全文获取类型
收费全文 | 11222篇 |
免费 | 820篇 |
国内免费 | 6篇 |
专业分类
12048篇 |
出版年
2024年 | 13篇 |
2023年 | 49篇 |
2022年 | 139篇 |
2021年 | 238篇 |
2020年 | 172篇 |
2019年 | 203篇 |
2018年 | 327篇 |
2017年 | 293篇 |
2016年 | 481篇 |
2015年 | 679篇 |
2014年 | 810篇 |
2013年 | 856篇 |
2012年 | 1031篇 |
2011年 | 1012篇 |
2010年 | 661篇 |
2009年 | 567篇 |
2008年 | 749篇 |
2007年 | 668篇 |
2006年 | 567篇 |
2005年 | 519篇 |
2004年 | 500篇 |
2003年 | 406篇 |
2002年 | 344篇 |
2001年 | 156篇 |
2000年 | 119篇 |
1999年 | 104篇 |
1998年 | 60篇 |
1997年 | 52篇 |
1996年 | 32篇 |
1995年 | 25篇 |
1994年 | 18篇 |
1993年 | 18篇 |
1992年 | 23篇 |
1991年 | 29篇 |
1990年 | 25篇 |
1989年 | 25篇 |
1988年 | 13篇 |
1987年 | 6篇 |
1986年 | 6篇 |
1985年 | 15篇 |
1984年 | 10篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1972年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Jung SH Ha YJ Shim EK Choi SY Jin JL Yun-Choi HS Lee JR 《The Biochemical journal》2007,403(2):243-250
Five pentacyclic triterpenoids isolated from Campsis grandiflora were tested for insulin-mimetic and insulin-sensitizing activity. The compounds enhanced the activity of insulin on tyrosine phosphorylation of the IR (insulin receptor) beta-subunit in CHO/IR (Chinese-hamster ovary cells expressing human IR). Among the compounds tested, CG7 (ursolic acid) showed the greatest enhancement and CG11 (myrianthic acid) the least. We characterized the effect of CG7 further, and showed that it acted as an effective insulin-mimetic agent at doses above 50 mug/ml and as an insulin-sensitizer at doses as low as 1 mug/ml. Additional experiments showed that CG7 increased the number of IRs that were activated by insulin. This indicates that a major mechanism by which CG7 enhances total IR auto-phosphorylation is by promoting the tyrosine phosphorylation of additional IRs. CG7 not only potentiated insulin-mediated signalling (tyrosine phosphorylation of the IR beta-subunit, phosphorylation of Akt and glycogen synthase kinase-3beta), but also enhanced the effect of insulin on translocation of glucose transporter 4 in a classical insulin-sensitive cell line, 3T3-L1 adipocytes. The results of the present study demonstrate that a specific pentacyclic triterpenoid, CG7, exerts an insulin-sensitizing effect as an IR activator in CHO/IR cells and adipocytes. The enhancement of insulin activity by CG7 may be useful for developing a new class of specific IR activators for treatment of Type 1 and Type 2 diabetes. 相似文献
952.
RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatin 总被引:1,自引:0,他引:1 下载免费PDF全文
Repair of DNA double-strand breaks (DSBs) protects cells and organisms, as well as their genome integrity. Since DSB repair occurs in the context of chromatin, chromatin must be modified to prevent it from inhibiting DSB repair. Evidence supports the role of histone modifications and ATP-dependent chromatin remodeling in repair and signaling of chromosome DSBs. The key questions are, then, what the nature of chromatin altered by DSBs is and how remodeling of chromatin facilitates DSB repair. Here we report a chromatin alteration caused by a single HO endonuclease-generated DSB at the Saccharomyces cerevisiae MAT locus. The break induces rapid nucleosome migration to form histone-free DNA of a few hundred base pairs immediately adjacent to the break. The DSB-induced nucleosome repositioning appears independent of end processing, since it still occurs when the 5'-to-3' degradation of the DNA end is markedly reduced. The tetracycline-controlled depletion of Sth1, the ATPase of RSC, or deletion of RSC2 severely reduces chromatin remodeling and loading of Mre11 and Yku proteins at the DSB. Depletion of Sth1 also reduces phosphorylation of H2A, processing, and joining of DSBs. We propose that RSC-mediated chromatin remodeling at the DSB prepares chromatin to allow repair machinery to access the break and is vital for efficient DSB repair. 相似文献
953.
