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991.
992.
Antonella Converso Timothy Hartingh Robert M. Garbaccio Edward Tasber Keith Rickert Mark E. Fraley Youwei Yan Constantine Kreatsoulas Steve Stirdivant Bob Drakas Eileen S. Walsh Kelly Hamilton Carolyn A. Buser Xianzhi Mao Marc T. Abrams Stephen C. Beck Weikang Tao Rob Lobell Laura Sepp-Lorenzino Joan Zugay-Murphy George D. Hartman 《Bioorganic & medicinal chemistry letters》2009,19(4):1240-1244
A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at Km for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site ~13 Å from the ATP binding site. Preliminary data is presented for several of these compounds. 相似文献
993.
Hailing Yu Qiang Gao Zeqiang Shao Anning Ying Yuyang Sun Jingwei Liu Wei Mao Bin Zhang 《PloS one》2016,11(3)
In this study, we examined the influence of different nitrogen (N) application rates (0, 168, 240, 270 and 312 kg N ha-1) on soil properties, maize (Zea mays L.) yields and microbial communities of three types of soils (clay, alluvial and sandy soils). Phospholipid fatty acid analysis was used to characterize soil microbial communities. Results indicated that N fertilization significantly decreased microbial biomass in both clay and sandy soils regardless of application rate. These decreases were more likely a result of soil pH decreases induced by N fertilization, especially in the sandy soils. This is supported by structural equation modeling and redundancy analysis results. Nitrogen fertilization also led to significant changes in soil microbial community composition. However, the change differences were gradually dismissed with increase in N application rate. We also observed that N fertilization increased maize yields to the same level regardless of application rate. This suggests that farmers could apply N fertilizers at a lower rate (i.e. 168 kg N ha-1), which could achieve high maize yield on one hand while maintain soil microbial functions on the other hand. 相似文献
994.
995.
The reaction pathway for inhibition of human factor Xa (fXa) by recombinant tick anticoagulant peptide (rTAP) was studied by stopped-flow fluorometry. In the presence of the fluorogenic substrate N-tert-butyloxycarbonyl-L-isoleucyl-L-glutamylglycyl-L-arginyl-7-amido-4 - methylcoumarin (B-IEGR-AMC) and under pseudo-first-order conditions, inhibition appears to occur via a two-step process. Initially, a weak enzyme-inhibitor complex forms with a dissociation constant (Ki) of 68 +/- 6 microM. The initial complex then rearranges to a more stable fXa-rTAP complex with a rate constant (k2) of 123 +/- 5 s-1. The apparent second-order rate constant (k2/Ki) describing formation of the stable complex is (1.8 +/- 0.2) x 10(6) M-1 s-1. Studies of the reaction of rTAP with fXa in the presence of the fluorescent active-site probe p-amino-benzamidine (P) revealed a reaction pathway wherein rTAP initially binds to the fXa-P complex in a two-step process prior to displacing P from the active site. These results indicate that rTAP can bind fXa via a site distinct from the active site (an exosite). The subsequent displacement of P from the active site of fXa by rTAP exhibits a dependence on the concentration of P, indicating that rTAP is locked into the active site in a third step.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
996.
997.
998.
High glucose‐induced intestinal epithelial barrier damage is aggravated by syndecan‐1 destruction and heparanase overexpression 下载免费PDF全文
Qing Qing Shaoheng Zhang Ye Chen Runhua Li Hua Mao Qikui Chen 《Journal of cellular and molecular medicine》2015,19(6):1366-1374
Syndecan‐1 (Sdc1) and its endo‐beta‐d ‐glucuronidase heparanase (HPSE) are implicated in maintenance of intestinal epithelial barrier (IEB), but their alterations and roles in high‐glucose/hyperglycaemia (HG) conditions have not been fully investigated. This study aimed to determine the expression pattern, the possible regulation mechanism of Sdc1 and HPSE in HG conditions, and their potential effects on IEB. Therefore, diabetic mice/cell models were developed, and tissue/serum samples, cell lysate and culture supernatants were harvested. The expression of Sdc1 and HPSE in control, HG and designated interventions groups were detected. Phosphorylations of mitogen‐activated protein kinase signalling pathway (MAPK), the expressions of Occludin and ZO‐1, and the levels of transepithelial electrical resistance (TEER) were measured and monitored. The results showed that in HG conditions, intestinal tissue and cellular Sdc1 were significantly decreased, but the expression of HPSE, and soluble Sdc1 in serum and culture supernatants were remarkably increased. Such alterations of Sdc1 and HPSE were associated with solely p38 MAPK activation, and were correlated with the reductions of Occludin, ZO‐1 and TEER. Heparin (Sdc1 analogue) and SB203580 (a p38 MAPK inhibitor), instead of insulin, alleviated Sdc1 destruction and HPSE overexpression, and effectively prevented against the reductions of tight junctions and the abnormality of intestinal permeability in HG conditions. In conclusion, we confirm the unique alterations of Sdc1 and HPSE in HG conditions, and found their interactions with p38 MAPK activation and IEB. These indicate that Sdc1/HPSE modulation can be viewed as an important complementary treatment for relieving HG‐induced gastrointestinal damage. 相似文献
999.
