The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Solution Structure and Dynamics of the I214V Mutant of the Rabbit Prion Protein

Background: The conformational conversion of the host-derived cellular prion protein (PrP C) into the disease-associated scrapie isoform (PrP Sc) is responsible for the pathogenesis of transmissible spongiform encephalopathies (TSEs). Various single-point mutations in PrP C s could cause structural changes and thereby distinctly influence the conformational conversion. Elucidation of the differences between the wild-type rabbit PrP C (RaPrP C) and various mutants would be of great help to understand the ability of RaPrP C to be resistant to TSE agents. Methodology/Principal Findings: We determined the solution structure of the I214V mutant of RaPrP C (91–228) and detected the backbone dynamics of its structured C-terminal domain (121–228). The I214V mutant displays a visible shift of surface charge distribution that may have a potential effect on the binding specificity and affinity with other chaperones. The number of hydrogen bonds declines dramatically. Urea-induced transition experiments reveal an obvious decrease in the conformational stability. Furthermore, the NMR dynamics analysis discloses a significant increase in the backbone flexibility on the pico- to nanosecond time scale, indicative of lower energy barrier for structural rearrangement. Conclusions/Significance: Our results suggest that both the surface charge distribution and the intrinsic backbone flexibility greatly contribute to species barriers for the transmission of TSEs, and thereby provide valuable hints fo

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Time-dependent properties of steam cured non-proprietary ultra high-performance concretes

Steam curing of ultra-high-performance concrete (UHPC) has been a common practice to accelerate its material properties development in research and field applications. The time benefits of steam curing come with additional energy demands and CO2 emission. In this research, the effect of steam curing duration on development of UHPC material properties is systematically investigated on four non-proprietary UHPC matrices and two fiber reinforced UHPCs, and fills this current knowledge gap. Investigated material properties includes compressive strength, dynamic modulus of elasticity, electrical surface resistivity and shrinkage. Empirical relationships between these material properties and the duration of steam-curing were derived and compared to available results and relationships from other researchers. In addition, the results were compared to those from regular curing conditions. These research findings might be useful for the precast industry to tailor their energy input, fuel consumption and CO2 emission to the accelerated gain of material properties of non-proprietary UHPC developed using locally available materials. The results show that after 24 h of steam curing at 90 °C the compressive strength and dynamic modulus of elasticity of developed UHPC matrices and fiber reinforced UHPCs exceed 170 MPa and 60 GPa, respectively. In addition, the electrical surface resistivity exceeds 1000 K-ohm-cm and shrinkage is less than 0.04% after 24 h of steam curing. These properties surpass the properties when compared to 28 days of regular curing

Influence of Fiber Volume Fraction and Fiber Orientation on the Uniaxial Tensile Behavior of Rebar-Reinforced Ultra-High Performance Concrete

This paper studied the influence of fiber volume fraction ( V f ), fiber orientation, and type of reinforcement bar (rebar) on the uniaxial tensile behavior of rebar-reinforced strain-hardening ultra-high performance concrete (UHPC). It was observed that the tensile strength increased with the increase in V f . When V f was kept constant at 1%, rebar-reinforced UHPC with fibers aligned with the load direction registered the highest strength and that with fibers oriented perpendicular to the load direction recorded the lowest strength. The strength of the composite with random fibers laid in between. Moreover, the strength, as well as the ductility, increased when the normal strength grade 60 rebars embedded in UHPC were replaced with high strength grade 100 rebars with all other conditions remaining unchanged. In addition, this paper discusses the potential of sudden failure of rebar-reinforced strain hardening UHPC and it is suggested that the composite attains a minimum strain of 1% at the peak stress to enable the members to have sufficient ductility

Behavior of Colloidal Nanosilica in an Ultrahigh Performance Concrete Environment Using Dynamic Light Scattering

The dispersion quality of nanosilica (NS) is an essential parameter to influence and control the material characteristics of nanosilica-enhanced concrete. In this research, the dispersion quality of colloidal nanosilica in simulated concrete environments was investigated using dynamic light scattering. A concrete environment was simulated by creating a synthetic pore solution that mimicked the ionic concentration and pH value of ultrahigh-performance concrete in the fluid state. Four colloidal nanosilica samples were used, ranging in particle sizes from 5 to 75 nm, with differing solid contents and stabilizing ions. It was found that the sodium stabilized 20 nm NS sol remains dispersed at a solid concentration of 2 wt % through a variety of pH values with the inclusion of potassium ions. Calcium ions are a major contributor to the agglomeration of NS sols and only small concentrations of calcium ions can drastically affect the dispersion quality

Enhancing Printable Concrete Thixotropy by High Shear Mixing

Digital Concrete 2018 : First Rilem International Conference on Concrete and Digital Fabrication, ZURICH, SUISSE, 10-/09/2018 - 12/09/2018Our results show that the storage elastic modulus as a function of time increases at a higher rate for the cement paste mixed at higher versus lower mixing intensiy. Hence, higher mixing appears to be enhancing thixotropy. Using calorimetry analysis we find that higher mixing decreases the setting time and enhances the peak of the heat flow. By analyzing the nanoparticles present in the suspending fluid of the cement paste, we show, in accordance with literature, that an appropriate combination of mixing energy and superplasticizer dosage promotes hydration by scratching hydrates from the surface of cement particles, stabilizing them in the suspending fluid and hence generating additional nucleation surfaces. These results open the door for the design of printing heads including high-shear micro mixers allowing for a faster liquid-to-solid transition of the printable material

High shear mixing enhances the thixotropy of concrete for digital fabrication

International audienceEach digitally fabricated concrete layer has to evolve from a fluid suspension during mixing and pumping to a cohesive material after deposition that maintains a strong interface with, and mechanical resistance to, the next deposited layer [1]. Consequently, thixotropy is very important for concrete digital fabrication as it enhances the structuration of the cement paste [2]

Effects of the expansion mechanisms on the pyrrhotite-induced deterioration of concrete foundations

Using pyrrhotite containing aggregates in concrete foundations can lead to premature deterioration visibly identifiable by extensive map cracking, expansion and deformation of the concrete foundation. The two main expansion mechanisms are: (1) aggregate expansion induced directly by the oxidation of pyrrhotite inclusions and (2) matrix expansion due to the consequent internal sulfate attack (ISA). The relative contribution of these two mechanisms of expansion were investigated in this study. Theoretical calculations based on the practical combinations of oxidation products and degrees of oxidation indicated that aggregate expansion alone may not be sufficient to cause severe deterioration of the concrete incorporating pyrrhotite-bearing aggregate. Observations and this investigation show that this mechanism leads to microcracking which initiates the deterioration process. The combination of microcracking and the release of sulfate facilitates and intensifies the local ISA. The strain derived from the ISA is substantially higher than the typical ultimate tensile strain of a typical matrix used on foundation walls, thus adding additional mechanical stress on the material, and allowing the development of the typical map cracking throughout the concrete