A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A(1) adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.     

Nestedness patterns of container-dwelling mosquitoes: effects of larval habitat within variable terrestrial matrices

Distributions of mosquito larvae likely are a consequence of multiple factors, although two commonly studied factors (quality of the larval environment and the terrestrial matrix in which these habitats reside) have rarely and simultaneously been varied in the field to understand distributions of larvae. We monitored aquatic containers of two leaf detritus levels within a forest, prairie, and industrial habitat across five months to understand the temporal and spatial colonization of aquatic invertebrates in Northcentral Illinois, USA. Data were collected monthly on mosquito populations and the composition of other invertebrates colonizing containers. Overall, six species of mosquitoes colonized containers, with Culex restuans and Aedes triseriatus having the highest relative abundances. There were strong seasonal abundance patterns for these two mosquito species, with the dominant species changing over time in the forest habitat. The responses of other mosquito taxa were more variable, with abundances reflective of either the terrestrial matrix or larval habitat quality. High detritus containers supported the highest abundances of most species encountered, regardless of habitat. Non-mosquito taxa were less common numerically, but analyses suggested that some taxa, such as syrphid larvae, often co-occurred with mosquitoes. Nested subset analysis indicated communities were strongly nested, and that both habitat type and detritus level were important in explaining nested patterns of aquatic invertebrates. Our data show that both the larval habitat and the surrounding terrestrial matrix shape patterns of container mosquitoes, and that other container invertebrates vary in similar ways as mosquitoes. Handling editor: K. Martens     

Zn-binding AZUL domain of human ubiquitin protein ligase Ube3A

Ube3A (also referred to as E6AP for E6 Associated Protein) is a E3 ubiquitin-protein ligase implicated in the development of Angelman syndrome by controlling degradation of synaptic protein Arc and oncogenic papilloma virus infection by controlling degradation of p53. This article describe the solution NMR structure of the conserved N-terminal domain of human Ube3A (residues 24-87) that contains two residues (Cys44 and Arg62) found to be mutated in patients with Angelman syndrome. The structure of this domain adopts a novel Zn-binding fold we called AZUL (Amino-terminal Zn-finger of Ube3a Ligase). The AZUL domain has a helix-loop-helix architecture with a Zn ion coordinated by four Cys residues arranged in Cys-X(4)-Cys-X(4)-Cys-X(28)-Cys motif. Three of the Zn-bound residues are located in a 23-residue long and well structured loop that connects two α-helicies.     

Activation of promoter activity of the catalytic subunit of γ-glutamylcysteine ligase (GCL) in brain endothelial cells by insulin requires antioxidant response element 4 and altered glycemic status: implication for GCL expression and GSH synthesis

Our recent finding that insulin increased the expression of the glutamate-cysteine ligase catalytic subunit (GCLc) with coincident increases in GCL activity and cellular glutathione (GSH) in human brain microvascular endothelial cells (IHECs) suggests a role for insulin in vascular GSH maintenance. Here, using IHECs stably transfected with promoter-luciferase reporter vectors, we found that insulin increased GCLc promoter activity, which required a prerequisite increase or decrease in medium glucose. An intact antioxidant response element-4 was essential for promoter activation, which was attenuated by inhibitors of PI3-kinase/Akt/mTOR signaling. Interestingly, only under low-glucose conditions did promoter activation correlate with increased GCLc expression and GSH synthesis. Low tert-butylhydroperoxide (tBH) concentrations similarly mediated promoter activation, but the maximal activation dose was decreased 10-fold by insulin. Insulin-tBH coadministration abrogated the low or high glucose requirement for promoter activation, suggesting possible ROS involvement. ROS production was elevated at low glucose without or with insulin; however, GSH increases were not inhibited by tempol, suggesting that ROS did not achieve the threshold for driving GCLc promoter activation and de novo GSH synthesis. The minor effect of pyruvate also ruled out a major role for hypoglycemia (± insulin)-induced metabolic stress on GSH induction under these conditions.     

Mode of action investigation for the antibacterial cationic anthraquinone analogs

Reported previously by our group, we have developed a novel class of antibacterial cationic anthraquinone analogs with superb potency (MIC <1μg/mL) against Gram positive (G+) pathogens including Methicillin-resistant Staphylococcus aureus (MRSA). However, most of these compounds only manifest modest antibacterial activity against Gram negative (G-) bacteria. Further investigation on the antibacterial mode of action using fluorogenic dyes reveals that these compounds exert two different modes of action that account for the difference in their antibacterial profile. It was found that most of the compounds exert their antibacterial activity by disrupting the redox processes of bacteria. At high concentration, these compounds can also act as membrane disrupting agents. This information can help to design new therapeutics against various bacteria.     

An artifacts removal post-processing for epiphyseal region-of-interest (EROI) localization in automated bone age assessment (BAA)

Background

Guidewire (GW) size and stenosis dimensions are the two major factors affecting the translesional pressure drop. Studying the combined effect of these parameters on the mean pressure drop (Δp) across the stenosis is of high practical importance.

Methods

In this study, time averaged mass and momentum conservation equations are solved analytically to obtain pressure drop-flow, Δp-Q, curves for three different percentage area blockages corresponding to moderate (64%), intermediate (80%), and severe (90%) stenoses. Stenosis is considered to be axisymmetric consisting of three different sections namely converging, throat, and diverging regions. Analytical expressions for pressure drop are obtained for each of these regions separately. Using this approach, effects of lesion length and GW insertion on the mean translesional pressure drop and its component (loss due to momentum change and viscous loss) are analyzed.

Results and Conclusion

It is observed that for a given percent area stenosis (AS), increase in the throat length only increases the viscous loss. However, increase in the severity of stenosis and GW insertion increase both loss due to momentum change and viscous loss. GW insertion has greater contribution to the rise in viscous loss (increase by 2.14 and 2.72 times for 64% and 90% AS, respectively) than loss due to momentum change (1.34% increase for 64% AS and 25% decrease for 90% AS). It also alters the hyperemic pressure drop in moderate (48% increase) to intermediate (30% increase) stenoses significantly. However, in severe stenoses GW insertion has a negligible effect (0.5% increase) on hyperemic translesional pressure drop. It is also observed that pressure drop in a severe stenosis is less sensitive to lesion length variation (4% and 14% increase in Δp for without and with GW, respectively) as compared to intermediate (10% and 30% increase in Δp for without and with GW, respectively) and moderate stenoses (22% and 48% increase in Δp for without and with GW, respectively). Based on the contribution of pressure drop components to the total translesional pressure drop, it is found that viscous losses are dominant in moderate stenoses, while in severe stenoses losses due to momentum changes are significant. It is also shown that this simple analytical solution can provide valuable information regarding interpretation of coronary diagnostic parameters such as fractional flow reserve (FFR).