Adameová A Kuzelová M Andelová E Faberová V Pancza D Svec P Ziegelhöffer A Ravingerová T 《Molecular and cellular biochemistry》2007,295(1-2):129-136
Both, diabetes mellitus (DM) and hypercholesterolemia (HCH) are known as risk factors of ischemic heart disease, however,
the effects of experimental DM, as well as of HCH alone, on ischemia/reperfusion-induced myocardial injury are not unequivocal.
We have previously demonstrated an enhanced resistance to ischemia-induced arrhythmias in rat hearts in the acute phase of
DM. Our objectives were thus to extend our knowledge on how DM in combination with HCH, a model that is relevant to diabetic
patients with altered lipid metabolism, may affect the size of myocardial infarction and susceptibility to arrhythmias. A
combination of streptozotocin (STZ; 80 mg/kg, i.p.) and the fat–cholesterol diet (1% cholesterol, 1% coconut oil; FCHD) was
used as a double-disease model mimicking DM and HCH simultaneosly occurring in humans. Following 5 days after STZ injection
and FCHD leading to increased blood glucose and cholesterol levels, anesthetized open-chest diabetic, diabetic–hypercholesterolemic
(DM–HCH) and age-matched control rats were subjected to 6-min ischemia (occlusion of LAD coronary artery) followed by 10 reperfusion
to test susceptibility to ventricular arrhythmias in the in vivo experiments and to 30-min ischemia and subsequent 2-h reperfusion for the evaluation of the infarct size (IS) in the Langendorff-perfused
hearts. The incidence of the most life-threatening ventricular arrhythmia, ventricular fibrillation, was significantly increased
in the DM–HCH rats as compared with non-diabetic control animals (100% vs. 50%; p<0.05). Likewise, arrhythmia severity score (AS) was significantly higher in the DM–HCH rats than in the controls (4.9±0.2
vs. 3.5±0.5; p<0.05), but was not increased in the diabetic animals (AS 3.7±0.9; p>0.05 vs. controls). Diabetic hearts exhibited a reduced IS (15.1±3.0% of the area at risk vs. 37.6±2.8% in the control hearts;
p<0.05), however, a combination of DM and HCH increased the size of myocardial infarction to that observed in the controls.
In conclusion, HCH abrogates enhanced resistance to ischemia-reperfusion injury in the diabetic rat heart. 相似文献
954.
Construction and Characterization of Shuttle Vectors for Succinic Acid-Producing Rumen Bacteria 总被引:2,自引:0,他引:2 下载免费PDF全文
Yu-Sin Jang Young Ryul Jung Sang Yup Lee Ji Mahn Kim Jeong Wook Lee Doo-Byoung Oh Hyun Ah Kang Ohsuk Kwon Seh Hee Jang Hyohak Song Sang Jun Lee Kyu Young Kang 《Applied microbiology》2007,73(17):5411-5420
Shuttle vectors carrying the origins of replication that function in Escherichia coli and two capnophilic rumen bacteria, Mannheimia succiniciproducens and Actinobacillus succinogenes, were constructed. These vectors were found to be present at ca. 10 copies per cell. They were found to be stably maintained in rumen bacteria during the serial subcultures in the absence of antibiotic pressure for 216 generations. By optimizing the electroporation condition, the transformation efficiencies of 3.0 × 106 and 7.1 × 106 transformants/μg DNA were obtained with M. succiniciproducens and A. succinogenes, respectively. A 1.7-kb minimal replicon was identified that consists of the rep gene, four iterons, A+T-rich regions, and a dnaA box. It was found that the shuttle vector replicates via the theta mode, which was confirmed by sequence analysis and Southern hybridization. These shuttle vectors were found to be suitable as expression vectors as the homologous fumC gene encoding fumarase and the heterologous genes encoding green fluorescence protein and red fluorescence protein could be expressed successfully. Thus, the shuttle vectors developed in this study should be useful for genetic and metabolic engineering of succinic acid-producing rumen bacteria. 相似文献
955.
