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991.
A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.  相似文献   
992.
Few studies have examined the association of SNPs in the adiponectin (ADIPOQ) and adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) genes with the euglycemic clamp, i.e. the gold standard measure of insulin sensitivity. The association of comprehensive tag SNPs in these genes with insulin sensitivity was examined in a cohort of adolescents and their parents. Probands and siblings (n = 441, mean age = 17.9 years) were recruited along with their parents (n = 262, mean age = 47.9 years). Typed SNPs included 21 SNPs in ADIPOQ, 7 SNPs in ADIPOR1, and 13 SNPs in ADIPOR2. Mixed model linear regression was used to test the association of SNPs with euglycemic-clamp derived insulin sensitivity. All analyses were stratified by race. After corrections to account for multiple testing and the linkage disequilibrium structure of the genes, one SNP in the ADIPOQ gene (rs822393) was significantly associated with insulin sensitivity in white subjects. In whites, six SNPs in ADIPOQ, one SNP in ADIPOR1 and one SNP in ADIPOR2 were associated with insulin sensitivity at the P < 0.05 level. In African Americans, two SNPs in ADIPOR1 were associated with insulin sensitivity at the P < 0.05 level. These results suggest that a variant in the ADIPOQ gene influences levels of insulin sensitivity and age may modify the effects of this variant. There are several other variants in ADIPOQ, ADIPOR1, and ADIPOR2 that may influence insulin sensitivity and these variants should be further investigated in other populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.  相似文献   
993.
The Human Intestinal Microbiome: A New Frontier of Human Biology   总被引:2,自引:0,他引:2  
To analyze the vast number and variety of microorganisms inhabitingthe human intestine, emerging metagenomic technologies are extremelypowerful. The intestinal microbes are taxonomically complexand constitute an ecologically dynamic community (microbiota)that has long been believed to possess a strong impact on humanphysiology. Furthermore, they are heavily involved in the maturationand proliferation of human intestinal cells, helping to maintaintheir homeostasis and can be causative of various diseases,such as inflammatory bowel disease and obesity. A simplifiedanimal model system has provided the mechanistic basis for themolecular interactions that occur at the interface between suchmicrobes and host intestinal epithelia. Through metagenomicanalysis, it is now possible to comprehensively explore thegenetic nature of the intestinal microbiome, the mutually interactingsystem comprising the host cells and the residing microbialcommunity. The human microbiome project was recently launchedas an international collaborative research effort to furtherpromote this newly developing field and to pave the way to anew frontier of human biology, which will provide new strategiesfor the maintenance of human health.  相似文献   
994.
Laribacter hongkongensis is a newly discovered Gram-negative bacillus of the Neisseriaceae family associated with freshwater fish–borne gastroenteritis and traveler's diarrhea. The complete genome sequence of L. hongkongensis HLHK9, recovered from an immunocompetent patient with severe gastroenteritis, consists of a 3,169-kb chromosome with G+C content of 62.35%. Genome analysis reveals different mechanisms potentially important for its adaptation to diverse habitats of human and freshwater fish intestines and freshwater environments. The gene contents support its phenotypic properties and suggest that amino acids and fatty acids can be used as carbon sources. The extensive variety of transporters, including multidrug efflux and heavy metal transporters as well as genes involved in chemotaxis, may enable L. hongkongensis to survive in different environmental niches. Genes encoding urease, bile salts efflux pump, adhesin, catalase, superoxide dismutase, and other putative virulence factors—such as hemolysins, RTX toxins, patatin-like proteins, phospholipase A1, and collagenases—are present. Proteomes of L. hongkongensis HLHK9 cultured at 37°C (human body temperature) and 20°C (freshwater habitat temperature) showed differential gene expression, including two homologous copies of argB, argB-20, and argB-37, which encode two isoenzymes of N-acetyl-L-glutamate kinase (NAGK)—NAGK-20 and NAGK-37—in the arginine biosynthesis pathway. NAGK-20 showed higher expression at 20°C, whereas NAGK-37 showed higher expression at 37°C. NAGK-20 also had a lower optimal temperature for enzymatic activities and was inhibited by arginine probably as negative-feedback control. Similar duplicated copies of argB are also observed in bacteria from hot springs such as Thermus thermophilus, Deinococcus geothermalis, Deinococcus radiodurans, and Roseiflexus castenholzii, suggesting that similar mechanisms for temperature adaptation may be employed by other bacteria. Genome and proteome analysis of L. hongkongensis revealed novel mechanisms for adaptations to survival at different temperatures and habitats.  相似文献   
995.
