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Dr. Lukas Kröger Dr. Constantin G. Daniliuc Deeba Ensan Sebastian Borgert Dr. Christian Nienberg Miriam Lauwers Dr. Michaela Steinkrüger Prof. Joachim Jose Dr. Markus Pietsch Prof. Bernhard Wünsch 《ChemMedChem》2020,15(10):871-881
The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2α2β2 and its monomeric subunits CK2α and CK2β. A series of analogues of W16 ((3aR,4S,10S,10aS)-4-{[(S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydrofuro[3,4-b]carbazole-1,3(3aH)-dione ((+)- 3 a )) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide ( 9 ) and N-methylimide ( 10 ) substructure. The enantiomer (−)- 3 a (Ki=4.9 μM) of the lead compound (+)- 3 a (Ki=31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (−)- 3 a did not show an increased enzyme inhibition of the CK2α2β2 holoenzyme, the CK2α subunit or the mutated CK2α′ C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (−)- 9 a (Ki=3.6 μM) and the N-methylimide (+)- 10 a (Ki=2.8 μM) represent the most promising inhibitors of the CK2α/CK2β interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (±)- 12 , with a carboxy moiety in the 4-position, displays the highest CK2α/CK2β interaction inhibition (Ki=1.8 μM) of this series of compounds. 相似文献
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Pavlína Nekvasilov Michaela Hovorkov Zuzana Mszros Lucie Petrskov Helena Pelantov Vladimír Ken Kristýna Slmov Pavla Bojarov 《International journal of molecular sciences》2022,23(8)
Enzymatic synthesis is an elegant biocompatible approach to complex compounds such as human milk oligosaccharides (HMOs). These compounds are vital for healthy neonatal development with a positive impact on the immune system. Although HMOs may be prepared by glycosyltransferases, this pathway is often complicated by the high price of sugar nucleotides, stringent substrate specificity, and low enzyme stability. Engineered glycosidases (EC 3.2.1) represent a good synthetic alternative, especially if variations in the substrate structure are desired. Site-directed mutagenesis can improve the synthetic process with higher yields and/or increased reaction selectivity. So far, the synthesis of human milk oligosaccharides by glycosidases has mostly been limited to analytical reactions with mass spectrometry detection. The present work reveals the potential of a library of engineered glycosidases in the preparative synthesis of three tetrasaccharides derived from lacto-N-tetraose (Galβ4GlcNAcβ3Galβ4Glc), employing sequential cascade reactions catalyzed by β3-N-acetylhexosaminidase BbhI from Bifidobacterium bifidum, β4-galactosidase BgaD-B from Bacillus circulans, β4-N-acetylgalactosaminidase from Talaromyces flavus, and β3-galactosynthase BgaC from B. circulans. The reaction products were isolated and structurally characterized. This work expands the insight into the multi-step catalysis by glycosidases and shows the path to modified derivatives of complex carbohydrates that cannot be prepared by standard glycosyltransferase methods. 相似文献
14.
Comparative assessment of neural networks and regression models for forecasting summertime ozone in Athens 总被引:2,自引:0,他引:2
A comparison study has been performed with neural networks (NNs) and multiple linear regression models to forecast the next day's maximum hourly ozone concentration in the Athens basin at four representative monitoring stations that show very different behavior. All models use 11 predictors (eight meteorological and three persistence variables) and are developed and validated between April and October from 1992 to 1999. Performance results based on a wide set of forecast quality measures indicate that the NNs provide better estimates of ozone concentrations at the monitoring sites, whilst the more often used linear models are less efficient at accurately forecasting high ozone concentrations. The violation of the European information threshold of 180 microg/m(3) is successfully predicted by the NN in 72% of the cases on average. Results at all stations are consistent with similar ozone forecast studies using NNs in other European cities. 相似文献
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This paper explores the role of distant knowledge links and policy actions for the development of biotechnology clusters. It seeks to challenge the prevailing view that the birth and early development of high technology industries are always spontaneous phenomena which are mainly based on local knowledge. Departing from the theoretical concept of regional innovation systems (RIS), a distinction between “RIS with strong potentials for high technology industries” and “RIS with weak potentials for high technology industries” will be drawn. It will be argued that in the latter case the development of biotechnology clusters is more dependent on distant knowledge sources and proactive policy efforts to create a favourable environment for high technology activities. Furthermore, it will be shown that a far-reaching transformation of the regional innovation system is crucial for catching-up processes of regions which are latecomers in high technology sectors such as biotechnology. 相似文献
16.
Michaela D. Filiou 《Proteomics. Clinical applications》2015,9(9-10):885-888
Despite major advances in infrastructure and instrumentation, proteomics-driven translational applications have not yet yielded the results that the scientific community has envisaged. In this viewpoint, the perspective of proteomics-based diagnostics in the field of clinical psychiatry is explored. The challenges that proteomics faces in the context of translational approaches are outlined and directions toward a successful clinical implementation are provided. Additional challenges that psychiatric disorders pose for clinical proteomics are highlighted and the potential of proteomics-based, blood tests for psychiatric disorders is being assessed. Proteomics offers a valuable toolkit for clinical translation that needs to be handled in a pragmatic manner and with realistic expectations. 相似文献
17.
Kleinspehn-Ammerlahn Anna; Riediger Michaela; Schmiedek Florian; von Oertzen Timo; Li Shu-Chen; Lindenberger Ulman 《Canadian Metallurgical Quarterly》2011,47(3):632
Many social interactions require the synchronization—be it automatically or intentionally—of one's own behavior with that of others. Using a dyadic drumming paradigm, the authors delineate lifespan differences in interpersonal action synchronization (IAS). Younger children, older children, younger adults, and older adults in same- and mixed-age dyads were instructed to drum in synchrony with their interaction partner at a constant, self-chosen tempo. Adult-only dyads showed the highest and children-only the lowest levels of IAS accuracy. It is important to note that children improved reliably in IAS accuracy when paired with older partners. The observed age-related differences in IAS accuracy remained reliable after statistically controlling for individual differences in the ability to synchronize to a metronome and for between-dyad differences in tempo. The authors conclude that IAS improves from middle childhood to adulthood and that adult interaction partners may facilitate its development. (PsycINFO Database Record (c) 2011 APA, all rights reserved) 相似文献
18.
Two studies investigated adult age differences in the frequency and emotional consequences of motivational conflicts (i.e., feeling that one wants to or should do something else in a given situation). Study 1 compared younger and older adults. Study 2 included a more age-heterogeneous sample ranging from 20 to 70 years. Data were obtained using diary and experience-sampling methods. Multilevel regression showed that motivational conflict was associated with lower emotional well-being. With age, the frequency of motivational conflict decreased, while emotional well-being increased. Importantly, the age-related decrease in motivational conflicts partly accounted for the age-related increase in emotional well-being. Findings were consistent across studies and robust after the authors controlled for age differences in a number of control variables including time use. The authors conclude that an age-related decrease in motivational conflicts in daily life may be among the factors underlying the positive development of emotional well-being into older adulthood. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
19.
Current technological possibilities for implementing multi-service networks include both single technology ATM or IP networks and multi-technology networks such as SONET-based or flat networks. However, regardless of the technology employed, the synthesis problem – to optimally route traffic and divide the network's transmission resources between its virtual links – remains of prime importance.In this paper, we review, compare, and classify the extensive recent literature concerning multi-service network synthesis methods. In order to do this, we propose a typology based on switching and control strategies and a general notation that reflects the layered nature of the network. Technology independent mathematical models describe the various, essentially different, approaches presently found in the literature. 相似文献
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