Pleurocidin (Ple) is a 25-residue peptide which is derived from the skin mucous secretion of the winter flounder (Pleuronectes americanus). In this study, we investigated antifungal effects and its mode of action of Ple on human pathogenic fungi. Ple showed potent antifungal activity with low hemolytic activity. To investigate the antifungal mechanisms of Ple, the cellular localization and membrane interaction of Ple were examined. Protoplast regeneration and membrane-disrupting activity by DPH-labeled membrane support the idea, that Ple exerts fungicidal activity against the human pathogenic fungus Candida albicans with the disruption of a plasma membrane. To aim for which was the application of a therapeutic agent, we designed a synthetic enantiomeric peptide composed of all-d-amino acids to enhance proteolytic resistance. The synthetic all-d-Ple also displayed two-fold more potent antifungal activity than that of all-l-Ple, and its antifungal activity showed proteolytic resistance against various proteases. Therefore, these results suggest a therapeutic potential of all-d-Ple with regard to its proteolytic resistance against human fungal infections. 相似文献
956.
957.
Weight variation by sex and nature of risk factors in high-risk infants: an evolutionary perspective
A retrospective cohort study was conducted to explore growth variation during the intrauterine and early postnatal period by sex and nature of high-risk factors (i.e. physiological and pathological) in 831 Korean infants at a University hospital. The results showed that infants with a physiological risk showed a more congruent intrauterine growth pattern compared to those with a pathological risk. Particularly with a physiological risk, female infants experienced more compatible intrauterine and postnatal growth than males, although male infants were heavier than female infants at a given gestational age. In conclusion bigger may not necessarily be better for prenatal growth in humans. A more confluent intrauterine growth in infants with physiological risk can be beneficial for early postnatal catch-up growth. From an evolutionary perspective, female infants with a physiological risk may keep their advantageous edge over male infants during the early postnatal period although such an advantage may not be present with a pathological condition. 相似文献
958.
Ahn JH Shin MS Jun MA Jung SH Kang SK Kim KR Rhee SD Kang NS Kim SY Sohn SK Kim SG Jin MS Lee JO Cheon HG Kim SS 《Bioorganic & medicinal chemistry letters》2007,17(9):2622-2628
Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography. 相似文献
959.
Kwon YE Park JY No KT Shin JH Lee SK Eun JS Yang JH Shin TY Kim DK Chae BS Leem JY Kim KH 《Bioorganic & medicinal chemistry》2007,15(20):6596-6607
With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation. 相似文献
960.
Moon TC Quan Z Kim J Kim HP Kudo I Murakami M Park H Chang HW 《Bioorganic & medicinal chemistry》2007,15(22):7138-7143
Several prototypes of C-C biflavones (a-f) were synthesized and evaluated their inhibitory activity against phospholipase A(2)s (PLA(2)s) activity. The synthetic C-C biflavones (a-f) showed rather different inhibitory activity against various PLA(2)s. Most synthetic C-C biflavonoids exhibited potent and broad inhibitory activity against various sPLA(2)s and cPLA(2) tested regardless of their structural array. In particular, of natural and synthetic biflavonoids tested, the synthetic C-C biflavonoid (d) only showed inhibitory activity against sPLA(2) X. None of the natural and synthetic biflavonoids tested showed inhibitory activity against sPLA(2) IB. Further chemical modification of these basic structures will be carried out in order to investigate the synthetic C-C biflavones which possess more selective inhibitory activity against isozymes of PLA(2). 相似文献