全文获取类型
收费全文 | 529篇 |
免费 | 28篇 |
出版年
2022年 | 5篇 |
2021年 | 13篇 |
2020年 | 7篇 |
2019年 | 5篇 |
2018年 | 7篇 |
2017年 | 8篇 |
2016年 | 21篇 |
2015年 | 29篇 |
2014年 | 40篇 |
2013年 | 38篇 |
2012年 | 50篇 |
2011年 | 51篇 |
2010年 | 26篇 |
2009年 | 27篇 |
2008年 | 35篇 |
2007年 | 29篇 |
2006年 | 20篇 |
2005年 | 26篇 |
2004年 | 48篇 |
2003年 | 21篇 |
2002年 | 19篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 1篇 |
1995年 | 1篇 |
1992年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有557条查询结果,搜索用时 15 毫秒
131.
Kyeong Lee Ja-Il Goo Hwa Young Jung Minkyoung Kim Shanthaveerappa K. Boovanahalli Hye Ran Park Mun-Ock Kim Dong-Hyun Kim Hyun Sun Lee Yongseok Choi 《Bioorganic & medicinal chemistry letters》2012,22(24):7456-7460
A novel series of benzimidazole derivatives was prepared and evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity using microsome from rat liver. Among the newly synthesized compounds, furfurylamine containing benzimidazole carboxamide 10j showed the most potent DGAT inhibitory effect (IC50 = 4.4 μM) and inhibited triglyceride formation in HepG2 cells. Furthermore, compound 10j reduced body weight gain of Institute of Cancer Research mice on a high-fat diet and decreased levels of total triglyceride, total cholesterol, and LDL-cholesterol in the blood accompanied with a significant increase in HDL-cholesterol level. 相似文献
132.
LA Lallemand C Zubieta SG Lee Y Wang S Acajjaoui J Timmins S McSweeney JM Jez JG McCarthy AA McCarthy 《Plant physiology》2012,160(1):249-260
Chlorogenic acids (CGAs) are a group of phenolic secondary metabolites produced by certain plant species and an important component of coffee (Coffea spp.). The CGAs have been implicated in biotic and abiotic stress responses, while the related shikimate esters are key intermediates for lignin biosynthesis. Here, two hydroxycinnamoyl-coenzyme A shikimate/quinate hydroxycinnamoyl transferases (HCT/HQT) from coffee were biochemically characterized. We show, to our knowledge for the first time, that in vitro, HCT is capable of synthesizing the 3,5-O-dicaffeoylquinic acid diester, a major constituent of the immature coffee grain. In order to further understand the substrate specificity and catalytic mechanism of the HCT/HQT, we performed structural and mutagenesis studies of HCT. The three-dimensional structure of a native HCT and a proteolytically stable lysine mutant enabled the identification of important residues involved in substrate specificity and catalysis. Site-directed mutagenesis confirmed the role of residues leucine-400 and phenylalanine-402 in substrate specificity and of histidine-153 and the valine-31 to proline-37 loop in catalysis. In addition, the histidine-154-asparagine mutant was observed to produce 4-fold more dichlorogenic acids compared with the native protein. These data provide, to our knowledge, the first structural characterization of a HCT and, in conjunction with the biochemical and mutagenesis studies presented here, delineate the underlying molecular-level determinants for substrate specificity and catalysis. This work has potential applications in fine-tuning the levels of shikimate and quinate esters (CGAs including dichlorogenic acids) in different plant species in order to generate reduced or elevated levels of the desired target compounds. 相似文献
133.
SLC26A3 functions as a chloride/bicarbonate anion exchanger expressed in the secretory epithelial cells in the intestine, pancreas, and salivary glands. SLC26A3 has a C-terminal class I PDZ binding motif that assembles regulatory factors or other transporters by anchoring to various PDZ scaffold proteins. NHERF4 is an epithelial-enriched PDZ domain scaffold protein that has attracted attention because of its enriched tissue expression in the intestine and kidney. In this study, we identified SLC26A3 as a novel binding transporter of NHERF4. We investigated the functional role of NHERF4 in the regulation of SLC26A3 by using integrated biochemical and physiological approaches. A direct protein-protein interaction was identified between the PDZ-binding motif of SLC26A3 and the third PDZ domain of NHERF4. Interaction with NHERF4 decreased the level of SLC26A3 expression on the plasma membrane, which led to reduced SLC26A3 anion exchange activity. Notably, interaction with NHERF4 induced rapid internalisation of SLC26A3 from the plasma membrane. The SLC26A3-NHERF4 interaction was modulated by phosphorylation; serine 329 of NHERF4-PDZ3 played a critical role in modulating binding selectivity. Our findings suggest that NHERF4 is a novel modulator of luminal fluidity in the intestine by adjusting SLC26A3 expression and activity through a phosphorylation-dependent mechanism. 相似文献
134.
Lee SY Kim JH Jung H Chi SW Chung SJ Lee CK Park BC Bae KH Park SG 《Journal of microbiology and biotechnology》2012,22(4):571-573
Glyceraldehyde-3-phosphate (G-3-P), the substrate of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is a key intermediate in several metabolic pathways. Recently, we reported that G-3-P directly inhibits caspase-3 activity in a reversible noncompetitive mode, suggesting the intracellular G-3-P level as a cell fate decision factor. It has been known that apoptotic stimuli induce the generation of NO, and NO S-nitrosylates GAPDH at the catalytic cysteine residue, which confers GAPDH the ability to bind to Siah-1, an E3 ubiquitin ligase. The GAPDH-Siah-1 complex is translocated into the nucleus and subsequently triggers the apoptotic process. Here, we clearly showed that intracellular G-3-P protects GAPDH from S-nitrosylation at above a certain level, and consequently maintains the cell survival. In case G-3-P drops below a certain level as a result of exposure to specific stimuli, G-3-P cannot inhibit S-nitrosylation of GAPDH anymore, and consequently GAPDH translocates with Siah-1 into the nucleus. Based on these results, we suggest that G-3-P functions as a molecule switch between cell survival and apoptosis by regulating S-nitrosylation of GAPDH. 相似文献
135.
