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1.
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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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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KC Kocis PJ Radell WI Sternberger JE Benson RJ Traystman DG Nichols 《Canadian Metallurgical Quarterly》1997,83(5):1654-1659
Clinically, a noninvasive measure of diaphragm function is needed. The purpose of this study is to determine whether ultrasonography can be used to 1) quantify diaphragm function and 2) identify fatigue in a piglet model. Five piglets were anesthetized with pentobarbital sodium and halothane and studied during the following conditions: 1) baseline (spontaneous breathing); 2) baseline + CO2 [inhaled CO2 to increase arterial PCO2 to 50-60 Torr (6.6-8 kPa)]; 3) fatigue + CO2 (fatigue induced with 30 min of phrenic nerve pacing); and 4) recovery + CO2 (recovery after 1 h of mechanical ventilation). Ultrasound measurements of the posterior diaphragm were made (inspiratory mean velocity) in the transverse plane. Images were obtained from the midline, just inferior to the xiphoid process, and perpendicular to the abdomen. M-mode measures were made of the right posterior hemidiaphragm in the plane just lateral to the inferior vena cava. Abdominal and esophageal pressures were measured and transdiaphragmatic pressure (Pdi) was calculated during spontaneous (Sp) and paced (Pace) breaths. Arterial blood gases were also measured. Pdi(Sp) and Pdi(Pace) during baseline + CO2 were 8 +/- 0.7 and 49 +/- 11 cmH2O, respectively, and decreased to 6 +/- 1.0 and 27 +/- 7 cmH2O, respectively, during fatigue + CO2. Mean inspiratory velocity also decreased from 13 +/- 2 to 8 +/- 1 cm/s during these conditions. All variables returned to baseline during recovery + CO2. Ultrasonography can be used to quantify diaphragm function and identify piglet diaphragm fatigue. 相似文献
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Nabesna Glacier is one of the longest land-terminus mountain glaciers in North America. However, its flow has never been studied. We derived detailed motion patterns of Nabesna Glacier in winter and spring 1994–1996 from the synthetic aperture radar (SAR) images acquired by the European Remote Sensing satellites (ERS-1 and ERS-2) using interferometric SAR (InSAR) techniques. Special effort was made to assess the accuracy of the motion estimates, and remove data points with high uncertainty from the motion profiles, enabling us to obtain reliable glacier flow patterns along the highly curved main course of Nabesna Glacier. The results, covering 80 km of the 87 km main course of the glacier, were used to delineate four distinctive sections in terms of spatial and temporal variability of the glacier speed: (1) the upper section where glacier flow was apparently random both temporally and spatially presumably due to development of crevasses; (2) the upper-middle section with relatively steady flow around 0.27 to 0.4 m/day; (3) the middle section with a stable pattern of acceleration from 0.27–0.3 m/day to the maximum about 0.67–0.73 m/day, followed by a general deceleration to 0.17–0.33 m/day before reaching (4) the lower section where the glacier motion was generally slow yet highly variable although uncertainty in the estimation is high. Occurrence of the flow maximum, as well as many local maxima and minima at consistent locations over different periods suggests that the valley geometry affect the overall flow pattern. On top of this general trend, many small-scale temporal/spatial variations in the glacier flow patterns were observed along the glacier, especially in the lower sections. On average, the flow speeds were in the range of 0.3 to 0.7 m/day; however this lacks any measurements of summer flow speeds which are expected to be significantly higher. 相似文献
7.
The ability to accurately and reliably predict whether an older adult will commit suicide has eluded clinicians and researchers. A random national sample of psychologists who work with older adults was surveyed regarding their perception of 36 risk factors for completed suicide and indirect self-destructive behavior in older adults. This study produced a profile of psychologists' assessment and treatment practices when working with suicidal older adults. Determining what psychologists consider to be the most salient risk factors for completed suicide is important in identifying a minimum standard that clinicians should follow when assessing older adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
8.
Product optimization involves selecting design, manufacturing, and support attributes that can produce the best system. Producibility or manufacturability is the term often used to describe the relative ease of manufacturing a product. In complex systems, productibility optimization is a very difficult process, particularly when the values of many attributes are restricted by constraints. One challenge is to develop more universal producibility metrics for the conceptual design phase when design information is limited and drawings are nondimensional. This paper develops a new method for producibility optimization in conceptual design based on a combination of both decision theoretic and expert system techniques. Decision theoretic techniques provide the means to model the design for producibility problem in a manner that can deal with risk, uncertainty, and user (or corporate) preferences, and can effectively integrate diverse factors to provide a measure of the overall worth of a design. The particular decision theoretic approach employed is based on multi-attribute utility theory. An illustrative example of the methodology is applied to the conceptual design of a structural composite part. 相似文献
9.
Mazzocco Michèle M. M.; Freund Lisa S.; Baumgardner Thomas L.; Forman Lisa; Reiss Allan L. 《Canadian Metallurgical Quarterly》1995,9(4):470
An extensive evaluation was conducted with 16-yr-old monozygotic twins concordant for the fragile X full mutation but discordant for mental retardation. The clearly affected twin had an IQ score of 47; 77% of her neuropsychological z scores were at least 2 SDs below average. Her sister had an IQ score of 105 and average neuropsychological performance. However, each girl demonstrated relative verbal strengths and visual-spatial weaknesses. Their parents rated each girl as having significant problems with attention, conduct, anxiety-withdrawal, and hyperactivity. The girls did not rate themselves as having significant anxiety. These findings are consistent with group data on females with fragile X and demonstrate the wide range of effects associated with the fragile X full mutation. This case report implicates the importance of a psychosocial phenotype of fragile X independent of cognitive ability level. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
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Four experiments examined 10-mo-old infants' causal event perception. Exp 1 replicated previous studies except that the specific objects used as agent and recipient varied from trial to trial. Under these conditions infants did not process the causality. Instead they keyed on specific temporal and spatial differences among the events. Exp 2 showed that infants notice a change in the particular agent performing either a causal or noncausal action. Exp 3 showed that infants do not notice a change in the type of action done to a particular recipient. Exp 4 demonstrated that infants do not pay attention to the object used as a recipient. As a whole, the results indicate that 10-mo-old infants perceive the causality of simple events by associating a specific agent with the causal action. These results provide more support for an information-processing view than for the view that infants have a causal module. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献