24,581 research outputs found

    Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

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    The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

    Mark 3 interactive data analysis system

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    The interactive data analysis system, a major subset of the total Mark 3 very long baseline interferometry (VLBI) software system is described. The system consists of two major and a number of small programs. These programs provide for the scientific analysis of the observed values of delay and delay rate generated by the VLBI data reduction programs and product the geophysical and astrometric parameters which are among the ultimate products of VLBI. The two major programs are CALC and SOLVE. CALC generates the theoretical values of VLBI delay rate as well as partial derivatives based on apriori values of the geophysical and astronometric parameters. SOLVE is a least squares parameters estimation program which yields the geophysical and astrometric parameters using the observed values by the data processing system and theoretical values and partial derivatives provided by CALC. SOLVE is a highly interactive program in which the user selects the exact form of the recovered parameters and the data to be accepted into the solution

    Risk evaluations and condom use decisions of homeless youth: a multi-level qualitative investigation.

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    BackgroundHomeless youth are at higher risk for sexually transmitted infections and unwanted pregnancy than non-homeless youth. However, little is known about how they evaluate risk within the context of their sexual relationships. It is important to understand homeless youths' condom use decisions in light of their sexual relationships because condom use decisions are influenced by relationship dynamics in addition to individual attitudes and event circumstances. It is also important to understand how relationship level factors, sexual event circumstances, and individual characteristics compare and intersect.MethodsTo explore these issues, we conducted semi-structured interviews with 37 homeless youth in Los Angeles County in 2011 concerning their recent sexual relationships and analyzed the data using systematic methods of team-based qualitative data analysis.ResultsWe identified themes of risk-related evaluations and decisions at the relationship/partner, event, and individual level. We also identified three different risk profiles that emerged from analyzing how different levels of risk intersected across individual respondents. The three profiles included 1) Risk Takers, who consistently engage in risk and have low concern about consequences of risk behavior, 2) Risk Avoiders, who consistently show high concern about protection and consistently avoid risk, and 3) Risk Reactors, those who are inconsistent in their concerns about risk and protection and mainly take risks in reaction to relationship and event circumstances.ConclusionsInterventions targeting homeless youth should reflect multiple levels of risk behavior and evaluation in order to address the diversity of risk profiles. Relationship/partner-, event-, and individual-level factors are all important but have different levels of importance for different homeless youth. Interventions should be tailored to address the most important factor contributing to homeless youth reproductive needs

    Variable pitch fan system for NASA/Navy research and technology aircraft

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    Preliminary design of a shaft driven, variable-pitch lift fan and lift-cruise fan was conducted for a V/STOL Research and Technology Aircraft. The lift fan and lift-cruise fan employed a common rotor of 157.5 cm diameter, 1.18 pressure ratio variable-pitch fan designed to operate at a rotor-tip speed of 284 mps. Fan performance maps were prepared and detailed aerodynamic characteristics were established. Cost/weight/risk trade studies were conducted for the blade and fan case. Structural sizing was conducted for major components and weights determined for both the lift and lift-cruise fans

    Orbital control in strained ultra-thin LaNiO3_3/LaAlO3_3 superlattices

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    In pursuit of rational control of orbital polarization, we present a combined experimental and theoretical study of single unit cell superlattices of the correlated metal LaNiO3_3 and the band insulator LaAlO3_3. Polarized x-ray absorption spectra show a distinct asymmetry in the orbital response under strain. A splitting of orbital energies consistent with octahedral distortions is found for the case of compressive strain. In sharp contrast, for tensile strain, no splitting is found although a strong orbital polarization is present. Density functional theory calculations including a Hubbard U term reveal that this asymmetry is a result of the interplay of strain and confinement induces octahedral rotations and distortions and altered covalency in the bonding across the interfacial Ni-O-Al apical oxygen, leading to a charge disporportionation at the Ni sites for tensile strain.Comment: 4 pages. 5 figure

    Strain-mediated metal-insulator transition in epitaxial ultra-thin films of NdNiO3

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    We have synthesized epitaxial NdNiO3_{3} ultra-thin films in a layer-by-layer growth mode under tensile and compressive strain on SrTiO3_{3} (001) and LaAlO3_3 (001), respectively. A combination of X-ray diffraction, temperature dependent resistivity, and soft X-ray absorption spectroscopy has been applied to elucidate electronic and structural properties of the samples. In contrast to the bulk NdNiO3_{3}, the metal-insulator transition under compressive strain is found to be completely quenched, while the transition remains under the tensile strain albeit modified from the bulk behavior.Comment: 4 pages, 4 figure
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