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.     

Covalent triazine framework with efficient photocatalytic activity in aqueous and solid media

Covalent triazine frameworks (CTFs) have been recently employed for visible light-driven photocatalysis due to their unique optical and electronic properties. However, the usually highly hydrophobic nature of CTFs, which originates from their overall aromatic backbone, leads to limitations of CTFs for applications in aqueous media. In this study, we aim to extend the range of the application media of CTFs and design hybrid material of a CTF and mesoporous silica (SBA-15) for efficient photocatalysis in aqueous medium. A thiophene-containing CTF was directly synthesized in mesopores of SBA-15. Due to the high surface area and the added hydrophilic properties by silica, the hybrid material demonstrated excellent adsorption of organic molecules in water. This leads not only to high photocatalytic performance of the hybrid material for the degradation of organic dyes in water, but also for efficient photocatalysis in solvent-free and solid state. Furthermore, the reusability, stability and easy recovery of the hybrid material offers promising metal-free heterogeneous photocatalyst for broader applications in different reaction media.     

Milk from cows fed a diet with a high forage:concentrate ratio improves inflammatory state,oxidative stress,and mitochondrial function in rats

Excessive energy intake may evoke complex biochemical processes characterized by inflammation, oxidative stress, and impairment of mitochondrial function that represent the main factors underlying noncommunicable diseases. Because cow milk is widely used for human nutrition and in food industry processing, the nutritional quality of milk is of special interest with respect to human health. In our study, we analyzed milk produced by dairy cows fed a diet characterized by a high forage:concentrate ratio (high forage milk, HFM). In view of the low n-6:n-3 ratio and high content of conjugated linoleic acid of HFM, we studied the effects of this milk on lipid metabolism, inflammation, mitochondrial function, and oxidative stress in a rat model. To this end, we supplemented for 4 wk the diet of male Wistar rats with HFM and with an isocaloric amount (82 kJ, 22 mL/d) of milk obtained from cows fed a diet with low forage:concentrate ratio, and analyzed the metabolic parameters of the animals. Our results indicate that HFM may positively affect lipid metabolism, leptin:adiponectin ratio, inflammation, mitochondrial function, and oxidative stress, providing the first evidence of the beneficial effects of HFM on rat metabolism.     

The Role of Excitation Photons Energy in the Photoinduced Carrier Dynamics in InGaAs/InAlAs Superlattice Heterostructures

Technical Physics Letters - The influence of excitation photons energy on the relaxation times of photoexcited carriers is studied. The involved relaxation mechanisms are evaluated and the...     

Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics and Analogues

Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A₁, C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A₁- and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A₁-ring phenol and H-ring C-4’ hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates.     

Perfluorocarbons in Chemical Biology

Perfluorocarbons, saturated carbon chains in which all the hydrogen atoms are replaced with fluorine, form a separate phase from both organic and aqueous solutions. Though perfluorinated compounds are not found in living systems, they can be used to modify biomolecules to confer orthogonal behavior within natural systems, such as improved stability, engineered assembly, and cell-permeability. Perfluorinated groups also provide handles for purification, mass spectrometry, and ¹⁹F NMR studies in complex environments. Herein, we describe how the unique properties of perfluorocarbons have been employed to understand and manipulate biological systems.     

Influence of the Chemical Composition and Local Atomic Packing of Nanostructured MoSx and MoSex Solid Lubricant Coatings on Their Tribological Properties under Complicated Conditions

Technical Physics Letters - We present the results of a comparative investigation of the friction and wear characteristics of MoSx and MoSex coatings in an oxidizing medium (argon–air...