Jeong W Park SJ Chang TS Lee DY Rhee SG 《The Journal of biological chemistry》2006,281(20):14400-14407
Among many proteins with cysteine sulfinic acid (Cys-SO2H) residues, the sulfinic forms of certain peroxiredoxins (Prxs) are selectively reduced by sulfiredoxin (Srx) in the presence of ATP. All Srx enzymes contain a conserved cysteine residue. To elucidate the mechanism of the Srx-catalyzed reaction, we generated various mutants of Srx and examined their interaction with PrxI, their ATPase activity, and their ability to reduce sulfinic PrxI. Our results suggest that three surface-exposed amino acid residues, corresponding to Arg50, Asp57, and Asp79 of rat Srx, are critical for substrate recognition. The presence of the sulfinic form (but not the reduced form) of PrxI induces the conserved cysteine of Srx to take the gamma-phosphate of ATP and then immediately transfers the phosphate to the sulfinic moiety of PrxI to generate a sulfinic acid phosphoryl ester (Prx-Cys-S(=O)OPO3(2-)). This ester is reductively cleaved by a thiol molecule (RSH) such as GSH, thioredoxin, and dithiothreitol to produce a disulfide-S-monoxide (Prx-Cys-S(=O)-S-R). The disulfide-S-monoxide is further reduced through the oxidation of three thiol equivalents to complete the catalytic cycle and regenerate Prx-Cys-SH. 相似文献
136.
137.
Ik-Hwan Han Sung Young Goo Soon-Jung Park Se-Jin Hwang Yong-Seok Kim Michael Sungwoo Yang Myoung-Hee Ahn Jae-Sook Ryu 《The Korean journal of parasitology》2009,47(3):205-212
Trichomonas vaginalis commonly causes vaginitis and perhaps cervicitis in women and urethritis in men and women. Macrophages are important immune cells in response to T. vaginalis infection. In this study, we investigated whether human macrophages could be involved in inflammation induced by T. vaginalis. Human monocyte-derived macrophages (HMDM) were co-cultured with T. vaginalis. Live, opsonized-live trichomonads, and T. vaginalis lysates increased proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 by HMDM. The involvement of nuclear factor (NF)-κB signaling pathway in cytokine production induced by T. vaginalis was confirmed by phosphorylation and nuclear translocation of p65 NF-κB. In addition, stimulation with live T. vaginalis induced marked augmentation of nitric oxide (NO) production and expression of inducible NO synthase (iNOS) levels in HMDM. However, trichomonad-induced NF-κB activation and TNF-α production in macrophages were significantly inhibited by inhibition of iNOS levels with L-NMMA (NO synthase inhibitor). Moreover, pretreatment with NF-κB inhibitors (PDTC or Bay11-7082) caused human macrophages to produce less TNF-α. These results suggest that T. vaginalis stimulates human macrophages to produce proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, and NO. In particular, we showed that T. vaginalis induced TNF-α production in macrophages through NO-dependent activation of NF-κB, which might be closely involved in inflammation caused by T. vaginalis. 相似文献
138.
Hana Lee Seung Wook Chi Sunghyun Kang Chong-Kil Lee Byoung Chul Park Sung Goo Park 《Biochemical and biophysical research communications》2009,389(1):177-180
Dihydroxyacetone (DHA) induces the formation of advanced glycation endproducts (AGEs), which are involved in several diseases. Earlier, we identified dihydroxyacetone kinase 1 (Dak1) as a candidate glutathione peroxidase 3 (Gpx3)-interacting protein in Saccharomyces cerevisiae. This finding is noteworthy, as no clear evidence on the involvement of oxidative stress systems in DHA-induced AGE formation has been found to date. Here, we demonstrate that Gpx3 interacts with Dak1, alleviates DHA-mediated stress by upregulating Dak activity, and consequently suppresses AGE formation. Based on these results, we propose that defense systems against oxidative stress and DHA-induced AGE formation are related via interactions between Gpx3 and Dak1. 相似文献
139.
140.
Youn Wook Chung Daewon Jeong Ok Jeong Noh Yong Hwan Park Soo Im Kang Min Goo Lee Tae-Hoon Lee Moon Bin Yim Ick Young Kim 《Molecules and cells》2009,27(5):609-613
It has been reported that selenoprotein W (SelW) mRNA is highly expressed in the developing central nerve system of rats,
and its expression is maintained until the early postnatal stage. We here found that SelW protein significantly increased
in mouse brains of postnatal day 8 and 20 relative to embryonic day 15. This was accompanied by increased expression of SOD1
and SOD2. When the expression of SelW in primary cultured cells derived from embryonic cerebral cortex was knocked down with
small interfering RNAs (siRNAs), SelW siRNA-transfected neuronal cells were more sensitive to the oxidative stress induced
by treatment of H2O2 than control cells. TUNEL assays revealed that H2O2-induced apoptotic cell death occurred at a higher frequency in the siRNA-transfected cells than in the control cells. Taken
together, our findings suggest that SelW plays an important role in protection of neurons from oxidative stress during neuronal
development. 相似文献