全文获取类型
收费全文 | 580篇 |
免费 | 26篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 12篇 |
2020年 | 10篇 |
2019年 | 11篇 |
2018年 | 13篇 |
2017年 | 14篇 |
2016年 | 18篇 |
2015年 | 44篇 |
2014年 | 42篇 |
2013年 | 48篇 |
2012年 | 51篇 |
2011年 | 52篇 |
2010年 | 43篇 |
2009年 | 34篇 |
2008年 | 40篇 |
2007年 | 42篇 |
2006年 | 28篇 |
2005年 | 24篇 |
2004年 | 24篇 |
2003年 | 14篇 |
2002年 | 15篇 |
2001年 | 8篇 |
2000年 | 3篇 |
1999年 | 6篇 |
1998年 | 3篇 |
1997年 | 1篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
排序方式: 共有606条查询结果,搜索用时 359 毫秒
581.
Sun-Sil Choi Eun Sun Kim Minseob Koh Soo-Jin Lee Donghyun Lim Yong Ryoul Yang Hyun-Jun Jang Kyung-ah Seo Sang-Hyun Min In Hee Lee Seung Bum Park Pann-Ghill Suh Jang Hyun Choi 《The Journal of biological chemistry》2014,289(38):26618-26629
Thiazolidinedione class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but thiazolidinediones can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe a novel synthetic PPARγ ligand UNIST HYUNDAI Compound 1 (UHC1) that binds tightly to PPARγ without the classical agonism and which blocks cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation. We modified the non-agonist PPARγ ligand SR1664 chemically to improve its solubility and then developed a novel PPARγ ligand, UHC1. According to our docking simulation, UHC1 occupied the ligand-binding site of PPARγ with a higher docking score than SR1664. In addition, UHC1 more potently blocked CDK5-mediated PPARγ phosphorylation at Ser-273. Surprisingly, UHC1 treatment effectively ameliorated the inflammatory response both in vitro and in high-fat diet-fed mice. Furthermore, UHC1 treatment dramatically improved insulin sensitivity in high-fat diet-fed mice without causing fluid retention and weight gain. Taken together, compared with SR1664, UHC1 exhibited greater beneficial effects on glucose and lipid metabolism by blocking CDK5-mediated PPARγ phosphorylation, and these data indicate that UHC1 could be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders. 相似文献
582.
Ye Jin Kim Jae Sung Pyo Young-Suk Jung Jae-Hwan Kwak 《Bioorganic & medicinal chemistry letters》2017,27(3):607-611
A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl-methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a–b and 3d–e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents. 相似文献
583.
Jung Wha Kim Hong Pyo Kim Sang Hyun Sung 《Bioorganic & medicinal chemistry letters》2017,27(14):3144-3147
Two new pterosin glycosides, (2S,3S)-pterosin C 3-O-β-d-(4′-(E)-caffeoyl)-glucopyranoside (1) and (2S,3S)-pterosin C 3-O-β-d-(6′-(E)-p-coumaroyl)-glucopyranoside (2), were isolated from Pteris multifida (Pteridaceae) roots along with ten known pterosin compounds (3–12). The chemical structures of the isolated compounds were elucidated by extensive analysis of the 1D, 2D NMR, HRESIMS, and CD spectroscopic data. The cytotoxicities of 1–12 against HCT116 human colorectal cancer cell line were evaluated. Among the isolates, compound 1 showed moderate antiproliferative activity in HCT116 cells with an IC50 value of 8.0 ± 1.7 μM. Additionally, 1 induced the upregulation of the caspase-9 and procaspase-9 levels in Western blots and increased the annexin V/propidium iodide (PI)-positive cell population in flow cytometry. 相似文献
584.
Six‐membered cyclic carbonates from trimethylolpropane: Lipase‐mediated synthesis in a flow reactor and in silico evaluation of the reaction 下载免费PDF全文
Six‐membered cyclic carbonates with hydroxyl and methoxycarbonyloxy functional groups were prepared by transesterification of trimethylolpropane (TMP) with dimethylcarbonate (DMC) by solvent‐free lipase‐mediated flow reaction followed by thermal cyclization. The flow reaction efficiency was evaluated using different configurations of reactor consisting of packed beds of Novozym®435 (immobilized Candida antarctica lipase B—CalB—a.k.a. N435) and molecular sieves, flowrate, and biocatalyst loads. The mixed column of the biocatalyst and molecular sieves, allowing rapid and efficient removal of the by‐product—methanol—was the most efficient setup. Higher conversion (81.6%) in the flow reaction compared to batch process (72%) was obtained using same amount of N435 (20% (w/w) N435:TMP) at 12 h, and the undesirable dimer and oligomer formation were suppressed. Moreover, the product was recovered easily without extra separation steps, and the biocatalyst and the molecular sieves remained intact for subsequent regeneration and recycling. The reaction of CalB with DMC and the primary transesterification product, monocarbonated TMP, respectively, as acyl donors was evaluated by in silico modeling and empirically to determine the role of the enzyme in the formation of cyclic carbonates and other side products. DMC was shown to be the preferred acyl donor, suggesting that TMP and its carbonated derivatives serve only as acyl acceptors in the lipase‐catalyzed reaction. Subsequent cyclization to cyclic carbonate is catalyzed at increased temperature and not by the enzyme. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:375–382, 2017 相似文献
585.
