of phase advances in the liver and phase delays in the muscle in clock and metabolic genes and/or protein expression. In conclusion, our results demonstrate the differential effects of metformin in the liver and muscle and the critical role the circadian clock has in orchestrating metabolic processes. 相似文献
142.
Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability. 相似文献
143.
Selective stabilization by the bacteriophage 434 repressor of the plasmid expressing bovine growth hormone in Escherichia coli.
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The maintenance of a plasmid vector-host system that selects for bacteria carrying the plasmid without the need for antibiotics is described. In this system, the bacteriophage 434 repressor gene cloned on the plasmid protects the host from lysis by a lambda imm434 cI- prophage. Cells that occasionally lose the plasmid are killed by prophage induction and therefore do not accumulate in the growing culture. The presence of the phage 434 repressor in the cells does not interfere with the process of lambda repressor inactivation and the high-level production of bovine growth hormone. 相似文献
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146.
Haralambos Hadjivassiliou Oren S. Rosenberg Christine Guthrie 《RNA (New York, N.Y.)》2014,20(5):656-669
Sad1 is an essential splicing factor initially identified in a genetic screen in Saccharomyces cerevisiae for snRNP assembly defects. Based on sequence homology, Sad1, or USP39 in humans, is predicted to comprise two domains: a zinc finger ubiquitin binding domain (ZnF-UBP) and an inactive ubiquitin-specific protease (iUSP) domain, both of which are well conserved. The role of these domains in splicing and their interaction with ubiquitin are unknown. We first used splicing microarrays to analyze Sad1 function in vivo and found that Sad1 is critical for the splicing of nearly all yeast intron-containing genes. By using in vitro assays, we then showed that it is required for the assembly of the active spliceosome. To gain structural insights into Sad1 function, we determined the crystal structure of the full-length protein at 1.8 Å resolution. In the structure, the iUSP domain forms the characteristic ubiquitin binding pocket, though with an amino acid substitution in the active site that results in complete inactivation of the enzymatic activity of the domain. The ZnF-UBP domain of Sad1 shares high structural similarly to other ZnF-UBPs; however, Sad1''s ZnF-UBP does not possess the canonical ubiquitin binding motif. Given the precedents for ZnF-UBP domains to function as activators for their neighboring USP domains, we propose that Sad1''s ZnF-UBP acts in a ubiquitin-independent capacity to recruit and/or activate Sad1''s iUSP domain to interact with the spliceosome. 相似文献
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148.
S. R. Sampson E. Bucris M. Horovitz-Fried A. Parnas S. Kahana G. Abitbol M. Chetboun T. Rosenzweig C. Brodie S. Frankel 《Apoptosis : an international journal on programmed cell death》2010,15(10):1165-1176
Insulin resistance results, in part, from impaired insulin signaling in insulin target tissues. Consequently, increased levels
of insulin are necessary to control plasma glucose levels. The effects of elevated insulin levels on pancreatic beta (β) cell
function, however, are unclear. In this study, we investigated the possibility that insulin may influence survival of pancreatic
β cells. Studies were conducted on RINm, RINm5F and Min-6 pancreatic β-cells. Cell death was induced by treatment with H2O2, and was estimated by measurements of LDH levels, viability assay (Cell-Titer Blue), propidium iodide staining and FACS analysis,
and mitochondrial membrane potential (JC-1). In addition, levels of cleaved caspase-3 and caspase activity were determined.
Treatment with H2O2 increased cell death; this effect was increased by simultaneous treatment of cells with insulin. Insulin treatment alone
caused a slight increase in cell death. Inhibition of caspase-3 reduced the effect of insulin to increase H2O2-induced cell death. Insulin increased ROS production by pancreatic β cells and increased the effect of H2O2. These effects were increased by inhibition of IR signaling, indicative of an effect independent of the IR cascade. We conclude
that elevated levels of insulin may act to exacerbate cell death induced by H2O2 and, perhaps, other inducers of apoptosis. 相似文献
149.
Summary The water relations of Picea abies in a healthy stand with green trees only and a declining stand with trees showing different stages of needle yellowing were investigated in northern Bavaria. The present study is based on observations of trees differing in their nutritional status but apparently green on both sites in order to identify changes in the response pattern which might be caused by atmospheric concentrations of air pollutants and could lead to the phenomenon of decline. Transpiration was measured as water flow through the hydroactive xylem using an equilibrium mass-flow measurement system. Total tree transpiration was monitored diurnally, from July 1985 until October 1985 at both sites. The relationship between transpiration and meteorological measurements indicated that transpiration was a linear function of the vapor pressure deficit. No differences in transpiration of green trees were observed between the two sites. Canopy transpiration was 57%–68% of total throughfall and 41%–54% of total rainfall. Due to this positive water balance, soil water potential at 10 and 20 cm depths remained close to-0.02 MPa (max.-0.09 MPa) for most of the summer. Soil water potential was correlated with the difference between the weekly precipitation and transpiration. No differences in the water relations of apparently healthy trees in the two P. abies stands were observed. It is concluded that differences between green trees at the two sites in terms of nutrient relations or growth rate cannot be explained by changes in whole-tree transpiration or soil water status. 相似文献
150.
Summary The annual replacement of tillers of Agropyron desertorum (Fisch. ex Link) Schult., a grazing-tolerant, Eurasian tussock grass, was examined in the field following cattle grazing. Heavy grazing before internode (culm) elongation seldom affected tiller replacement. Heavy grazing during or after internode elongation, which elevates apical meristems, increased overwinter mortality of fall-produced tillers and reduced the number and heights of these replacement tillers. Unexpectedly, tussocks grazed twice within the spring growing season tended to have lower overwinter tiller mortality, greater tiller replacement, and larger replacement tillers than tussocks grazed only once in late spring. These responses of twice-grazed tussocks, however, were still less than those of ungrazed tussocks or tussocks grazed moderately in early spring. The presence of ungrazed tillers on partially grazed tussoks did not increase the replacement of associated grazed tillers relative to tillers on uniformly grazed plants. This result indicates that resource sharing among tillers, if present, is short-lived or ecologically unimportant in this species. Although A. desertorum is considered grazing-tolerant, tiller replacement on heavily grazed tussocks, particularly those grazed during or after internode elongation when apical meristems were removed, was usually inadequate for tussock maintenance. These observations at the tiller (ramet) level of organization in individual tussocks (genet) may explain the often noted reduction in stand (population) longevity with consistent heavy grazing. 相似文献