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81.
Identification and Structure–Activity Relationship Studies of Small‐Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1 下载免费PDF全文
Dr. Dina Robaa Dr. Tobias Wagner Chiara Luise Dr. Luca Carlino Joel McMillan Dr. Ralf Flaig Prof. Dr. Roland Schüle Prof. Dr. Manfred Jung Prof. Dr. Wolfgang Sippl 《ChemMedChem》2016,11(20):2327-2338
The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small‐molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure‐ and ligand‐based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4‐aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series. 相似文献
82.
A Catalytic Nanoreactor Based on in Vivo Encapsulation of Multiple Enzymes in an Engineered Protein Nanocompartment 下载免费PDF全文
Dr. Tobias W. Giessen Prof. Dr. Pamela A. Silver 《Chembiochem : a European journal of chemical biology》2016,17(20):1931-1935
Bacterial protein compartments concentrate and sequester enzymes, thereby regulating biochemical reactions. Here, we generated a new functional nanocompartment in Escherichia coli by engineering the MS2 phage capsid protein to encapsulate multiple cargo proteins. Sequestration of multiple proteins in MS2‐based capsids was achieved by SpyTag/SpyCatcher protein fusions that covalently crosslinked with the interior surface of the capsid. Further, the functional two‐enzyme indigo biosynthetic pathway could be targeted to the engineered capsids, leading to a 60 % increase in indigo production in vivo. The enzyme‐loaded particles could be purified in their active form and showed enhanced long‐term stability in vitro (about 95 % activity after seven days) compared with free enzymes (about 5 % activity after seven days). In summary, this engineered in vivo encapsulation system provides a simple and versatile way for generating highly stable multi‐enzyme nanoreactors for in vivo and in vitro applications. 相似文献
83.
84.
Tobias Schneider Lars Wietschel Denny Schüppel Jonas Riesner Kevin Konrad Andrea Thorenz Axel Tuma Dietmar Koch 《International Journal of Applied Ceramic Technology》2022,19(6):3247-3254
Over the past 40 years, development of Ceramic Matrix Composites (CMCs) has focused mainly on the improvement of material performance and optimization of cost-efficient production routes. Recently, more fields of application have opened up for CMCs, in which environmental impacts are relevant. These impacts have barely been investigated so far but receive growing interest due to increasing awareness of the environmental consequences. Our innovative approach frames material properties in relation to environmental impacts (e.g., global warming potential in CO2 emission) by varying process parameters to balance optimum performance against environmental considerations. First, the process of wet filament winding has been investigated up to the Carbon Fiber Reinforced Plastic (CFRP) state by changing both the curing and tempering temperatures. During the production of CFRP plates, mass and energy flows were tracked in each step. Three point-bending and interlaminar shear tests have been performed on the resulting samples to identify basic mechanical properties. The environmental impacts are determined by a cradle-to-gate Life Cycle Assessment (LCA), using the software SimaPro. The resulting tradeoffs between mechanical properties and environmental impacts show nonlinear behavior, thus revealing optimum points above which improved mechanical properties are associated with significantly higher CO2 emissions. 相似文献
85.
Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat. Thermogenesis inevitably comes at a high energetic cost and brown fat, ultimately, is an energy-wasting organ. A constrained strategy that minimizes brown fat activity unless obligate will have been favored during natural selection to safeguard metabolic thriftiness. Accordingly, UCP1 is constitutively inhibited and is inherently not leaky without activation. It follows that increasing brown adipocyte number or UCP1 abundance genetically or pharmacologically does not lead to an automatic increase in thermogenesis or subsequent metabolic consequences in the absence of a plausible route of concomitant activation. Despite its apparent obviousness, this tenet is frequently ignored. Consequently, incorrect conclusions are often drawn from increased BAT or brite/beige depot mass, e.g., predicting or causally linking beneficial metabolic effects. Here, we highlight the inherently inactive nature of UCP1, with a particular emphasis on the molecular brakes and releases of UCP1 activation under physiological conditions. These controls of UCP1 activity represent potential targets of therapeutic interventions to unlock constraints and efficiently harness the energy-expending potential of brown fat to prevent and treat obesity and associated metabolic disorders. 相似文献
86.