Seung-Whan Kim In-Hwa Choi Su-Nam Kim Yong-Hwan Kim Suhk-Neung Pyo Dong-Kwong Rhee 《FEMS microbiology letters》1998,161(2):217-224
DnaK is known to be highly conserved in all species and is a major immunogen in Streptococcus pneumoniae. To elucidate the role of dnaK in S. pneumoniae, dnaK was cloned in Escherichia coli using a homologous dnaK probe generated by PCR. The His-tagged DnaK was overexpressed in soluble form and purified from E. coli. Alignment of the deduced DnaK amino acid sequence from nucleotide sequences of the cloned dnaK revealed high homology with DnaK analogs in E. coli (53%) and Staphylococcus aureus (73%). However, anti-pneumococcal DnaK antiserum did not crossreact with DnaK analogs in E. coli, S. aureus and human cells suggesting that pneumococcal DnaK might be a good candidate as a vaccine. 相似文献
586.
587.
588.
Sang-Hyun Lee Jin-Man Kim Dong Gwang Lee Jangwook Lee Jong-Gil Park Tae-Su Han Hyun-Soo Cho Young-Lai Cho Kwang-Hee Bae Young-Jun Park Seon-Jin Lee Moo-Seung Lee Yong-Min Huh Deog Yeon Jo Hwan-Jung Yun Heung Jin Jeon Nayoung Kim Mina Joo Jang-Seong Kim Hyo Jin Lee Jeong-Ki Min 《Cell death and differentiation》2021,28(3):968
Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.Subject terms: Tumour biomarkers, Tumour-suppressor proteins 相似文献
589.
Oxidation of 5-hydroxymethylfurfural with a novel aryl alcohol oxidase from Mycobacterium sp. MS1601
Mahmoud Sayed Yasser Gaber Fredrik Junghus Eric Valdés Martín Sang-Hyun Pyo Rajni Hatti-Kaul 《Microbial biotechnology》2022,15(8):2176-2190
Bio-based 5-hydroxymethylfurfural (HMF) serves as an important platform for several chemicals, among which 2,5-furan dicarboxylic acid (FDCA) has attracted considerable interest as a monomer for the production of polyethylene furanoate (PEF), a potential alternative for fossil-based polyethylene terephthalate (PET). This study is based on the HMF oxidizing activity shown by Mycobacterium sp. MS 1601 cells and investigation of the enzyme catalysing the oxidation. The Mycobacterium whole cells oxidized the HMF to FDCA (60% yield) and hydroxymethyl furan carboxylic acid (HMFCA). A gene encoding a novel bacterial aryl alcohol oxidase, hereinafter MycspAAO, was identified in the genome and was cloned and expressed in Escherichia coli Bl21 (DE3). The purified MycspAAO displayed activity against several alcohols and aldehydes; 3,5 dimethoxy benzyl alcohol (veratryl alcohol) was the best substrate among those tested followed by HMF. 5-Hydroxymethylfurfural was converted to 5-formyl-2-furoic acid (FFCA) via diformyl furan (DFF) with optimal activity at pH 8 and 30–40°C. FDCA formation was observed during long reaction time with low HMF concentration. Mutagenesis of several amino acids shaping the active site and evaluation of the variants showed Y444F to have around 3-fold higher kcat/Km and ~1.7-fold lower Km with HMF. 相似文献
590.
The specificity and efficiency of cell signaling is largely governed by the complex formation of signaling proteins. The precise spatio-temporal control of the complex assembly is crucial for proper signaling and cell survival. Protein phosphorylation is a key mechanism of signal processing in most of cell signaling networks. Phosphatases, along with kinases, control the phosphorylation state of many proteins and thus play a critical role in the precise regulation of signaling at each stage such as activation, propagation, and adaptation. Identification and functional analysis of pathway-specific phosphatase is, therefore, crucial for the understanding of cell signaling mechanisms. Here, we have developed a novel screening strategy to identify pathway-specific phosphatases, in which the entire repertoire of cell’s phosphatases was tethered to a signaling complex and the changes in signaling response were monitored. As a model target, we have chosen the mating MAP kinase pathway in the budding yeast, which is composed of three kinases and Ste5 scaffold protein. Using this strategy, a putative Ser/Thr phosphatase, Ppq1, was identified to be mating-specific. Results show that Ppq1 down-regulates mating signaling by targeting at or upstream of the terminal MAP kinase Fus3 in the cascade. The catalytic activity of Ppq1 as a phosphatase was confirmed in vitro and is necessary for its function in the regulation of mating signaling. Overall, the data suggest that Ppq1 functions as a negative regulator of mating MAPK pathway by dephosphorylating target pathway protein(s) and plays a key role in the control of the background signaling noise. 相似文献