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...     

Colloidal Synthesis of Hollow Cobalt Sulfide Nanocrystals

Formation of cobalt sulfide hollow nanocrystals through a mechanism similar to the Kirkendall Effect has been investigated in detail. It is found that performing the reaction at > 120 °C leads to fast formation of a single void inside each shell, whereas at room temperature multiple voids are formed within each shell, which can be attributed to strongly temperature‐dependent diffusivities for vacancies. The void formation process is dominated by outward diffusion of cobalt cations; still, the occurrence of significant inward transport of sulfur anions can be inferred as the final voids are smaller in diameter than the original cobalt nanocrystals. Comparison of volume distributions for initial and final nanostructures indicates excess apparent volume in shells, implying significant porosity and/or a defective structure. Indirect evidence for fracture of shells during growth at lower temperatures was observed in shell‐size statistics and transmission electron microscopy images of as‐grown shells. An idealized model of the diffusional process imposes two minimal requirements on material parameters for shell growth to be obtainable within a specific synthetic system.     

Optimal space-time constellations from groups

We consider the design of space-time constellations based on group codes for fading channels with multiple transmit and receive antennas. These codes can be viewed as multiantenna extensions of phase-shift keying (PSK), in the sense that all codewords have equal energy, all are rotations of a fixed codeword, and there is a simple differential transmission rule that allows data to be sent without channel estimates at the transmitter or receiver. For coherent detection, we show that all optimal full-rank space-time group codes are unitary (each code matrix has equal-energy, orthogonal rows). This leads to a simpler code design criterion and suggests that unitary codes may play an important role in coherent as well as noncoherent communication. For any number of transmit antennas t, we then use the design criterion to characterize all full-rank unitary space-time group codes of minimum block length (also t) which have 2/sup p/ codewords. These results allow us to characterize all optimal 2/sup p/-ary unitary group codes with square code matrices. This restricted class of block codes matches the class proposed for differential modulation by Hughes (see IEEE Trans. Inform. Theory, vol.46, p.2567-78, Nov. 2000), and by Hochwald and Sweldens (see IEEE Trans. Commun., vol.48, p.2041-2052, Dec. 2000).     

Secobarbital in humans discriminating triazolam under two-response and novel-response procedures

The percentage of long-term survivors after intensive chemotherapy and the outcome of MDS patients who achieve partial remission (PR) with intensive chemotherapy (IC) are not known. Between 1981 and 1996 we treated 99 patients with de novo MDS who had high-risk MDS or progression to AML, with IC. 41 (41%) achieved CR, 16 (16%) achieved partial remission (PR), 26 (26%) had failure, and 16 (16%) died in aplasia. Eight of the patients who achieved CR were autografted, three were allografted and the remaining cases received moderate consolidation chemotherapy. After IC, the 16 PR patients fulfilled the criteria for RA in 15 cases and CMML in one case. Median PR duration was 17 months, and three PR were > 3 years (39, 50+, 82+ months). Median actuarial survival of patients who achieved PR and CR was 18 months and 20 months from the onset of IC, respectively (difference not significant). Of the 71 patients treated before 1993, with sufficient follow-up, 10 (14%) had survived > 4 years (long-term survivors). Four of them were alive in first CR after 49+ to 110+ months and probably cured, two were alive in PR after 50+ and 82+ months and four had died after 49-78 months. Long-term survivors were characterized by a significantly higher incidence of RAEB-T at diagnosis, and with normal or favourable cytogenetic findings. In patients with RAEB-T at diagnosis included before 1993, 8/23 (35%) cases who had no unfavourable karyotype had survived > 4 years. Our findings suggest that MDS patients who achieve PR with IC, and not only those who achieve CR, can benefit from this type of treatment. The percentage of long-term survivors remains low, however, and is almost restricted to patients with RAEB-T at diagnosis and no unfavourable karyotype.     

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)