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.     

Procedures for analysis of strain transfer in the acetabular region in vitro

The failure of acetabular cups via loosening, migration or fracture is partially related to the stress distribution existing in the acetabular region. The complexity of the investigation of these stresses demands the application of a variety of model testing techniques involving combined embedded strain gauging, finite element analysis, transmission and reflective photoelasticity and crack propagation studies. The application of these procedures are described and the difficulties of obtaining representative loadings and restraints are commented upon.     

Correlation of vibrational intensity with fluorescence lifetimes in π conjugated polymers

A series of novel pi (π) conjugated polymers, originating from the archetypical Polyphenylene vinylene, in which the phenyl units are successively replaced by the larger naphthyl and anthryl acene units, were previously found to have a well-defined relationship between their relative fluorescence yields and their vibrational characteristics, as determined by Raman spectroscopy. In this study the Strickler-Berg equation is used to probe the influence of continual substitution of higher order acene units into the conjugated backbone in terms of the variation of the radiative and non-radiative rates. The deconvolution of the radiative and non-radiative rates enables the correlation of the reduction of the Raman intensity and concomitant increase in the fluorescence yield with the reduction of the non-radiative rate. This confirms that the reduction of the non-radiative rate is the dominant process introduced by the vibrational confinement originating from systematic substitution of higher order acene units into the polymer backbone.     

Carbohydrate type and amount alter intravascular processing and catabolism of plasma lipoproteins in guinea pigs

To test the effects of exchanging dietary complex and simple carbohydrate for fat calories on lipoprotein metabolism, guinea pigs were fed two different fat/carbohydrate ratios: 2.5∶58% (w/w) or 25∶29% (w/w) with either sucrose or starch as the carbohydrate source. Animals fed high-fat had higher plasma low-density lipoprotein (LDL) and hepatic cholesterol concentrations than animals fed low-fat diets (P<0.01). The cholesteryl ester content per particle was higher, and the number of triacylglycerol (TAG) molecules was lower in very low density lipoprotein (VLDL) and LDL from animals fed high-fat diets. Intake of high-fat/sucrose resulted in higher plasma LDL concentrations than intake of high-fat/starch, and animals fed low-fat/starch had the highest plasma TAG concentrations associated with VLDL particles containing more TAG molecules, as well as a TAG-enriched LDL. The activity of plasma lecithin cholesteryl:acyl transferase (LCAT) was highest in animals fed high-fat/sucrose, and heart lipoprotein lipase (LPL) activity was higher in animals fed high-fat diets. Hepatic apoprotein B/E (apo B/E) receptor number (B_max) was increased 21% with low-fat diets (P<0.01). These results suggest that the hypercholesterolemia induced by high-fat and by sucrose intake are associated with a higher plasma LCAT activity which results in a cholesteryl ester-enriched VLDL which, by the action of LPL, might be more readily converted to LDL through the delipidation cascade leading to downregulation of hepatic apo B/E receptors. The hypertriglyceridemia associated with low-fat intake may result from increased production of VLDL TAG, which would explain the increased TAG content and the higher TAG/CE ratio of VLDL from animals fed the low-fat/starch diet.     

Evaluation of diamond films by nuclear magnetic resonance and Raman spectroscopy

The quality of chemically vapor deposited diamond films was assessed in terms of sp²/sp³ content as determined by solid-state nuclear magnetic resonance (NMR) and Raman spectroscopy. While the results of the two techniques are in qualitative agreement, only the NMR spectra yield quantitative values for the sp²/sp³ ratio. Only sp³ carbon was observed in the NMR spectra of very high quality hot-filament, microwave plasma, and d.c. arc-jet chemically vapor deposited films. As expected, Raman spectroscopy is extremely sensitive to sp² bonded carbon, identifying small amounts below the detection limit of the NMR spectrometer. Comparison of the two techniques, however, indicates that Raman spectroscopy may be so sensitive to sp² bonded carbon that sp³ bonded carbon in films containing as much as 90% sp³ bonded material may remain undetected. NMR linewidths indicate that the sp³ carbon in such material shows more disorder than that found in high-quality polycrystalline films.     

It's the Thought that Counts: The Mediating Effects of Information Processing in Virtual Team Decision Making

Abstract

Previous research shows that although collaboration technology can improve the exchange of information during team decision making, one of the challenges is that this better discussion often does not lead to better decisions. In this paper, we investigate the impact of individual information processing on team decision making. We investigated the effects of two types of collaboration technology when participants were either the member of a team majority or a team minority. There was little impact due to the majority/minority, but the use of collaboration technology that required users to categorize the comments they received from others resulted in increased information processing, which in turn led to better decisions and more satisfied participants.     

Precarious employment, working hours, work-life conflict and health in hotel work

Precarious or temporary work is associated with adverse outcomes including low control over working hours, work-life conflict and stress. The rise in precarious employment is most marked in the service sector but little research has been done on its health effects in this sector. This study compares permanent and temporary workers in the hotel industry, where working hours are highly variable. Survey data from 150 workers from eight 3-Star hotels in urban and regional areas around Sydney were analyzed. Forty-five per cent were male and 52 per cent were female. Fifty four per cent were permanent full-time and 46 per cent were temporary workers. The effects of employment status on perceived job security, control over working hours, and work-life conflict are investigated using PLS-Graph 3.0. The effects of control over working hours, on work-life conflict and subsequent health outcomes are also explored. Temporary workers perceived themselves as less in control of their working hours, than permanent workers (β = .27). However, they also reported lower levels of work intensity (β = .25) and working hours (β = .38). The effects of low hours control (β = .20), work intensity (β = .29), and excessive hours (β = .39) on work-life conflict (r² = .50), and subsequent health effects (r² = .30), are illustrated in the final structural equation model.     

Correlations between flaw tolerance and reliability in zirconia

Interrelations between flaw tolerance and reliability in Y-TZP, Ce-TZP and Mg-PSZ ceramics are investigated. Indentation-strength tests indicate an enhanced flaw tolerance with increasing R-curve behaviour from tetragonal martensite transformation. The Weibull modulus of unindented specimens increases with the enhanced tolerance. However, even the most tolerant zirconias show persistent scatter in strength, implying that variability in material microstructure may be as important a factor in reliability evaluation in these materials as variability in flaw size.     

Cell morphology and focal adhesion location alters internal cell stress

Extracellular mechanical cues have been shown to have a profound effect on osteogenic cell behaviour. However, it is not known precisely how these cues alter intracellular mechanics to initiate changes in cell behaviour. In this study, a combination of in vitro culture of MC3T3-E1 cells and finite-element modelling was used to investigate the effects of passive differences in substrate stiffness on intracellular mechanics. Cells on collagen-based substrates were classified based on the presence of cell processes and the dimensions of various cellular features were quantified. Focal adhesion (FA) density was quantified from immunohistochemical staining, while cell and substrate stiffnesses were measured using a live-cell atomic force microscope. Computational models of cell morphologies were developed using an applied contraction of the cell body to simulate active cell contraction. The results showed that FA density is directly related to cell morphology, while the effect of substrate stiffness on internal cell tension was modulated by both cell morphology and FA density, as investigated by varying the number of adhesion sites present in each morphological model. We propose that the cells desire to achieve a homeostatic stress state may play a role in osteogenic cell differentiation in response to extracellular mechanical cues.