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.     

Apparent power-law distributions in animal movements can arise from intraspecific interactions

Lévy flights have gained prominence for analysis of animal movement. In a Lévy flight, step-lengths are drawn from a heavy-tailed distribution such as a power law (PL), and a large number of empirical demonstrations have been published. Others, however, have suggested that animal movement is ill fit by PL distributions or contend a state-switching process better explains apparent Lévy flight movement patterns. We used a mix of direct behavioural observations and GPS tracking to understand step-length patterns in females of two related butterflies. We initially found movement in one species (Euphydryas editha taylori) was best fit by a bounded PL, evidence of a Lévy flight, while the other (Euphydryas phaeton) was best fit by an exponential distribution. Subsequent analyses introduced additional candidate models and used behavioural observations to sort steps based on intraspecific interactions (interactions were rare in E. phaeton but common in E. e. taylori). These analyses showed a mixed-exponential is favoured over the bounded PL for E. e. taylori and that when step-lengths were sorted into states based on the influence of harassing conspecific males, both states were best fit by simple exponential distributions. The direct behavioural observations allowed us to infer the underlying behavioural mechanism is a state-switching process driven by intraspecific interactions rather than a Lévy flight.     

Compensation paradox: the influence of monetary rewards on user behaviour

Many e-commerce companies collect users’ personal data for marketing purposes despite privacy concerns. Information-collecting companies often offer a monetary reward to users to alleviate privacy concerns and ease the collection of personal information. This study focused on the negative effects of monetary rewards on both information privacy concerns (IPC) and information disclosure. A survey approach was used to collect data and 370 final responses were analysed using a two-way analysis of variance and a binomial logistic regression model. The results show that monetary rewards increase IPC when an information-collecting company requires sensitive information. Additional results indicate that building trust is a more effective way of collecting personal data. This study identifies how organisations can best execute information-collection activities and contributes additional insights for academia and practitioners.     

A quarter century of wine pigment discovery

The red grape berry pigments, anthocyanins, were characterized in the early 20th century, but investigations of wine pigments were stymied during that era. The question of their identity was a major challenge for wine chemists. A number of techniques showed that the pigments were polymeric in nature. Some structures were postulated by mid-century based on reactions between anthocyanins and condensed tannin, and later postulated wine pigments were observed in model reactions. Some related compounds were then observed in wine. By the end of the 20th century, the ionization of non-volatiles for mass spectrometry opened the door to these compounds. In addition, a new class of compounds was observed, the pyranoanthocyanins, a product of fermentation and aging metabolites with anthocyanins. These compounds possess the pigment stability to SO₂ and pH change that is characteristic of aged red wine. Aging experiments show a dynamic situation with shifts in the population of pigment classes over time. The very large number of diverse pigments explains why it has been so difficult to answer the century-old question of the structure of wine pigments. Our current understanding is founded on the use of mass spectral analysis using electrospray and related ionization techniques over the last 25 years. Future progress will rely on more sophisticated analysis of this very complex mixture of substances. © 2019 Society of Chemical Industry     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Role of Perceived Importance in Intergroup Contact.

Furthering G. W. Allport's (1954) contentions for optimal contact, the authors introduce a new construct: the perceived importance of contact. They propose that perceived importance is the best proximal predictor of contact's reduction of prejudice. If individuals have opportunities for contact at work or in the neighborhood, their chances to have intergroup acquaintances and friends increase. Intergroup contact among acquaintances and friends can be perceived as more or less important, which in turn determines intergroup evaluations. A 1st study shows that the new measure of perceived importance is indeed distinct from established quantity and quality indicators. The results are cross-validated in a 2nd study that also sheds light on the meaning of importance. In 3rd and 4th studies, structural equation analyses and a meta-analysis support the hypotheses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Use of weibull statistics to quantify property variability in TiAl alloys

Tensile experiments have been performed on specimens of four different investment-cast TiAl-based alloys with variations in casting conditions. The average ductilities obtained in these experiments vary between approximately 0.8 to 2.0 pct plastic strain to failure in tension. By using the three-parameter form of the Weibull relation, with the 0.2 pct offset yield strength as the minimum failure strength, the resulting variability in the data can be quantified and is found to be similar for those alloys with similar microstructural scale (grain size). Large variations in lamellar volume fraction, segregation, and phase distribution have a minor influence on property variability, compared to changes in the scale of the grain structure caused by either variations in cooling rate during casting or the addition of grain refiners.