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.     

Ferroelastic domain structure and phase transition in single-crystalline [PbZn1/3Nb2/3O3]1-x[PbTiO3]x observed via in situ x-ray microbeam

(1-x)Pb(Zn_1/3Nb_2/3)O₃-xPbTiO₃ ((1-x)PZN-xPT in short) is one of the most important piezoelectric materials. In this work, we extensively investigated (1-x)PZN-xPT (x = 0.07–0.11) ferroelectric single crystals using in-situ synchrotron μXRD, complemented by TEM and PFM, to correlate microstructures with phase transitions. The results reveal that (i) at 25 °C, the equilibrium state of (1-x)PZN-xPT is a metastable orthorhombic phase for x = 0.07 and 0.08, while it shows coexistence of orthorhombic and tetragonal phases for x = 0.09 and x = 0.11, with all ferroelectric phases accompanied by ferroelastic domains; (ii) upon heating, the phase transformation in x = 0.07 is Orthorhombic → Monoclinic → Tetragonal → Cubic. The coexistence of ferroelectric tetragonal and paraelectric cubic phases was in-situ observed in x = 0.08 above Curie temperature (T_C), and (iii) phase transition can be explained by the evolution of the ferroelectric and ferroelastic domains. These results disclose that (1-x)PZN-xPT are in an unstable regime, which is possible factor for its anomalous dielectric response and high piezoelectric coefficient.     

On stochastic comparisons of finite mixtures for some semiparametric families of distributions

In this paper, we consider the classical finite mixture model, which is an effective tool for modeling lifetime distributions for random samples from heterogeneous populations. We discuss new results on stochastic comparison for two finite mixtures when each of them is drawn from one of the following semiparametric families, i.e., proportional hazards, accelerated lifetime and proportional reversed hazards.     

Is the List of Incomplete Open Cubes Complete?

Variations of Incomplete Open Cubes is the major project by the twentieth-century conceptual artist Sol LeWitt. In this paper we interpret the enumerative component of the project as embeddings of graphs. This formulation permits use of an algorithm to check the completeness of the list of the structures produced by the artist. Our conclusion is that the artist found the correct number of structures (that is, 122), but that his list contains a mistake in the presentation of a pair of incomplete cubes, a discovery that appears not to have been noted before.     

Large increase of Curie temperature in (110)-oriented La0.7Sr0.3MnO3 films

From the perspectives of scientific researches and practical applications, it is desirable to explore high operating temperature ferromagnetic films. The effect of biaxial strain on magnetic properties of (110)-oriented La_0.7Sr_0.3MnO₃ films was studied. High quality La_0.7Sr_0.3MnO₃ films were grown on (110)-oriented perovskite single crystal substrates using pulsed laser deposition, varying substrate-induced misfit strains from ??2.27–0.75%. A remarkable enhancement of Curie temperature has been achieved for (110)-oriented La_0.7Sr_0.3MnO₃ films clamped with small misfit strains (i.e., grown on LAST (110)). The enhanced Curie temperature of (110)-oriented La_0.7Sr_0.3MnO₃ films could be attributed to the misfit strain between the films and the underlying substrates and may have technological implication for applications at high temperature environments.