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11.
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
12.
13.
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
15.
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.
Thomas Bürgi Fachri Atamny Axel Knop‐Gericke Michael Hävecker Thomas Schedel‐Niedrig Robert Schlögl Alfons Baiker 《Catalysis Letters》2000,66(3):109-112
The adsorption of ethyl pyruvate on Pt(111) has been studied by in situ XANES measurements in the presence and absence of
hydrogen. Depending on the hydrogen and ethyl pyruvate pressure, the C and O K‐edge spectra exhibit distinctly different angular
dependence. Without hydrogen ethyl pyruvate is oriented preferentially perpendicular to the surface, indicating bonding via
the O lone pairs. In the presence of hydrogen the mean orientation is more tilted towards the surface. Likely, ethyl pyruvate
also interacts with Pt via its π system under these conditions. The observed angle‐dependent shift of the energy of the π*
and σ* resonances indicates the coexistence of differently adsorbed ethyl pyruvate species. The experimental findings demonstrate
the importance of the in situ approach for unraveling the adsorption mode of ethyl pyruvate in the enantioselective hydrogenation
over cinchona‐alkaloid‐modified Pt.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
18.
Roads represent an important landscape element affecting both biotic and abiotic components. Alteration of soil properties along roads (addition of nutrients) is assumed to have a great impact on vegetation structure especially in nutrient poor ecosystems. Existing studies focus mainly on road dust. In our study we assessed the overall effects of roads upon adjacent alpine tundra vegetation and soils in Krkonoše Mts, Czech Republic. Our aims were to (1) reconstruct the road-related changes using aerial data and GPS mapping to study colonization of roadside plant species; (2) assess the road effects on physical-chemical soil properties and vegetation composition along transects; and (3) propose conservation measures to stop further damage. Changes were reconstructed from historical multispectral aerial photography (1986 to 1997), measured by GPS device (1997, 2004), and accompanied by detailed soil (1998, 2000 and 2001) and vegetation (2000 and 2004) surveys along transects. Along alkaline roads, fast and profound shifts in physical-chemical soil properties (pH increased from 3.9 up to 7.6, base saturation from 9-30% up to 100%), and species composition were recorded. The roadside vegetation doubled in area during the studied decade. Stress-tolerant tundra species were replaced by meso- to nitrophilous species and species preferring man-made habitats. The intensity of changes depended significantly on the type of road material and the position relative to the road (slope position, distance from the road). Our findings support the assumption that alkaline gravel is the main cause of changes along roads in the area, and indicate the leading role of water transport in the soil and consequent vegetation alteration. To prevent the further damage we recommended replacement of alkaline gravel by granite, even though expensive and technically complicated. Based on our recommendations, the National Park authorities started to reconstruct the trails, although recovery is expected to be slow. 相似文献
19.
Johannes Jacobi Renke Maas Michaela Arend Nada Cordasic Karl F. Hilgers 《International journal of molecular sciences》2014,15(4):5522-5535
The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model. 相似文献
20.
Michaela Schubert Christian Münch Sophie Schuurman Véronique Poulain Jaroslaw Kita Ralf Moos 《Journal of the European Ceramic Society》2018,38(2):613-619
NiMn2O4+δ thermistor thick films have been successfully deposited by the so-called Aerosol Deposition Method (ADM) at room temperature on alumina substrates, Si-wafers, as well as on special planar four-wire interdigital electrode structures for high-precision electrical characterization. The NTCR films are homogeneous, completely dense and scratch resistant. Both as-deposited and tempered, the NTCR films exhibit a cubic spinel structure. Between 25 °C and 90 °C, the NTCR film resistance behaves as it is typical for variable range hopping (VRH) with parabolic density of states. As a result of moderate film tempering, the thermistor constant B and the specific resistance at 25 °C (ρ25) decrease from 4250 K to 4020 K and 65 Ω·m to 40 Ω·m respectively, and are close to bulk values. In combination with the excellent reproducibility of the ρ25 and B values, AD processing of films appears to be a promising alternative for classical ceramic bulk processes. 相似文献