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1.
Viktoria M. S. Kjær Loukas Ieremias Dr. Viktorija Daugvilaite Dr. Michael Lückmann Prof. Thomas M. Frimurer Prof. Trond Ulven Prof. Mette M. Rosenkilde Dr. Jon Våbenø 《ChemMedChem》2021,16(17):2623-2627
The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch. 相似文献
2.
Dr. Yahu A. Liu Dr. Qihui Jin Qiang Ding Dr. Xueshi Hao Tingting Mo Shanshan Yan Dr. Yefen Zou Dr. Zhihong Huang Xiaoyue Zhang Wenqi Gao Dr. Tom Y.-H. Wu Chun Li Dr. Badry Bursalaya Dr. Michael Di Donato Dr. You-Qing Zhang Lisa Deaton Dr. Weijun Shen Dr. Brandon Taylor Anwesh Kamireddy Dr. George Harb Dr. Jing Li Dr. Yong Jia Dr. Andrew M. Schumacher Dr. Bryan Laffitte Dr. Richard Glynne Dr. Shifeng Pan Dr. Peter McNamara Dr. Valentina Molteni Dr. Jon Loren 《ChemMedChem》2020,15(16):1562-1570
Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation. 相似文献
3.
Prediction of Power Consumption in a Mechanically Agitated Gassed Reactor in Viscous Batches 下载免费PDF全文
Volumetric mass transfer coefficient, power input, and gas holdup are key parameters in the design of mechanically agitated gas‐liquid contactors. Although the majority of industrial batches are of higher viscosity, reliable transport characteristics correlations for viscous batches are lacking in literature. These correlations are often based on the power input as the scale of energy dissipation. In order to develop reliable power input correlations, its measurements were carried out in a pilot‐plant vessel using multiple impellers of various types and diameters. Power input correlation shapes providing the best match with the comprehensive database are also expected to predict most precisely the impeller power in industrial‐scale vessels. 相似文献
4.
Martí Horts Jon Anakabe Alex Arrillaga Sebastin Espino Jordi J Bou 《Polymer International》2019,68(10):1767-1775
The thermomechanical properties of poly(lactide) (PLA) are strongly related to its semicrystalline microstructure and morphology. Thermal annealing is a strategy to improve the crystallinity of PLA. However, the different techniques and specimen types needed for each kind of characterization could lead to misleading conclusions. In this work, annealed samples of three PLA grades with different molecular weights were studied by DSC, wide angle X‐ray scattering and polarized optical microscopy (POM) and the results are related to their thermomechanical and impact properties. Special focus is put on the POM results obtained by different approaches and the suitability of each of them to be related to the thermomechanical properties. By annealing medium molecular weight PLA specimens at 140 °C an important increase of the heat distortion temperature was obtained, which was not related to the spherulite size but to the combination of high crystallinity degree together with high α/α′ crystal type ratio. However, the impact properties of annealed PLA decreased with increase in the annealing temperature according to an increment in crystallinity and in the α/α′ crystal ratio. © 2019 Society of Chemical Industry 相似文献
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7.
Ian Mabbett Jon Elvins Catherine Gowenlock Carol Glover Paul Jones Geraint Williams David Worsley 《Progress in Organic Coatings》2014
Near infrared (NIR) is becoming a popular option for rapid cure of coatings in the coil coating industry particularly where fast line speeds are required. The technology has the potential to reduce the cure time of a 20 μm polyester coating on a galvanised steel substrate from around 30 s via conventional heating methods down to <10 s under the lamps. Previous work suggested that the ideal situation in this case is to have a topcoat which is slightly transparent to NIR and an absorbing substrate to heat the coating from the substrate outwards in a two stage process which separates solvent removal from cross linking and film formation. This can be taken further by tinting the primer layer with a pigment that absorbs in the NIR region. In this study spectroscopy was used to show that a coated steel system could appear white in the visible region because of the reflectance of TiO2 but the NIR absorption could be altered by adding absorbing pigments such as carbon black. Lamp settings could be reduced by 20% to achieve equivalent cure with tinted primer systems. The potential degradation in corrosion protection afforded by carbon-black containing pigments at various loadings was assessed for model organic coatings applied to galvanised steel specimens. In situ scanning Kelvin probe studies showed that rates of corrosion-driven coating delamination by cathodic disbondment remained unchanged by pigment loadings of up to 3.5 wt%. 相似文献
8.
Natalia Remirez de Esparza Nerea Cocera Lexuri Vazquez Jon Alkorta Ibon Ocaña Jose M. Sanchez 《Journal of the American Ceramic Society》2014,97(12):3958-3966
The oxidation of highly porous ceramic matrix composites (PCMCs) based on different Tyranno® fibers has been analyzed by means of thermogravimetry and electron microscopy. Both uncoated fibers and PCMC materials exhibit parabolic kinetics between 900°C and 1250°C, these being faster for Ti‐doped than for Zr‐doped Tyranno fibers. Oxide layers in Ti‐doped fibers are porous and partially crystalline, whereas in Zr‐doped materials a significant fraction of relatively coarse β‐SiC grains is still found embedded in the amorphous silica matrix. On the other hand, the CVD‐SiC coatings exhibit higher oxidation rates from the outer surface than from the inner one, a phenomenon that has been associated not only with the more difficult access of oxygen to the inner face but also with the highly <111> textured structure of these coatings, for which very different oxidation rates have been published for the inward and outward directions. Cracking phenomena observed above 1100°C for long dwelling times do not lead to an acceleration of the oxidation process, which could be due to the simultaneous crystallization of the amorphous silica layers. 相似文献
9.
Jiang‐Ping Wu Anjan K. Saha Nizar Haddad Carl A. Busacca Jon C. Lorenz Heewon Lee Chris H. Senanayake 《Advanced Synthesis \u0026amp; Catalysis》2016,358(12):1924-1928
A simple N‐heterocyclic carbene (NHC) derived from 1‐methyl‐3‐ethylimidazolium tetrafluoroborate was found to be an efficient ligand for a range of copper‐catalyzed cross‐coupling reactions, leading to the formation of aromatic ethers and thioethers.
10.
Rajesh L. Thangapazham Thomas N. Darling Jon Meyerle 《International journal of molecular sciences》2014,15(5):8407-8427
Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue. They are primarily responsible for synthesizing collagen and glycosaminoglycans; components of extracellular matrix supporting the structural integrity of the skin. Dermal fibroblasts play a pivotal role in cutaneous wound healing and skin repair. Preclinical studies suggest wider applications of dermal fibroblasts ranging from skin based indications to non-skin tissue regeneration in tendon repair. One clinical application for autologous dermal fibroblasts has been approved by the Food and Drug Administration (FDA) while others are in preclinical development or various stages of regulatory approval. In this context, we outline the role of fibroblasts in wound healing and discuss recent advances and the current development pipeline for cellular therapies using autologous dermal fibroblasts. The microanatomic and phenotypic differences of fibroblasts occupying particular locations within the skin are reviewed, emphasizing the therapeutic relevance of attributes exhibited by subpopulations of fibroblasts. Special focus is provided to fibroblast characteristics that define regional differences in skin, including the thick and hairless skin of the palms and soles as compared to hair-bearing skin. This regional specificity and functional identity of fibroblasts provides another platform for developing regional skin applications such as the induction of hair follicles in bald scalp or alteration of the phenotype of stump skin in amputees to better support their prosthetic devices. 相似文献