全文获取类型
收费全文 | 762篇 |
免费 | 32篇 |
出版年
2024年 | 1篇 |
2023年 | 2篇 |
2022年 | 12篇 |
2021年 | 10篇 |
2020年 | 7篇 |
2019年 | 13篇 |
2018年 | 16篇 |
2017年 | 5篇 |
2016年 | 25篇 |
2015年 | 38篇 |
2014年 | 42篇 |
2013年 | 37篇 |
2012年 | 62篇 |
2011年 | 68篇 |
2010年 | 31篇 |
2009年 | 26篇 |
2008年 | 43篇 |
2007年 | 46篇 |
2006年 | 40篇 |
2005年 | 49篇 |
2004年 | 41篇 |
2003年 | 45篇 |
2002年 | 44篇 |
2001年 | 5篇 |
2000年 | 3篇 |
1999年 | 6篇 |
1998年 | 9篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 1篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 2篇 |
排序方式: 共有794条查询结果,搜索用时 15 毫秒
101.
Kurata H Kusumi K Otsuki K Suzuki R Kurono M Tokuda N Takada Y Shioya H Mizuno H Komiya T Ono T Hagiya H Minami M Nakade S Habashita H 《Bioorganic & medicinal chemistry letters》2012,22(1):144-148
Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice. 相似文献
102.
The Japanese soft scaleTakahashia citricola Kuwana, 1909 is redescribed and transferred to the genus PulvinariaTargioni Tozzettias Pulvinaria citricola (Kuwana, 1909), comb. n.(Coccoidea: Coccidae). Pulvinaria gamazumii Kanda, 1960 is synonymized with Pulvinaria citricolacomb. n. and Pulvinaria nipponica Lindinger, 1933, is resurrected as the replacement name for Pulvinaria citricola Kuwana, 1914 (nec Kuwana, 1909). The adult female of Pulvinaria citricola (Kuwana, 1909) is redescribed and illustrated. 相似文献
103.
Makiko Fujii Hayao Nakanishi Takeshi Toyoda Ichidai Tanaka Yutaka Kondo Hirotaka Osada Yoshitaka Sekido 《Cell cycle (Georgetown, Tex.)》2012,11(18):3373-3379
Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4–Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity. 相似文献
104.
Kashiwagi H Ono Y Ohta M Morikami K Takahashi T 《Bioorganic & medicinal chemistry》2012,20(14):4495-4506
A series of nonsecosteroidal vitamin D(3) analogs with carboxylic acid were explored. Through our systematic SAR studies on the side chain moiety, compound 6b was identified as the optimal compound showing excellent vitamin D receptor (VDR) agonistic activity. Compound 6b had the diethyl group in the terminal which was bound by (E)-olefin linker to the bisphenyl core. Calculating the volume of the side chain showed that the diethyl group in 6b filled the hydrophobic region of VDR with the ideal packing coefficient based on the 55% rule, and that this resulted in the most potent in vitro activity. 相似文献
105.
Furuichi M Suzuki N Dhakshnamoorhty B Minagawa H Yamagishi R Watanabe Y Goto Y Kaneko H Yoshida Y Yagi H Waga I Kumar PK Mizuno H 《Journal of molecular biology》2008,378(2):436-446
l-Lactate oxidase (LOX) belongs to a family of flavin mononucleotide (FMN)-dependent α-hydroxy acid-oxidizing enzymes. Previously, the crystal structure of LOX (pH 8.0) from Aerococcus viridans was solved, revealing that the active site residues are located around the FMN. Here, we solved the crystal structures of the same enzyme at pH 4.5 and its complex with d-lactate at pH 4.5, in an attempt to analyze the intermediate steps. In the complex structure, the d-lactate resides in the substrate-binding site, but interestingly, an active site base, His265, flips far away from the d-lactate, as compared with its conformation in the unbound state at pH 8.0. This movement probably results from the protonation of His265 during the crystallization at pH 4.5, because the same flip is observed in the structure of the unbound state at pH 4.5. Thus, the present structure appears to mimic an intermediate after His265 abstracts a proton from the substrate. The flip of His265 triggers a large structural rearrangement, creating a new hydrogen bonding network between His265-Asp174-Lys221 and, furthermore, brings molecular oxygen in between d-lactate and His265. This mimic of the ternary complex intermediate enzyme-substrate-O2 could explain the reductive half-reaction mechanism to release pyruvate through hydride transfer. In the mechanism of the subsequent oxidative half-reaction, His265 flips back, pushing molecular oxygen into the substrate-binding site as the second substrate, and the reverse reaction takes place to produce hydrogen peroxide. During the reaction, the flip-flop action of His265 has a dual role as an active base/acid to define the major chemical steps. Our proposed reaction mechanism appears to be a common mechanistic strategy for this family of enzymes. 相似文献
106.
