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排序方式： 共有125条查询结果，搜索用时 31 毫秒
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Dr. Michael Morgen Raphael R. Steimbach Dr. Magalie Géraldy Lars Hellweg Dr. Peter Sehr Dr. Johannes Ridinger Dr. Olaf Witt Dr. Ina Oehme Dr. Corey J. Herbst-Gervasoni Dr. Jeremy D. Osko Dr. Nicholas J. Porter Dr. David W. Christianson Dr. Nikolas Gunkel Dr. Aubry K. Miller 《ChemMedChem》2020,15(13):1163-1174
We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors. 相似文献
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Jonah J. Klowss Alexander P. Browning Ryan J. Murphy Elliot J. Carr Michael J. Plank Gency Gunasingh Nikolas K. Haass Matthew J. Simpson 《Journal of the Royal Society Interface》2022,19(189)
In vitro tumour spheroids have been used to study avascular tumour growth and drug design for over 50 years. Tumour spheroids exhibit heterogeneity within the growing population that is thought to be related to spatial and temporal differences in nutrient availability. The recent development of real-time fluorescent cell cycle imaging allows us to identify the position and cell cycle status of individual cells within the growing spheroid, giving rise to the notion of a four-dimensional (4D) tumour spheroid. We develop the first stochastic individual-based model (IBM) of a 4D tumour spheroid and show that IBM simulation data compares well with experimental data using a primary human melanoma cell line. The IBM provides quantitative information about nutrient availability within the spheroid, which is important because it is difficult to measure these data experimentally. 相似文献
55.
Peter Nguyen Kyle Hess Larissa Smulders Dat Le Carolina Briseno Christina M. Chavez Nikolas Nikolaidis 《International journal of molecular sciences》2020,21(24)
Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one of these proteins that function in a wide range of cellular processes, including apoptosis, protein refolding, and degradation, as well as tumorigenesis. However, the origin of BAG-1 proteins and their evolution between and within species are mostly uncharacterized. This report investigated the macro- and micro-evolution of BAG-1 using orthologous sequences and single nucleotide polymorphisms (SNPs) to elucidate the evolution and understand how natural variation affects the cellular stress response. We first collected and analyzed several BAG-1 sequences across animals, plants, and fungi; mapped intron positions and phases; reconstructed phylogeny; and analyzed protein characteristics. These data indicated that BAG-1 originated before the animals, plants, and fungi split, yet most extant fungal species have lost BAG-1. Furthermore, although BAG-1’s structure has remained relatively conserved, kingdom-specific conserved differences exist at sites of known function, suggesting functional specialization within each kingdom. We then analyzed SNPs from the 1000 genomes database to determine the evolutionary patterns within humans. These analyses revealed that the SNP density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BAG domain region, which is an indication of positive selection. To further explore this notion, we performed several biochemical assays and found that only one out of five mutations tested altered the major co-chaperone properties of BAG-1. These data collectively suggest that although the co-chaperone functions of BAG-1 are highly conserved and can probably tolerate several radical mutations, BAG-1 might have acquired specialized and potentially unexplored functions during the evolutionary process. 相似文献
56.
Media K. Ismail Dr. Zahra Khan Marium Rana Dr. Sarah L. Horswell Dr. Louise Male Dr. Huy V. Nguyen Dr. Alessio Perotti Dr. Isolda Romero-Canelón Edward A. Wilkinson Dr. Nikolas J. Hodges Prof. James H. R. Tucker 《Chembiochem : a European journal of chemical biology》2020,21(17):2487-2494
Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1 -(S,Rp), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1 -(S,Rp), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic. On the other hand, methylated derivatives of 1 -(S,Rp) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1 -(S,Rp) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity. 相似文献
57.
The procedure for the engineering of products and production systems in manufacturing companies is often distributed over several organisational units. The different units involved in these procedures use their respective methods and tools, resulting in silo-like and distributed information and data sources for engineering. In this paper, the open platform amePLM is introduced. This platform is based on a semantic data model. The ontology as explicitly formulated data model allows an integrated view on data and information available in the systems used along the product lifecycle, and the automatic provision of suitable information to the user. Furthermore, this open approach allows the linking of the solution to existing engineering software systems in the sense of a continuous flow of information. 相似文献
58.
Investigation of thermochemical conversion of biomass in supercritical water using a batch reactor 总被引：1，自引：0，他引：1
This study focused on gasification of biomass and a biomass model compound. Data are presented that show the presence of supercritical water enhances gasification efficiency, as it participates as both a solvent and a reactant. It is established that biomass gasification efficiencies are in the same range for all types of biomass. The thermodynamic changes of state are functions of elemental composition, not biomass species. The oxidation state of carbon atom of biomass is a key variable in determining the changes in enthalpy during both conventional combustion and supercritical water gasification. The oxidation state of the feed (together with the reaction conditions that influence the degree to which water participates as a reactant) also determines the vapor product composition.Decomposition reactions to vapor products are rapid and complete at high temperature (?550 °C), catalytic mediation is not required. Temperature and residence time are important operating parameters for SCW gasification. Less important are the pressure of gasification (in the range of 40-67 MPa) and the presence of catalyst. The vapor yield, gas composition, the carbon and hydrogen balance of SCW gasification are functions of gasification temperature, residence time and biomass load (concentration). 相似文献
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The application of hot cathode ionisation gauges in vacuum deposition processes (PVD, CVD) is critical regarding durability of the sensors, due to the inherent risk of contamination and discharges. Unstable calibration after relatively short periods of operation is an often reported problem, which arises from contamination with film forming substances contained in the residual gas. Furthermore, contamination often lead to early gauge drop outs and consequently to unsatisfyingly short life cycles of the gauges. Research was conducted to obtain improved solutions for prevention of gauge contamination on the one side, as well as optimised sensor designs for improved robustness and insensitivity against contaminants on the other side. This contribution discusses approaches for the desired improvements by evaluating the effectiveness of system-based methods to reduce the exposure of the sensor to contaminations, by indicating interactions between those system-based means and gauges, and by indicating options for improving gauge durability. 相似文献