A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

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.     

Within-class multimodal classification

Multimedia Tools and Applications - In many real-world classification problems there exist multiple subclasses (or clusters) within a class; in other words, the underlying data distribution is...     

Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase

Previous in vitro analyses have shown that the human immunodeficiency virus type 1 (HIV-1) integrase uses either manganese or magnesium to assemble as a stable complex on the donor substrate and to catalyze strand transfer. We now demonstrate that subsequent to assembly, catalysis of both 3' end processing and strand transfer requires a divalent cation cofactor and that the divalent cation requirements for assembly and catalysis can be functionally distinguished based on the ability to utilize calcium and cobalt, respectively. The different divalent cation requirements manifest by these processes are exploited to uncouple assembly and catalysis, thus staging the reaction. Staged 3' end processing and strand transfer assays are then used in conjunction with exonuclease III protection analysis to investigate the effects of integrase inhibitors on each step in the reaction. Analysis of a series of related inhibitors demonstrates that these types of compounds affect assembly and not either catalytic process, therefore reconciling the apparent disparate results obtained for such inhibitors in assays using isolated preintegration complexes. These studies provide evidence for a distinct role of the divalent cation cofactor in assembly and catalysis and have implications for both the identification and characterization of integrase inhibitors.     

Possible anatomical basis of recovery of function after neonatal frontal lesions in rats.

Rats given medial frontal lesions on Postnatal Day 1 or Day 10 were trained on the Morris water task on Days 19–21 or Days 56–58. The operated groups were equally impaired at the water task on Days 19–21, but the Day 10 rats had recovered by 56 days. Dendritic arborization and spine density were analyzed in parietal layer II–III pyramidal cells. At Day 60, but not at Day 22, the Day 10 animals had more dendritic spines per unit dendritic length than did the controls or Day 1 rats. Thus, there was functional recovery rather than sparing after frontal lesions at 10 days, and the recovery was correlated with an increase in dendritic spines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Effects of H2O, CO and CO2 on the H2 Permeance and Surface Characteristics of 1 mm Thick Pd80wt%Cu Membranes

The hydrogen permeance of 1 mm-thick Pd_80wt%Cu foils was measured in the presence of equimolar mixtures of H₂ with CO, CO₂ or H₂O over the temperature and total pressure ranges of 623–1,173 K and 0.62–2.86 MPa, respectively. In all cases, permeance losses at 623 and 738 K were very modest. At higher temperatures, more significant decreases in membrane permeance were observed with the highest reduction of about 50% occurring when macroscopic carbon deposition occurred on the membrane surface during H₂–CO exposure at 908 K. The more worrisome effects of exposure to these gases, however, were the micron-scale surface defects observed at 908 and 1,038 K. Although the 1 mm thick disk membranes retained their mechanical integrity, such defects could cause catastrophic failure of ultra-thin, Pd–Cu membranes (1–5 μm thick) deposited on porous substrates.     

Operant conditioning of hippocampal theta: Dissociating reward from performance deficits.

Dopaminergic blocking agents have been known to suppress intracranial self-stimulation, but whether the suppression results from a reduction in the rewarding value of stimulation or from motor deficits has remained controversial. We have resolved this controversy by developing an operant technique minimally dependent on motor activity; rats were trained to perform a bar-holding response for 3s or to produce hippocampal theta waves for 3s when the bar was retracted. Decamethonium bromide (a muscle relaxant) reduced bar holding without affecting theta production for brain stimulation. Pimozide (a dopaminergic blocking-agent) reduced both bar holding and theta production for stimulation, though rats were still capable of making the theta response at a rate comparable to the preinjection rate. Dopaminergic blocking at low doses reduces the rewarding value of brain stimulation at the level of the lateral hypothalamus. The method described in this report has wide applicability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Case Study of an Aerosol Explosion and a Method to Determine Explosion Temperatures

A failure analysis case study is presented for a two-piece aerosol containing tetrafluoroethane, commonly referred to as Refrigerant 134a. A gentleman was preparing to recharge the air conditioning system of an automobile when the bottom exploded off the aerosol container, propelling the body of the aerosol container like a rocket, which hit the man in the eye and blinded him in that eye. The aerosol was never connected to the air conditioner, therefore backpressure from the air conditioner (AC) compressor was ruled out as a cause for the explosion. The objective of the study was to determine why the aerosol exploded. Several recently developed test methods were used, including two types of heat-to-burst tests and a puncture chamber to measure the pressure-versus-temperature behavior of aerosols. More common test methods were also used, such as water bath pressure tests, hydro pressure burst tests, pneumatic pressure burst tests, hardness measurements, weight measurements, metallography, scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), and an accident scenario recreation. A semi-empirical correlation between the hardness and weights of the container bottoms was used to determine the explosion temperature and/or pressure. This semi-empirical correlation agrees in principle with an analysis of the explosion pressures using finite-element analysis (FEA). The root cause for the explosion was determined to be a lack of strength of the bottom of the two-piece aerosol coupled with heating the aerosol to temperatures significantly above room temperature.     

Gheo-shih: an ancient pre-Columbian plaza

This paper describes the configuration and cultural context of the oldest known designed space in central America, Gheo-Shih, dating from 5,000 - 4,000 BC. This site may have been a ceremonial space, being employed in a similar fashion to ceremonial spaces of Native American cultures from the North American Great Basin. It contains physical features that set precedents and are similar to the geomantic features of later nearby Mesoamerican cultures.     

A simple SCC specimen incorporating heat transfer with a crevice or deposits

A simple stress-corrosion cracking (SCC) specimen, suitable for slow strain rate testing and incorporating heat transfer, with an artificial crevice or deposits has been designed and tested. It appears that when the solute level is above a certain value it can concentrate. The kinetics of solute accumulation and the concentration that can be induced in the specimen have been determined. Build up of solute from the ppm level in the bulk environment to the level required to cause cracking can take hours, not days or years. The limiting concentration reached is controlled by thermodynamics, specifically the available superheat. A brief review of relevant literature suggests that this experimental approach to predicting SCC has significant advantages over a modelling or measurement approach. The specimen also lends itself to a monitoring role--a modern version of the Schroeder embrittlement detector.