The phosphate solubilizing fungi Penicillium radicum, Penicillium bilaiae (strain RS7B-SD1), and an unidentified Penicillium sp. designated strain KC6-W2 were tested for their ability to increase the growth and phosphorus (P) nutrition of wheat, medic, and lentil in three soils of neutral to alkaline pH reaction. The strongest plant growth promoting (PGP) strain was Penicillium sp. KC6-W2, which stimulated significant increases in shoot growth and dry mass in seven of the nine experiments conducted. Levels of PGP by Penicillium sp. KC6-W2 ranged from 6.6% to 19% and were associated with increased uptake of P to the shoot. The PGP properties of Penicillium sp. KC6-W2 were evident on each of the three different plant species and soil types, a level of reliability not observed in other strains tested. Inoculation of seed with P. radicum increased lentil growth by 5.5% (P < 0.05) in soil from Tarlee but did not affect plant growth in the eight other experiments. Inoculation of plant seed with P. bilaiae RS7B-SD1 resulted in significant PGP in two of the nine experiments conducted. However, when significant, stimulation of PGP by P. bilaiae RS7B-SD1 was strong and resulted in increases in medic dry matter (19%) and lentil shoot dry matter (15%). A soil microcosm experiment investigated the effect of Penicillium fungi on cycling of soil P. Penicillium bilaiae RS7B-SD1 was the only fungus to significantly increase HCO3-extractable P (23% increase; P < 0.05). Production of phosphatase enzymes was not associated with increased HCO3-extractable P. Addition of carbon in the form of ryegrass seed significantly increased microbial respiration and movement of P to the microbial biomass (P < 0.05), but these parameters were irrespective of Penicillium treatment. This work has established the potential for use of Penicillium inoculants to increase plant growth on alkaline soils in Australia. The role of Penicillium fungi in plant P uptake and soil P cycling requires further exploration.  相似文献   
996.
Predicting absolute ligand binding free energies to a simple model site   总被引:2,自引:0,他引:2  
A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved.  相似文献   
997.
998.
Contractile actomyosin bundles are critical for numerous aspects of muscle and nonmuscle cell physiology. Due to the varying composition and structure of actomyosin bundles in vivo, the minimal requirements for their contraction remain unclear. Here, we demonstrate that actin filaments and filaments of smooth muscle myosin motors can self-assemble into bundles with contractile elements that efficiently transmit actomyosin forces to cellular length scales. The contractile and force-generating potential of these minimal actomyosin bundles is sharply sensitive to the myosin density. Above a critical myosin density, these bundles are contractile and generate large tensile forces. Below this threshold, insufficient cross-linking of F-actin by myosin thick filaments prevents efficient force transmission and can result in rapid bundle disintegration. For contractile bundles, the rate of contraction decreases as forces build and stalls under loads of ∼0.5 nN. The dependence of contraction speed and stall force on bundle length is consistent with bundle contraction occurring by several contractile elements connected in series. Thus, contraction in reconstituted actomyosin bundles captures essential biophysical characteristics of myofibrils while lacking numerous molecular constituents and structural signatures of sarcomeres. These results provide insight into nonsarcomeric mechanisms of actomyosin contraction found in smooth muscle and nonmuscle cells.  相似文献   
999.
1000.
Macrophages play important roles in both lipid metabolism and innate immunity. We show here that macrophage ATP-binding cassette transporter A1 (ABCA1), a transporter known for its ability to promote apolipoprotein-dependent cholesterol efflux, also participates in the removal of an immunostimulatory bacterial lipid, lipopolysaccharide (LPS). Whereas monocytes require an exogenous lipoprotein acceptor to remove cell-associated LPS, macrophages released LPS in the absence of an exogenous acceptor by a mechanism that was driven, in part, by endogenous apolipoprotein E (apoE). Agents that increased ABCA1 expression increased LPS efflux from wild-type but not ABCA1-deficient macrophages. Preexposure of peritoneal macrophages to LPS for 24 h increased the expression of ABCA1 and increased LPS efflux with a requirement for exogenous apolipoproteins due to suppression of endogenous apoE production. In contrast, LPS preconditioning of ABCA1-deficient macrophages significantly decreased LPS efflux and led to prolonged retention of cell-surface LPS. Although the initial response to LPS was similar in wild-type and ABCA1-deficient macrophages, LPS-induced tolerance was greater and more prolonged in macrophages that lacked ABCA1. Our results define a new role for macrophage ABCA1 in removing cell-associated LPS and restoring normal macrophage responsiveness.  相似文献   
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