Murine lymphokine-activated killer (LAK) cells were generated from spleen cells of C57/BL6 mice by culture of spleen cells in vitro for 72 hours in medium containing 500 units/ml recombinant human interleukin 2 (IL-2), and effects of these LAK cells on proliferation of syngenic myeloid progenitor cells (CFU-GM) were observed. After 3 days culture, LAK cells were assayed for their cytotoxicity in a 4 hours 51Cr-release test. Either natural killer (NK) cell sensitive YAC-1 lymphoma cells or NK cell resistant LP-3 and WEHI-164 fibrosarcoma cells were efficiently lysed by murine LAK cells. When LAK cells were added into culture system in a final concentration of 5 x 10(4)/ml, 2 x 10(5)/ml, 8 x 10(5)/ml, CFU-GM were increased by 55.2%, 165.5%, and 194.4% of control respectively. LAK-CM also showed augmentative effect on CFU-GM growth. When 10% (v/v) of LAK-CM were added into culture system, CFU-GM were increased by 51.4% of control, but LAK-CM alone could not stimulate CFU-GM growth. Again, effects of LAK-BMC interaction on CFU-GM formation were investigated. CFU-GM were inhibited to 27.6% of control when 1 x 10(5) BMC were mixed with 8 x 10(5) LAK cells and incubated for 4 hours prior to CFU-GM culture. These data suggest that (1) LAK cells may secrete co-CSF which showed synergistic effect with CSF on CFU-GM proliferation: (2) When LAK cells contact with BMC, they showed significant cytotoxicity to myeloid progenitor cells which mediated decrease of CFU-GM formation. 相似文献
1000.
C Mao G Merlin R Ballotti M Metzler M Aguet 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(12):4257-4264
Various cell surface receptors are phosphorylated upon binding of their ligand, and this phosphorylation seems to be involved in the signal transduction or in the feedback regulation of this signal. The possibility of a phosphorylation of the human IFN-gamma receptor (hu-IFN-gamma-R) has been investigated with 32P-labeled whole Raji cells and receptor purification either by immunoprecipitation with an anti-hu-IFN-gamma-R polyclonal antiserum or by affinity chromatography. The hu-IFN-gamma-R was found to be phosphorylated at a basal level. Upon incubation of the cells with recombinant hu-IFN-gamma, a dose-dependent two-fold increase of this phosphorylation was observed. Phosphoamino acid analysis by TLC showed that the same amino acids, serine and threonine, are phosphorylated at a basal level and after incubation with hu-IFN-gamma. Protein kinase C and Ca2+/calmodulin-dependent kinase pathways have been reported in some cases to be involved in the signal transduction pathway of hu-IFN-gamma. Both pathways involved the activation of a serine/threonine kinase and therefore we have investigated the possibility of hu-IFN-gamma-R phosphorylation by these kinases. PMA, an activator of protein kinase C, induced a rapid increase of the receptor phosphorylation in Raji cells, whereas the Ca2+ ionophore A23187 did not. PMA-induced hu-IFN-gamma-R phosphorylation was not associated with any effect on expression or inactivation of the receptor. PMA alone did not mimic the hu-IFN-gamma effect in Raji cells as measured by induction of IP-10 gene expression, a high specific marker of hu-IFN-gamma response. But the protein kinase C inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) and staurosporine, reduced this IFN-gamma-induced expression. However, H7 and staurosporine treatment as well as protein kinase C depletion suppressed PMA-induced receptor phosphorylation, whereas constitutive and hu-IFN-gamma-induced phosphorylation remained unchanged. Our results suggest that the serine/threonine kinase involved in the hu-IFN-gamma-R phosphorylation induced by IFN-gamma is different from protein kinase C. 相似文献