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101.
Cytochrome P450 26A1 (cyp26a1) is expressed in the mouse uterus during peri‐implantation. The repression of this protein is closely associated with a reduction in implantation sites, suggesting a specific role for cyp26a1 in pregnancy and prompting questions concerning how a metabolic enzyme can generate this distinct outcome. To explore the effective downstream targets of cyp26a1 and confirm if its role in peri‐implantation depends on its metabolic substrate RA (retinoic acid), we characterized the changes in the peripheral blood, spleen and uterine implantation sites using the cyp26a1 gene vaccine constructed before. Flow cytometry results showed a significant increase in CD4+RORγt+ Th17 cells in both the peripheral blood and spleen in the experimental group. The expression of RORγt and IL‐17 presented the Th17 cells reduction in uterus followed by the suppression of cyp26a1 expression. For greater certainty, cyp26a1 antibody blocking model and RNA interference model were constructed to determine the precise target immune cell group. High performance liquid chromatography results showed a significant increase in uterine at‐RA followed by the immunization of cyp26a1 gene vaccine. Both the ascertain by measuring RARα protein levels in peri‐implantation uterus after gene vaccine immunization and researches using the specific agonist and antagonist against RARα suggested that RARα may be the main RA receptor for signal transduction. These results provided more evidence for the signal messenger role of RA in cyp26a1 regulation from the other side. Here, we showed that the cyp26a1‐regulated Th17 cells are dependent on at‐RA signalling, which is delivered through RARα in mouse peri‐implantation.  相似文献   
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The Mre11–Rad50–Nbs1 (MRN) complex plays important roles in sensing DNA damage, as well as in resecting and tethering DNA ends, and thus participates in double-strand break repair. An earlier structure of Mre11 bound to a short duplex DNA molecule suggested that each Mre11 in a dimer recognizes one DNA duplex to bridge two DNA ends at a short distance. Here, we provide an alternative DNA recognition model based on the structures of Methanococcus jannaschii Mre11 (MjMre11) bound to longer DNA molecules, which may more accurately reflect a broken chromosome. An extended stretch of B-form DNA asymmetrically runs across the whole dimer, with each end of this DNA molecule being recognized by an individual Mre11 monomer. DNA binding induces rigid-body rotation of the Mre11 dimer, which could facilitate melting of the DNA end and its juxtaposition to an active site of Mre11. The identified Mre11 interface binding DNA duplex ends is structurally conserved and shown to functionally contribute to efficient resection, non-homologous end joining, and tolerance to DNA-damaging agents when other resection enzymes are absent. Together, the structural, biochemical, and genetic findings presented here offer new insights into how Mre11 recognizes damaged DNA and facilitates DNA repair.  相似文献   
104.
Excess biomass accumulation and activity loss in vapor-phase bioreactors (VPBs) can lead to unreliable long-term operation. In this study, temporal and spatial variations in biomass accumulation, distribution and activity in VPBs treating toluene-contaminated air were monitored over a 96-day period. Two laboratory-scale bioreactors were subjected to a toluene loading rate of 45.8 g/m(3)-h with one VPB operating in a unidirectional (UD) mode and a second identical VPB operating in a directionally switching (DS) mode. In the UD bioreactor, the contaminated air stream was continuously fed to the bottom of the reactor, while, in the DS bioreactor, the direction of the contaminated gas flow was reversed every three days. Overall, the DS system performed better with respect to biomass distribution and microbial activity across the bioreactor, resulting in more stable bioreactor performance. In contrast, most of the biomass accumulation and activity was confined to the front half of the UD bioreactor column which caused high pressure drops, rapid activity loss and eventually toluene breakthrough. A carbon balance reveals that excess biomass accumulated continuously in both bioreactors, and biomass yield coefficients were very similar (0.59 g dry biomass/g toluene for the UD and 0.63 g dry biomass/g toluene for the DS). The viable biomass population remained relatively constant in both bioreactors over the operational period, while the inactive biomass fraction steadily increased over the same time frame. Biodegradation activity determined by the dehydrogenase enzyme activity assay was found to be a function of biomass accumulation and reflected pollutant removal profiles along the columns. In addition, biomass activity correlated well with the toluene-degrading fraction of the total bacterial population.  相似文献   
105.
Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.  相似文献   
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108.
Assembly of an infectious retrovirus requires the incorporation of the envelope glycoprotein complex during the process of particle budding. We have recently demonstrated that amino acid substitutions of a tyrosine residue in the cytoplasmic domain block glycoprotein incorporation into budding Mason-Pfizer monkey virus (M-PMV) particles and abrogate infectivity (C. Song, S. R. Dubay, and E. Hunter, J. Virol. 77:5192-5200, 2003). To investigate the contribution of other amino acids in the cytoplasmic domain to the process of glycoprotein incorporation, we introduced alanine-scanning mutations into this region of the transmembrane protein. The effects of the mutations on glycoprotein biosynthesis and function, as well as on virus infectivity, have been examined. Mutation of two cytoplasmic residues, valine 20 and histidine 21, inhibits viral protease-mediated cleavage of the cytoplasmic domain that is observed during virion maturation, but the mutant virions show only moderately reduced infectivity. We also demonstrate that the cytoplasmic domain of the M-PMV contains three amino acid residues that are absolutely essential for incorporation of glycoprotein into virions. In addition to the previously identified tyrosine at residue 22, an isoleucine at position 18 and a leucine at position 25 each mediate the process of incorporation and efficient release of virions. While isoleucine 18 may be involved in direct interactions with immature capsids, antibody uptake studies showed that leucine 25 and tyrosine 22 are part of an efficient internalization signal in the cytoplasmic domain of the M-PMV glycoprotein. These results demonstrate that the cytoplasmic domain of M-PMV Env, in part through its YXXL-mediated endocytosis and intracellular trafficking signals, plays a critical role in the incorporation of glycoprotein into virions.  相似文献   
109.
A new screening method was developed for the detection of CAG expanded alleles in patients with hereditary ataxia using polymerase chain reaction-based microtiter plate hybridization (PCR-MPH). The system can be applied to detect pathologic alleles by hybridization with the immobilized (CAG)48 repeat probe derived from the unrelated gene 'ERDA1' except for the CAG repeats. We examined 10 individuals with SCA3, 10 with Huntington disease and 30 normal controls (31 controls for SCA3) using this method. The results showed that a clear discrimination was possible in all cases. We suggest that this system be made available for mass screening of patients with hereditary ataxia disorders. This report is the first to demonstrate that a PCR-MPH system can be successfully applied to DNA size differentiation in addition to base pair mismatches. Also, our design of the probe is unique in that the probe motif stem from the unrelated gene sequence and not from the synthetic oligonucleotides.  相似文献   
110.
It appears advantageous for many non-human animals to store energy body fat extensively and efficiently because their food supply is more labile and less abundant than in their human counterparts. The level of adiposity in many of these species often shows predictable increases and decreases with changes in the season. These cyclic changes in seasonal adiposity in some species are triggered by changes in the photoperiod that are faithfully transduced into a biochemical signal through the nightly secretion of melatonin (MEL) via the pineal gland. Here, we focus primarily on the findings from the most commonly studied species showing seasonal changes in adiposity-Siberian and Syrian hamsters. The data to date are not compelling for a direct effect of MEL on white adipose tissue (WAT) and brown adipose tissue (BAT) despite some recent data to the contrary. Thus far, none of the possible hormonal intermediaries for the effects of MEL on seasonal adiposity appear likely as a mechanism by which MEL affects the photoperiodic control of body fat levels indirectly. We also provide evidence pointing toward the sympathetic nervous system as a likely mediator of the effects of MEL on short day-induced body fat decreases in Siberian hamsters through increases in sympathetic drive on WAT and BAT. We speculate that decreases in the SNS drive to these tissues may underlie the photoperiod-induced seasonal increases in body fat of species such as Syrian hamsters. Clearly, we need to deepen our understanding of seasonal adiposity, although, to our knowledge, this is the only form of environmentally induced changes in body fat where the key elements of its external trigger have been identified and can be traced to and through their transduction into a physiological stimulus that ultimately affects identified responses of white adipocyte physiology and cellularity. Finally, the comparative physiological approach to the study of seasonal adiposity seems likely to continue to yield significant insights into the mechanisms underlying this phenomenon and for understanding obesity and its reversal in general.  相似文献   
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