Annika Linke Tobias Linke Reinhard Kohlus 《European Journal of Lipid Science and Technology》2020,122(8)
Microencapsulation aims to protect polyunsaturated fatty acids against oxidation by embedding oil droplets in a solid matrix. In such a system the internal (dissolved and entrapped) and external (in the environment) oxygen can be differentiated. The study aims to quantify the impact of both oxygen sources on the oxidation of microencapsulated fish oil. The impact of the solubilized oxygen in bulk fish oil is investigated by saturating the oil with nitrogen, synthetic air, and pure oxygen. Even though more dissolved oxygen results in more oxidation products, the difference between the oxidation of the nitrogen and air saturated oil is significant but low. For encapsulated fish oil powders, the internal oxygen is modified by preparing oil‐in‐water emulsions under atmospheric and inert conditions. The feed is atomized and spray dried with either nitrogen or air. Powders are stored under vacuum and in vials and the hydroperoxides and anisidine value are determined in the total‐ and encapsulated oil. The internal oxygen has a minor impact, whereas the external oxygen is the main determinant for autoxidation. Apart from oxidizing the non‐encapsulated oil, the external O2 penetrates into the particle and reacts with the encapsulated oil. Practical Applications: Comparing the contribution of the internal and external oxygen to the oxidative stability shows that the internal O2 plays a minor role and can be neglected. This means that the emulsion preparation as well as the spray drying process can be conducted under ambient conditions. An inert production is not extending the shelf life significantly as long as the external O2 determines oxidation. The focus should be on optimizing the diffusion barrier properties of the wall matrix to reduce the penetration of the external oxygen into the particle system. Alternatively, packaging solution reducing the external O2 will extend the shelf life of the microencapsulated oil. 相似文献
87.
Björn Schulz Tobias Meinert David Bierbüsse Michel Busen Nina Körtzinger Michael Stankowski Gunnar Seide 《化学,工程师,技术》2016,88(10):1501-1507
Aerogels are high‐performance materials used for space and aviation purposes. Cellulose aerogel fibers have been investigated under real space conditions for their insulation properties. The experiments were carried out in a one‐stage high‐altitude research rocket of the improved ORION type. A cuboid module with measurement cells, camera modules, and electronic devices has been developed for monitoring the insulation behavior of cellulose aerogel non‐woven samples. The thermal behavior of these samples has been analyzed and compared to cellulose cloth (cotton) and aluminum for reference. 相似文献
88.
Stephan W. Reinhold Thomas Scherl Benjamin Stölcker Tobias Bergler Ute Hoffmann Christian Weingart Miriam C. Banas Dmitrij Kollins Martin C. Kammerl Bernd Krüger Bernhard Kaess Bernhard K. Krämer Bernhard Banas 《Lipids》2013,48(2):167-175
Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection. 相似文献
89.
Holger Rhm Tobias Leonhard Michael J. Hoffmann Alexander Colsmann 《Advanced functional materials》2020,30(5)
Seemingly contradictory reports on polar domains and their origin have surrounded the controversial discussion about the ferroelectricity of the methyl ammonium lead iodide (MAPbI3) thin films that are commonly employed in perovskite solar cells. In this work, microscopic modulations of the polar domain patterns upon application of an electric poling field are correlated with macroscopic changes to the currents through the MAPbI3 layer. Piezoresponse force microscopy is used to monitor the widening, narrowing, generation or extinction of polar domains, as well as shifts of the domain walls at room temperature under an in‐plane electric poling field that is applied between two laterally organized electrodes. This poling leads to a net polarization of individual grains and the thin film itself. Macroscopically, this net polarization results in a persistent shift of the diode characteristics that is measured across the channel between the electrodes. Both the modulation of the polar domains upon electric poling and the concurrent persistent shift of the electric currents through the device are the unambiguous hallmarks of ferroelectricity, which demonstrate that MAPbI3 is a ferroelectric semiconductor. 相似文献
90.
本文论述了CO2双级系统在超市应用中各种运行工况和相应的运行特性,也论及不同负荷和运行工况下的主要原则和挑战。另外,分析了小型双级制冷系统中模拟和测量的运行结果,以帮助系统设计人员建模并避免可能存在的问题。 相似文献