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

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

Deconstructing the relationship between entrepreneurial orientation and business performance at the embryonic stage of firm growth

Studies of entrepreneurial orientation tend to examine its three most common features only (risk-taking, innovativeness, and proactiveness), merging these into a Gestalt construct of entrepreneurial orientation and then analyzing its effect on business performance. This is in contrast to Lumpkin and Dess who stressed an entrepreneurial orientation is best characterized by five dimensions which can vary independently and may not be equally valuable across performance metrics or at different stages of development. We rectify these problems by examining the independent impact of risk-taking, innovativeness, proactiveness, competitive aggressiveness, and autonomy on performance of young high-technology firms at an embryonic stage of development. Our results support the concerns of Lumpkin and Dess. Only proactiveness and innovativeness have a positive influence on business performance while risk-taking has a negative relationship. Competitive aggressiveness and autonomy appear to hold no business performance value at this stage of firm growth. From these results, we offer implications for managers in addition to guidance for future research

Effects of shear on eggs and larvae of striped bass, morone saxatilis, and white perch, M. americana

Shear stress, generated by water movement, can kill fish eggs and larvae by causing rotation or deformation. Through the use of an experimental apparatus, a series of shear (as dynes/cm2)-mortality equations for fixed time exposures were generated for striped bass and white perch eggs and larvae. Exposure of striped bass eggs to a shear level of 350 dynes/cm2 kills 36% of the eggs in 1 min; 69% in 2 min, and 88% in 4 min; exposure of larvae to 350 dynes/cm2 kills 9.3% in 1 min, 30.0% in 2 min, and 68.1% in 4 min. A shear level of 350 dynes/cm2 kills 38% of the white perch eggs in 1 min, 41% in 2 min, 89% in 5 min, 96% in 10 min, and 98% in 20 min. A shear level of 350 dynes/cm2 applied to white perch larvae destroys 38% of the larvae in 1 min, 52% in 2 min, and 75% in 4 min. Results are experimentally used in conjunction with the determination of shear levels in the Chesapeake and Delaware Canal and ship movement for the estimation of fish egg and larval mortalities in the field

On the evolution of the inner disk radius with flux in the neutron star low-mass X-ray binary Serpens X-1

We analyze the latest \emph{Suzaku} observation of the bright neutron star low-mass X-ray binary Serpens X-1 taken in 2013 October and 2014 April. The observation was taken using the burst mode and only suffered mild pile-up effects. A broad iron line is clearly detected in the X-ray spectrum. We test different models and find that the iron line is asymmetric and best interpreted by relativistic reflection. The relativistically broadened iron line is generally believed to originate from the innermost regions of the accretion disk, where strong gravity causes a series of special and general relativistic effects. The iron line profile indicates an inner radius of $\sim8$ $R_{\rm G}$, which gives an upper limit on the size of the neutron star. The asymmetric iron line has been observed in a number of previous observations, which gives several inner radius measurements at different flux states. We find that the inner radius of Serpens X-1 does not evolve significantly over the range of $L/L_{\rm Edd}\sim0.4-0.6$, and the lack of flux dependence of the inner radius implies that the accretion disk may be truncated outside the innermost stable circular orbit by the boundary layer rather than the stellar magnetic field.Comment: 8 pages, 6 figures, accepted for publication in Ap

FIRE-BGC--A Mechanistic Ecological Process Model for Simulating Fire Succession on Coniferous Forest Landscapes of the Northern Rocky Mountains

An ecological process model of vegetation dynamics mechanistically simulates long-term stand dynamics on coniferous landscapes of the Northern Rocky Mountains. This model is used to investigate and evaluate cumulative effects of various fire regimes, including prescribed burning and fire exclusion, on the vegetation and fuel complex of a simulation landscape composed of many stands. Detailed documentation of the model FIRE-BGC (a FIRE BioGeoChemical succession model) with complete discussion of all model parameters is followed with results of an application of the FIRE-BGC to a whitebark pine landscape in the Bob Marshall Wilderness Complex. Simulation results of several management scenarios are contrasted to predict the fate of whitebark pine over 200 years. Model testing reveals predictions within 10 to 30 percent of observed values