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Dr. Raysa Khan Tareque Dr. Storm Hassell-Hart Dr. Tobias Krojer Dr. Anthony Bradley Dr. Srikannathasan Velupillai Dr. Romain Talon Dr. Michael Fairhead Dr. Iain J. Day Kamlesh Bala Dr. Robert Felix Dr. Paul D. Kemmitt Prof. Paul Brennan Prof. Frank von Delft Dr. Laura Díaz Sáez Prof. Kilian Huber Prof. John Spencer 《ChemMedChem》2020,15(24):2513-2520
Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified. 相似文献
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Dr. Maria L. Di Paolo Dr. Michael S. Christodoulou Dr. Alessandra M. Calogero Dr. Luca Pinzi Prof. Giulio Rastelli Prof. Daniele Passarella Prof. Graziella Cappelletti Prof. Lisa Dalla Via 《ChemMedChem》2019,14(18):1641-1652
A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub-micromolar range and a good selectivity index (Ki MAO-A/Ki MAO-B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity. 相似文献
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Hypoxia formation and breakdown were tracked during 2015 in Muskegon Lake estuary at multiple locations, and five years (2011–2015) of time-series buoy observatory data were evaluated for the effect of episodic wind-events on lake mixing. Bi-weekly water temperature and dissolved oxygen (DO) profiles at four locations revealed that hypoxia occurred at all sites and persisted for 2–3 months during summer 2015. On one date in late-summer, up to 24% of the lake’s volume was estimated to be mildly hypoxic (DO < 4 mg L?1) as defined by lake sturgeon requirements. Patterns of wind speed and water column stability in late spring indicated that high winds and low stability delayed the onset of hypoxia while in late summer low winds and high stability delayed degradation of hypoxia. Wind speeds appear to play a great role in the interannual variability of stratification and subsequent hypoxia. Water temperature and DO profiles taken before and after one mid-summer mixing event (wind speed >7.7 m s?1 for 10 h), indicated that while the wind was unable to completely mix the entire water column, it deepened the epilimnion by ~1.5 m and sheared a thin layer from the upper hypolimnion. By entraining internally loaded nutrients, such episodic wind-events may initiate and sustain algal blooms in nutrient limited surface waters. Quantifying the variable role of wind and mixing events will be key to integrating limnological processes into climate models of the future. 相似文献
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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
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Li Zhang Huiqun Yuan Sheng-Hung Chang Anthony Lam 《The International Journal of Advanced Manufacturing Technology》2020,107(3):1081-1089
With the continuous development of the Internet of Things technology and the proposal of “Made in China 2025”, the construction of IoT applicat 相似文献
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Anthony E. Bentley 《国际强度与非线性控制杂志
》1994,4(1):119-160
》1994,4(1):119-160
Two different control systems were developed using quantitative feedback theory for weld quality improvement. The first application to be discussed was designed for the resistance pinch welding process and uses electrode displacement and force as feedback parameters. A correlation between weld quality and electrode displacement is established for constant electrode force. The system is capable of producing repeatable welds of consistent quality, with wide variations in weld parameters. This is the first time feedback control has been successfully applied to pinch welding. The second example presented in this paper was developed for penetration control of the gas-tungsten-arc welding process. The feedback signal is obtained by measuring the amount of light emitted from the back side of the weld. Welds of constant penetration have been demonstrated in tests with travel speeds varying from 1.5 to 6 inches per minute and with 200 per cent changes in part thickness. 相似文献
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