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排序方式: 共有115条查询结果,搜索用时 15 毫秒
1.
Meng Yao Zhang Hyunjun Yang Gloria Ortiz Michael J. Trnka Nektaria Petronikolou Alma L. Burlingame William F. DeGrado Danica Galoni Fujimori 《Chemical science》2022,13(22):6599
Chemical probes for chromatin reader proteins are valuable tools for investigating epigenetic regulatory mechanisms and evaluating whether the target of interest holds therapeutic potential. Developing potent inhibitors for the plant homeodomain (PHD) family of methylation readers remains a difficult task due to the charged, shallow and extended nature of the histone binding site that precludes effective engagement of conventional small molecules. Herein, we describe the development of novel proximity-reactive cyclopeptide inhibitors for PHD3—a trimethyllysine reader domain of histone demethylase KDM5A. Guided by the PHD3–histone co-crystal structure, we designed a sidechain-to-sidechain linking strategy to improve peptide proteolytic stability whilst maintaining binding affinity. We have developed an operationally simple solid-phase macrocyclization pathway, capitalizing on the inherent reactivity of the dimethyllysine ε-amino group to generate scaffolds bearing charged tetraalkylammonium functionalities that effectively engage the shallow aromatic ‘groove’ of PHD3. Leveraging a surface-exposed lysine residue on PHD3 adjacent to the ligand binding site, cyclic peptides were rendered covalent through installation of an arylsulfonyl fluoride warhead. The resulting lysine-reactive cyclic peptides demonstrated rapid and efficient labeling of the PHD3 domain in HEK293T lysates, showcasing the feasibility of employing proximity-induced reactivity for covalent labeling of this challenging family of reader domains.We describe the development of covalent cyclic peptide ligands which target a chromatin methylation reader domain using a proximity-reactive sulfonyl fluoride moiety. 相似文献
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John G. D'Angelo Jeremy A. Cody Christian Larrabee Danica J. Ostrander Kyle W. Rugg Donna Mamangun 《合成通讯》2013,43(23):3224-3232
Herein, we report new reactivity of the conducting polymer, poly-(3,4-ethylenedioxy thiophene) (PEDOT), where PEDOT mediates a Ritter reaction between alcohols and acetonitrile. The yields were variable and in most cases competitive with results obtained using sulfuric acid. Attempts at a stoichiometric reaction between benzonitrile and diphenylmethanol are also reported herein. Finally, described here are preliminary mechanistic studies that suggest PEDOT is behaving as an alcohol-selective or specific Lewis acid. Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for full experimental and spectral details. 相似文献
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Danica L. Resuello Stephen B. Lirio Analin E. Porto Allan Patrick G. Macabeo Hsi-Ya Huang Mary Jho-Anne T. Corpuz 《Natural product research》2020,34(4):525-529
AbstractThe methanolic extract of Callyspongia samarensis (MCS) significantly inhibited β-secretase 1 (IC50 99.82?µg/mL) in a dose-dependent manner and demonstrated a noncompetitive type of inhibition. Furthermore, it exhibited the highest AMPK activation (EC50 14.47?μg/mL) as compared with the standard, Aspirin (EC50 >100?μg/mL). HPLC/ESI-MS analysis of MCS extract revealed 15 peaks, in which nine peaks demonstrated similar fragmentation pattern with the known compounds in literature and in database library: 5-aminopentanoic acid (1), 4-aminobutanoic acid (3), Luotonin A (4), (E)-3-(1H-imidazol-5-yl) prop-2-enoic acid (8), Galactosphingosine (10), D-sphingosine (11), 5,7,4′-trihydroxy-3′,5′-dimethoxyflavone (12), hydroxydihydrovolide (13), and 3,5-dibromo-4-methoxyphenylpyruvic acid (14); and 6 peaks are not identified (2, 5–7, 9, and 15). Acute oral toxicity test of MCS extract revealed that it is nontoxic, with an LD50 of >2000?mg/kg. Assessment of BBB permeability of MCS extract showed that compound 15 was able to cross the BBB making it a suitable candidate for developing CNS drugs. 相似文献
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Bajuk-Bogdanović Danica Holclajtner-Antunović Ivanka Jovanović Zoran Mravik Željko Krstić Jugoslav Uskoković-Marković Snežana Vujković Milica 《Journal of Solid State Electrochemistry》2019,23(9):2747-2758
Journal of Solid State Electrochemistry - The synergistic effects between two Keggin-type heteropoly acids (HPAs) and carbon surface were examined and elucidated. An improved high rate capability... 相似文献
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Di X Andrews DM Tucker CJ Yu L Moore AB Zheng X Castro L Hermon T Xiao H Dixon D 《Experimental & molecular medicine》2012,44(4):281-292
Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ≥ 1.5 fold, P ≤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 µg/ml) in UtLM cells. Downregulation of TGF-β signaling pathway genes, activin A, activin B, Smad3, TGF-β2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-β pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. 相似文献
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Gupta R Sheth DM Boone TK Sevilla AB Fréchette J 《Langmuir : the ACS journal of surfaces and colloids》2011,27(24):14923-14929
Pinning of the triple contact line adversely affects electrowetting on dielectric. Electrowetting response of substrates with contact angle hysteresis ranging from 1° to 30° has been characterized, and the results are interpreted within the framework of electromechanics corrected for pinning. The relationship between contact angle hysteresis, threshold potential for liquid actuation, and electrowetting hysteresis is quantified. Our results demonstrate that a modified electrowetting equation, based on balance of forces (including the pinning forces) acting on the triple contact line and on the drop, describes the electrowetting response of substrates with significant contact angle hysteresis. Finally, the surface properties of PDMS Sylgard 184 were found to be influenced by the electric field. 相似文献
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Marek Bučko Danica Mislovičová Jozef Nahálka Alica Vikartovská Jana Šefčovičová Jaroslav Katrlík Ján Tkáč Peter Gemeiner Igor Lacík Vladimír Štefuca Milan Polakovič Michal Rosenberg Martin Rebroš Daniela Šmogrovičová Juraj Švitel 《Chemical Papers》2012,66(11):983-998
Biological molecules such as enzymes, cells, antibodies, lectins, peptide aptamers, and cellular components in an immobilized form are extensively used in biotechnology, in biorecognition and in many medicinal applications. This review provides a comprehensive summary of the developments in new immobilization materials, techniques, and their practical applications previously developed by the authors. A detailed overview of several immobilization materials and technologies is given here, including bead cellulose, encapsulation in ionotropic gels and polyelectrolyte complexes, and various immobilization protocols applied onto surfaces. In addition, the review summarises the screening and design of an immobilization protocol, practical applications of immobilized biocatalysts in the industrial production of metabolites, monitoring, and control of fermentation processes, preparation of electrochemical/optical biosensors and biofuel cells. 相似文献
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