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

Remote Access and Computerized User Control of Robotic Micromanipulators

Nano- and micromanipulators are critical research tools in numerous fields including micro-manufacturing and disease study. Despite their importance, nano- and micromanipulation systems remain inaccessible to many groups due to price and lack of portability. An intuitive and remotely accessible manipulation system helps mitigate this access problem. Previously, optimal control hardware for single-probe manipulation and the effect of latency on user performance were not well understood. Remote access demands full computerization; graphical user interfaces with networking capabilities were developed to fulfill this requirement and allow the use of numerous hardware controllers. Virtual environments were created to simulate the use of a manipulator with full parametric control and measurement capabilities. Users completed simulated tasks with each device and were surveyed about their perceptions. User performance with a commercial manipulator controller was exceeded by performance with both a computer mouse and pen tablet. Latency was imposed within the virtual environment to study it’s effects and establish guidelines as to which latency ranges are acceptable for long-range remote manipulation. User performance began to degrade noticeably at 100 ms and severely at 400 ms and performance with the mouse degraded the least as latency increased. A computer vision system for analyzing carbon nanotube arrays was developed so the computation time could be compared to acceptable system latency. The system characterizes the arrays to a high degree of accuracy and most of the measurement types of obtainable fast enough for real-time analysis

Product selection for a startup animal health company

Master of AgribusinessDepartment of Agricultural EconomicsVincent Amanor-BoaduMost corporations seem geared to buy assets, not sell them. Estimates suggest corporations acquire three businesses for every one they divest (Mankins 2008). A corporation with a disciplined approach to divestiture seems more likely to sharpen strategic focus and deliver value to shareholders. This thesis defines and explores the concept of an orphan product as an opportunity for divestiture from a parent company and subsequent acquisition for a startup company. Orphan product is defined by reviewing literature and selecting the following criteria for a given product; the product has a lack of marketing support/focus, the product is not considered core to the parent company, product sales trend over a 5-year time frame is decreasing, cash flows are uncertain, market growth for the category the product competes in is smaller than the industry average, the product life cycle position is mature, and portfolio synergy is low due to the parent company having other products that deliver similar benefits. A scorecard is developed and used to score orphan characteristics of four products in the animal health industry. Two of the four products analyzed are classified as orphan products and therefore potential candidates for purchase by the startup company. A Strategy Canvas is developed and value curves are assigned per product to show how the startup company can market an acquired product relative to the critical success factors in the animal health industry (Kim and Mauborgne, 2005). A framework of critical questions is posed to each product resulting in recommendations for the startup on critical success factors to eliminate, reduce, raise, or create. For the orphan products, a recommendations include: raise price, increase marketing support, and/or create new factors to differentiate such as to offer additional services or to develop pricing models that are simple and clear. Application of this research can be applied to companies seeking to acquire animal health products that would like to better understand how to improve their chances for success

Wood-Fired Train Kiln

My research focused on constructing a wood-fired train kiln. I utilized ashlar fine tooled masonry techniques to create a dry-stacked formation. Primarily, I analyzed the different materials to which I had access and determined the proper steps to create an ideal structure. In order to accomplish this, I sorted, cut, and shaved various series of both insulating and dense fire bricks to create a perfect fit, an expansion joint or a level surface. If a level surface could not be attained using solely bricks then a compound termed “butter” was applied, but I utilized a high temperature refractory mortar when I required a brick to be held in place. Furthermore, arches are formed to span the door, chamber, firebox and throat of the kiln using skewback along with varying arch brick, and subsequently, a steel frame is used to buttress the arches as well as hold the bricks in place during expansion; for this reason, I ascertained the importance of inspecting the structure to be true, level, flush, and plum. Through my research, I determined it is of the utmost importance one understands everything about their materials on hand; this allowed me to design a kiln to fit together in both a tight and level manner atop an unlevel foundation. I found that the efficiency of building a dry-stacked kiln is reliant upon organizing bricks according to their differences in height by sixteenths of an inch. In addition, a brick saw and several levels must be used with precision accuracy

