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.     

Nonzero repair times dependent on the failure hazard

It is common in the literature on the reliability and maintenance of repairable systems to model the repair times as instantaneous. However, this is an unreasonable assumption for some complex systems, especially those requiring a high level of reliability, and such systems may spend a significant proportion of their lifetimes under maintenance and repair. We model the ageing of such a system with alternating stochastic processes. Operational times are generated at random and may have an increasing failure rate. Repair times are generated from a random process where the repair time is related to the hazard rate at failure. This yields lengthened repair times at late stages in a system subject to an increasing failure hazard rate but also accommodates long repair times at young ages in systems with a bathtub-shaped hazard rate function. We derive analytic results for a set of special cases of the model, show how simulation and inference can be carried out, and apply our method to real data from a large car manufacturer.     

Crystallization-Directed Anisotropic Electroactuation in Selectively Solvated Olefinic Thermoplastic Elastomers: A Thermal and (Electro)Mechanical Property Study

Dielectric elastomers (DEs), a class of soft electroactive polymers that change size upon exposure to an external electric field, constitute an increasingly important class of stimuli-responsive polymers due primarily to their large actuation strains, facile and low-cost fabrication, scalability, and mechanical robustness. Unless purposefully constrained, most DEs exhibit isotropic actuation wherein size changes are the same in all actuation directions. Previous studies of DEs containing oriented, stiff fibers have demonstrated, however, that anisotropic actuation along a designated direction is more electromechanically efficient since this design eliminates energy expended in nonessential directions. To identify an alternative, supramolecular-level route to anisotropic electroactuation, we investigate the thermal and mechanical properties of novel thermoplastic elastomer gels composed of a selectively solvated olefinic block copolymer that not only microphase-separates but also crystallizes upon cooling from the solution state. While these materials possess remarkable mechanical attributes (e.g., giant strains in excess of 4000%), their ability to be strain-conditioned enables huge anisotropic actuation levels, measured to be greater than 30 from the ratio of orthogonal actuation strains. This work establishes that crystallization-induced anisotropic actuation can be achieved with these DEs.     

Light-Responsive Colloidal Crystals Engineered with DNA

A novel method for synthesizing and photopatterning colloidal crystals via light-responsive DNA is developed. These crystals are composed of 10–30 nm gold nanoparticles interconnected with azobenzene-modified DNA strands. The photoisomerization of the azobenzene molecules leads to reversible assembly and disassembly of the base-centered cubic (bcc) and face-centered cubic (fcc) crystalline nanoparticle lattices. In addition, UV light is used as a trigger to selectively remove nanoparticles on centimeter-scale thin films of colloidal crystals, allowing them to be photopatterned into preconceived shapes. The design of the azobenzene-modified linking DNA is critical and involves complementary strands, with azobenzene moieties deliberately staggered between the bases that define the complementary code. This results in a tunable wavelength-dependent melting temperature (T_m) window (4.5–15 °C) and one suitable for affecting the desired transformations. In addition to the isomeric state of the azobenzene groups, the size of the particles can be used to modulate the T_m window over which these structures are light-responsive.     

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of ¹⁷⁷Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.     

Is it possible to disregard obsolete requirements? a family of experiments in software effort estimation

Requirements Engineering - Expert judgement is a common method for software effort estimations in practice today. Estimators are often shown extra obsolete requirements together with the real ones...     

Lipidomic Analysis of Plasma from Healthy Men and Women Shows Phospholipid Class and Molecular Species Differences between Sexes

The phospholipid composition of lipoproteins is determined by the specificity of hepatic phospholipid biosynthesis. Plasma phospholipid 20:4n-6 and 22:6n-3 concentrations are higher in women than in men. We used this sex difference in a lipidomics analysis of the impact of endocrine factors on the phospholipid class and molecular species composition of fasting plasma from young men and women. Diester species predominated in all lipid classes measured. 20/54 Phosphatidylcholine (PtdCho) species were alkyl ester, 15/48 phosphatidylethanolamine (PtdEtn) species were alkyl ester, and 12/48 PtdEtn species were alkenyl ester. There were no significant differences between sexes in the proportions of alkyl PtdCho species. The proportion of alkyl ester PtdEtn species was greater in women than men, while the proportion of alkenyl ester PtdEtn species was greater in men than women. None of the phosphatidylinositol (PtdIns) or phosphatidylserine (PtdSer) molecular species contained ether-linked fatty acids. The proportion of PtdCho16:0_22:6, and the proportions of PtdEtn O-16:0_20:4 and PtdEtn O-18:2_20:4 were greater in women than men. There were no sex differences in PtdIns and PtdSer molecular species compositions. These findings show that plasma phospholipids can be modified by sex. Such differences in lipoprotein phospholipid composition could contribute to sexual dimorphism in patterns of health and disease.