Flexible and Stretchable PEDOT-Embedded Hybrid Substrates for Bioengineering and Sensory Applications.

Herein, we introduce a flexible, biocompatible, robust and conductive electrospun fiber mat as a substrate for flexible and stretchable electronic devices for various biomedical applications. To impart the electrospun fiber mats with electrical conductivity, poly(3,4-ethylenedioxythiophene) (PEDOT), a conductive polymer, was interpenetrated into nitrile butadiene rubber (NBR) and poly(ethylene glycol) dimethacrylate (PEGDM) crosslinked electrospun fiber mats. The mats were fabricated with tunable fiber orientation, random and aligned, and displayed elastomeric mechanical properties and high conductivity. In addition, bending the mats caused a reversible change in their resistance. The cytotoxicity studies confirmed that the elastomeric and conductive electrospun fiber mats support cardiac cell growth, and thus are adaptable to a wide range of applications, including tissue engineering, implantable sensors and wearable bioelectronics.

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor.

Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1.

Representational difference analysis identifies specific genes in the interaction of Giardia duodenalis with the murine intestinal epithelial cell line, IEC-6.

Giardia duodenalis is a re-emerging protozoan parasite that causes diarrhoea in humans, significantly affecting the health of many people globally. To date, little is known about the genetic events underpinning the establishment of infection in host cells; however, the parasite's ventral disc, proteases and variable surface proteins (VSPs) are recognised as important pathogenic factors. In this study, representational difference analysis (RDA) was used to identify differentially expressed genes in four different Giardia isolates (WB, P-1, NF and GS/M) during the first 2h of in vitro interaction with the rat intestinal epithelial cell line, IEC-6. RDA showed that more than 40 genes were differentially expressed in each of the four Giardia isolates upon IEC-6 cells infection. Most of the up-regulated genes were common to the four isolates except for those encoding proteins possibly involved in immune evasion such as VSPs, high cysteine membrane proteins (HCMp), hypothetical proteins, and oxygen defence proteins (e.g., thioredoxin, peroxiredoxin 1). Differences in the expressed VSPs and HCMp may account for the variation in symptoms during giardiasis. Interestingly, the NF isolate solely expressed genes involved in encystation during interaction with IEC-6 (e.g., glucosamine 6-phosphate isomerase, dynamin, acid sphingomyelinase-like phosphodiesterase) suggesting that encystation signals could be different for this isolate. Common to the four isolates, transcripts for genes involved in glycolysis (e.g., glucose-6-phosphate dehydrogenase, fructose bisphosphate aldolase, enolase), attachment (γ and α1 giardins) and cysteine proteases were frequently detected. Genes involved in transcription, translation, signalling and cell cycle control were also up-regulated. This study shows that the RDA technique has selectively isolated genes involved in host-parasite interactions and complements previous microarray data. Some of the detected genes are also discussed as potential virulence factors and treatment targets in giardiasis.

Molecular epidemiologic evidence for diabetogenic effects of dioxin exposure in U.S. Air force veterans of the Vietnam war.

BACKGROUND: One of the outcomes positively associated with dioxin exposure in humans is type 2 diabetes. OBJECTIVES: This study was conducted in order to find the molecular biological evidence for the diabetogenic action of dioxin in adipose samples from Vietnam veterans. METHODS: We obtained 313 adipose tissue samples both from Vietnam veterans who were exposed to dioxin (Operation Ranch Hand) and from comparison veterans who served in Southeast Asia with no record of dioxin exposure. We conducted quantitative reverse-transcribed polymerase chain reaction studies on selected marker mRNAs from these samples. RESULTS: We found the most sensitive and reliable molecular indicator of dioxin-induced diabetes to be the ratio of mRNA of glucose transporter 4 (GLUT4) and nuclear transcription factor kappa B (NFkappaB), a marker of inflammation. This ratio showed significant correlations to serum dioxin residues and to fasting glucose among those in the Ranch Hand group and, surprisingly, even in the comparison group, who have low levels of dioxin comparable to the general public. Such a correlation in the comparison group was particularly significant among those with known risk factors such as obesity and family history of diabetes. CONCLUSIONS: These results show that the GLUT4:NFkappaB ratio is a reliable marker for the diabetogenic action of dioxin, particularly at very low exposure levels that are not much higher than those found in the general public, implying a need to address current exposure levels.