Nishimura J Saiga H Sato S Okuyama M Kayama H Kuwata H Matsumoto S Nishida T Sawa Y Akira S Yoshikai Y Yamamoto M Takeda K 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(6):4032-4039
Secretory leukocyte protease inhibitor (SLPI) has multiple functions, including inhibition of protease activity, microbial growth, and inflammatory responses. In this study, we demonstrate that mouse SLPI is critically involved in innate host defense against pulmonary mycobacterial infection. During the early phase of respiratory infection with Mycobacterium bovis bacillus Calmette-Guérin, SLPI was produced by bronchial and alveolar epithelial cells, as well as alveolar macrophages, and secreted into the alveolar space. Recombinant mouse SLPI effectively inhibited in vitro growth of bacillus Calmette-Guérin and Mycobacterium tuberculosis through disruption of the mycobacterial cell wall structure. Each of the two whey acidic protein domains in SLPI was sufficient for inhibiting mycobacterial growth. Cationic residues within the whey acidic protein domains of SLPI were essential for disruption of mycobacterial cell walls. Mice lacking SLPI were highly susceptible to pulmonary infection with M. tuberculosis. Thus, mouse SLPI is an essential component of innate host defense against mycobacteria at the respiratory mucosal surface. 相似文献
107.
Ito T Watanabe H Yamamichi N Kondo S Tando T Haraguchi T Mizutani T Sakurai K Fujita S Izumi T Isobe T Iba H 《The Biochemical journal》2008,411(1):201-209
108.
Eguchi R Naitou H Kunimasa K Ayuzawa R Fujimori Y Ohashi N Kaji K Ohta T 《Proteomics》2008,8(14):2897-2906
We recently reported that hypoxia could induce the breakdown of capillary-like tubes formed by human umbilical vein endothelial cells (HUVECs) and that this breakdown was regulated by p38 and not by a caspase cascade, although the exact molecular mechanisms remain unknown. The aim of this study was to identify proteins that regulated hypoxia-induced tube breakdown through p38-regulated and caspase-independent mechanisms. The involvement of adhesion proteins, integrins, VE-cadherin, PECAM-1, and occludin was first investigated. Although some of these proteins decreased after hypoxia, none of them met the conditions of being quantitatively restored by p38 inhibition but not by caspase inhibition. We then conducted 2-D DIGE coupled with MALDI-TOF/TOF-MS to identify altered protein expression. The differential proteomic analysis of tube-forming HUVECs treated with normoxia or hypoxia and treated with hypoxia in the presence or absence of SB203580, a specific p38 inhibitor, revealed the involvement of heat shock proteins in this tube breakdown. We also confirmed that the amount of HSP27 and HSP70 changed in a p38-regulated and caspase-independent manner during hypoxia. Knocking down HSP27 expression using RNAi further augmented hypoxia-induced tube breakdown. Taken together, it was shown that p38-regulated and caspase-independent reduction of HSP27 plays an important role in hypoxia-induced tube breakdown. 相似文献
109.
DNA-binding specificity, transcriptional activation potential, and the rin mutation effect for the tomato fruit-ripening regulator RIN 总被引:1,自引:0,他引:1
110.
Hirotaka Minagawa Jiro Shimada Hiroki Kaneko 《European journal of biochemistry》2003,270(17):3628-3633
We have obtained two types of thermostable mutant lactate oxidase - one that exhibited an E-to-G point mutation at position 160 (E160G) through error-prone PCR-based random mutagenesis, and another that exhibited an E-to-G mutation at position 160 and a V-to-I mutation at position 198 (E160G/V198I) through DNA shuffling-based random mutagenesis - both of which we have previously reported. Our molecular modeling of lactate oxidase suggests that the substitution of G for E at position 160 reduces the electrostatic repulsion between the negative charges of E160 and E130 in the (beta/alpha)8 barrel structure, but a thermal-inactivation experiment on the five kinds of single-mutant lactate oxidase at position 160 (E160A, E160Q, E160H, E160R, and E160K) showed that the side-chain volume of the amino acid at position 160 mainly contributes to the thermostability of lactate oxidase. We also produced V198I single-mutant lactate oxidase through site-directed mutagenesis, and analysed the thermostability of wild-type, V198I, E160G, and E160G/V198I lactate oxidase enzymes. The half-life of E160G/V198I lactate oxidase at 70 degrees C was about three times longer than that of E160G lactate oxidase, and was about 20 times longer than that of wild-type lactate oxidase. In contrast, the thermostability of the V198I lactate oxidase was almost identical to that of wild-type lactate oxidase. This indicates that the V198I mutation alone does not affect lactate oxidase thermostability, but does affect it when combined with the E160G mutation. 相似文献