Influence of anneal atmosphere on ZnO-nanorod photoluminescent and morphological properties with self-powered photodetector performance

OA Monitor ExerciseEPSR

Using quantitative intravital multiphoton microscopy to dissect hepatic transport in rats

Hepatic solute transport is a complex process whose disruption is associated with liver disease and drug-induced liver injury. Intravital multiphoton fluorescence excitation microscopy provides the spatial and temporal resolution necessary to characterize hepatic transport at the level of individual hepatocytes in vivo and thus to identify the mechanisms and cellular consequences of cholestasis. Here we present an overview of the use of fluorescence microscopy for studies of hepatic transport in living animals, and describe how we have combined methods of intravital microscopy and digital image analysis to dissect the effects of drugs and pathological conditions on the function of hepatic transporters in vivo

Performance Improvements from Heat Acclimation, Heat Acclimatization

Heat acclimation/acclimatization (HA/HAz) are important heat mitigation strategies that help develop heat tolerance from prolonged and repeated exposure to a hot environment, subsequently improving exercise performance in the heat. PURPOSE: To assess and quantify the magnitude of performance benefits of short- (STHA), medium- (MTHA), and long-term HA (LTHA) in endurance-trained athletes. METHODS: A literature search was conducted in PubMed, SPORTDiscus, Scopus, and Cochrane-Library, with data from 23 studies extracted for analysis. Subgroup analysis distinguished differences in performance and thermoregulatory adaptations between short-, medium- and long-term HA interventions. RESULTS: HA produced significant improvements in time trial performance (Effect size [95% confidence intervals] 0.72 [0.42– 1.03]), with LTHA displaying the most significant performance time decrease (-15.29%). MTHA and STHA showed a slight reduction in time trial performance time (-4.28% and -4.40%, respectively). Mean power output during exercise in the heat increased by 7.2% following MTHA, which was greater than STHA (-3.4%). HA showed a significant, small reduction in mean resting skin temperature (Tsk) (0.34 [0.00–0.68]) and core temperature (Tc) (0.40 [0.16–0.63]). Subgroup analysis demonstrated that mean Tsk reduction was more significant in the STHA (-0.35 ± 0.32°C) compared to MTHA (-0.24 ± 0.40°C), whereas Tc showed the greatest decrease in temperature from LTHA (0.66 [0.40–0.92]). CONCLUSION: Results indicate a noticeable improvement in endurance performances in the heat, with a trend towards longer-duration protocols eliciting the greatest performance adaptations. Findings show that long-term HA/HAz results in improved endurance performance in the heat which is influenced by thermoregulatory adaptations that increase thermal tolerance in hot and humid environments. These findings are important for athletes and their support teams to evidence-inform and individualize HA prescription

Attribution of Responsibility after Failures within Platform Ecosystems

Increasingly, new hardware and software are embedded within ecosystems that include a platform and modules. Ideally these ecosystems perform reliably. However, if an ambiguously sourced failure occurs within one of these ecosystems, users are left to distribute blame across the various components of the ecosystem. The actual distribution of this blame, however, can be difficult to predict. This study investigates attribution of blame and discontinuance recommendations for ecosystem components after an ambiguously sourced failure. To extend platform ecosystems and attribution theory, we conducted a scenario-based experiment investigating the negative consequences of failure for platform and module components and the contingent effects from design elements (border strength) and contextual factors (task goal directedness, disruption severity). Results demonstrated a diffusion of negative consequences for failure across ecosystem components, but ecosystem modules (apps) received the majority of the blame and highest discontinuance recommendations. High border strength shifted negative consequences for failure away from the OS to the device. Low goal-directedness resulted in users taking more of the blame for the failure, and higher disruption severity resulted in higher discontinuance recommendations for the OS and device. Importantly, the amount of blame attributed to one component in an ecosystem predicted discontinuance recommendations for other components