全文获取类型
收费全文 | 234篇 |
免费 | 31篇 |
国内免费 | 6篇 |
专业分类
综合类 | 4篇 |
化学工业 | 217篇 |
金属工艺 | 1篇 |
机械仪表 | 6篇 |
建筑科学 | 1篇 |
能源动力 | 2篇 |
轻工业 | 23篇 |
无线电 | 2篇 |
一般工业技术 | 1篇 |
冶金工业 | 3篇 |
原子能技术 | 1篇 |
自动化技术 | 10篇 |
出版年
2023年 | 2篇 |
2022年 | 27篇 |
2021年 | 37篇 |
2020年 | 12篇 |
2019年 | 9篇 |
2018年 | 10篇 |
2017年 | 9篇 |
2016年 | 10篇 |
2015年 | 11篇 |
2014年 | 21篇 |
2013年 | 23篇 |
2012年 | 16篇 |
2011年 | 13篇 |
2010年 | 21篇 |
2009年 | 13篇 |
2008年 | 6篇 |
2007年 | 10篇 |
2006年 | 3篇 |
2005年 | 6篇 |
2004年 | 4篇 |
2003年 | 3篇 |
2002年 | 2篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
排序方式: 共有271条查询结果,搜索用时 15 毫秒
41.
42.
Barbara Pucelik Agata Barzowska Janusz M. Dbrowski Anna Czarna 《International journal of molecular sciences》2021,22(16)
Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases. 相似文献
43.
Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket. 相似文献
44.
45.
A functional comparison of three human SAPKs with fungal Hog1p was undertaken, using Saccharomyces cerevisiae as a heterologous expression system. We characterized the role of mammalian MAP kinases in sensitivity to both osmotic and oxidative stress of a S. cerevisiae hog1 mutant. Western blot analyses indicated that S. cerevisiae can only phosphorylate mammalian MAP kinases in response to osmotic stress but not to oxidative stress, while morphogenetic defects characteristic of hog1 mutants under hyperosmotic stress are only suppressed by fungal and not mammalian Hog1p. Our data demonstrate the functional conservation of MAPKs although they also evidence differential aspects among the three human SAPKs and the fungal MAPKs. 相似文献
46.
Xiaolin Gao Nannan Ning Beihua Kong Yongping Xu Hui Xu Chengjun Zhou Su Li Yi Shao Jianqing Qiu Jingxin Li 《Lipids》2013,48(10):989-995
Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is generated via phosphorylation of sphingosine by sphingosine kinases (SphK). It acts via a family of G protein-coupled receptors or as an intracellular second messenger for agonists acting through the S1P receptors (S1P1–5). In our study, the expression of SphK1 and S1P1 was identified by immunohistochemistry and immunoblot. The concentration of S1P was measured using ELISA. The spontaneous contraction of isolated fallopian tube strips was determined by tension recording. Our results showed that SphK1 and S1P1 were localized in the fallopian tube epithelial cells. In addition, smooth muscle cells also contained S1P1. Compared with the intrauterine pregnancy group, SPHK1 and S1P1 were overexpressed in ectopic pregnancy. However, the S1P concentration within the human oviduct from ectopic pregnancy subjects was largely reduced than that from normal pregnancy subject. The results from tension recording indicated that exogenous and intracellularly generated S1P can regulate the spontaneous contraction of oviduct isolated from rats and human. In conclusion, the sphingolipid metabolism signal pathway functionally existed in the human fallopian tube. Aberrant sphingolipid metabolism in the human fallopian tube may be involved in ectopic pregnancy. 相似文献
47.
Dr. Paula Lorenzo Dr. María A. Ortiz Prof. Dr. Rosana Álvarez Dr. F. Javier Piedrafita Prof. Dr. Ángel R. de Lera 《ChemMedChem》2013,8(7):1184-1198
A series of analogues of the adamantyl arotinoid (AdAr) chalcone MX781 with halogenated benzyloxy substituents at C2′ and heterocyclic derivatives replacing the chalcone group were found to inhibit IκBα kinase α (IKKα) and IκBα kinase β (IKKβ) activities. The growth inhibitory capacity of some analogues against Jurkat T cells as well as prostate carcinoma (PC‐3) and chronic myelogenous leukemia (K562) cells, which contain elevated basal IKK activity, correlates with the induction of apoptosis and increased inhibition of recombinant IKKα and IKKβ in vitro, pointing toward inhibition of IKK/NFκB signaling as the most likely target of the anticancer activities of these AdArs. While the chalcone functional group present in many dietary compounds has been shown to mediate interactions with IKKβ via Michael addition with cysteine residues, AdArs containing a five‐membered heterocyclic ring (isoxazoles and pyrazoles) in place of the chalcone of the parent system are potent inhibitors of IKKs as well, which suggests that other mechanisms for inhibition exist that do not depend on the presence of a reactive α,β‐unsaturated ketone. 相似文献
48.
Dr. Cristina Tintori Ilaria Laurenzana Francesco La Rocca Dr. Federico Falchi Prof. Fabio Carraro Alba Ruiz Prof. José A. Esté Miroslava Kissova Dr. Emmanuele Crespan Prof. Giovanni Maga Prof. Mariangela Biava Dr. Chiara Brullo Prof. Silvia Schenone Prof. Maurizio Botta 《ChemMedChem》2013,8(8):1353-1360
Hematopoietic cell kinase (Hck) is a member of the Src family of non‐receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV‐1. Herein, structure‐based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in‐house library of pyrazolo[3,4‐d]pyrimidine derivatives, which were previously shown to be dual Abl and c‐Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell‐free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with Ki values ranging from 0.14 to 18.4 μM , confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU‐812, and one compound was found to block HIV‐1 replication at sub‐toxic concentrations. 相似文献
49.
Chantal Pallier Michle Valens Valrie Puzos Hiroshi Fukuhara Genevive Chret Frdric Sor Monique Bolotin-Fukuhara 《Yeast (Chichester, England)》1993,9(10):1149-1155
We report in this paper the sequence of a part of chromosome XI of Saccharomyces cerevisiae. This 17 kbp nucleotide sequence represents the right half of cosmid pUKG151 and contains nine open reading frames, YKL453, 450, 449, 448, 445, 443, 442, 441 and the 5′ part of YKL440. YKL440 was previously identified as the MBR1 gene and plays a role in mitochondrial biogenesis. YKL443 is a homologue of the yeast serine-rich protein (SRP1), while YKL453 presents strong homologies with the KIN1/KIN2/SNF1 kinase family. It must be pointed out that the size of this gene is well above average for yeast. 相似文献
50.
Development of Potent Pyrazolopyrimidinone‐Based WEE1 Inhibitors with Limited Single‐Agent Cytotoxicity for Cancer Therapy 下载免费PDF全文
Dr. Christopher J. Matheson Kimberly A. Casalvieri Dr. Donald S. Backos Dr. Philip Reigan 《ChemMedChem》2018,13(16):1681-1694
WEE1 kinase regulates the G2/M cell‐cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA‐damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single‐agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single‐agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA‐targeted chemotherapy. 相似文献