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
Laboratory tests, including compressibility, permeability, and microstructure tests, were conducted on tailings samples using custom-designed test apparatus to investigate the effect of metal contamination (Cu2+) on the hydromechanical behavior of compacted tailings. Infiltrating samples with various dry densities with distilled water or CuSO4 solution at various concentrations showed that the void ratio of compacted tailings decreased with increased dry density. An increase in the metal contaminant concentrations from 0 to 0.1 mol/L increased the compression coefficient of the tailings from 0.14 to 0.84 MPa?1 under a vertical load of 0.01 to 2.0 MPa, while the yield stress of the tailings decreased from 204.3 to 98.7 kPa, respectively. The linear relationship between permeability coefficient (k) and void ratio (e) is described by k?=???6.48?+?17.17e. Microstructure test results showed that the diffusion double layer thinned, and the surface potential decreased, indicating that the contaminant of Cu2+ enhanced the compressibility and permeability of the tailings. The microstructure test results also showed that the amount of fine-grained soil in the copper tailings was significantly less after the hydromechanical test. Therefore, the permeability and compressibility of copper tailings increased. The experimental results are in good agreement with the estimated results.
Rapid and sensitive point-of-care testing (POCT) is an extremely critical mission in practical applications, especially for rigorous military medicine, home health care, and in the third world. Here, we report a visual POCT method for adenosine triphosphate (ATP) detection based on Taylor rising in the corner of quadratic geometries between two rod surfaces. We discuss the principle of Taylor rising, demonstrating that it is significantly influenced by contact angle, surface tension, and density of the sample, which are controlled by ATP-dependent rolling circle amplification (RCA). In the presence of ATP, RCA reaction effectively suppresses Taylor-rising behavior, due to the increased contact angle, density, and decreased surface tension. Without addition of ATP, untriggered RCA reaction is favorable for Taylor rising, resulting in a significant height. With this proposed method, visual sensitive detection of ATP without the aid of other instruments is realized with only a 5 μL droplet, which has good selectivity and a low detection limit (17 nM). Importantly, this visual method provides a promising POCT tool for user-friendly molecular diagnostics. 相似文献