Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model

Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 family 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.     

Simplification of genetic programs: a literature survey

Data Mining and Knowledge Discovery - Genetic programming (GP), a widely used evolutionary computing technique, suffers from bloat—the problem of excessive growth in individuals’ sizes....     

Comparison of two dust collection methods for reservoir indoor allergens and endotoxin on carpets and mattresses

Variable methods of dust collection may lead to uncertainty in the measurement of biomarkers. The purpose of this study was to examine the effect of two different dust collection devices on dust weight, Der p 1, Fel d 1, and endotoxin levels. We compared: (1) a nylon mesh sock inserted between the furniture attachment and the vacuum hose (the reference method) and (2) the ALK device. Duplicate dust samples were collected for 2 min from 2 m(2) of 37 living room floors and from each longitudinal half of 37 mattresses. Measurement of Der p 1 and Fel d 1 were by double monoclonal antibody enzyme-linked immunosorbent assay (ELISA) and endotoxin by a Limulus Amobocyte Lysate assay. Geometric mean ratios (95% confidence intervals) were calculated to show the differences between sampling devices for each measurement. Compared with the ALK device, the reference method collected significantly more dust from floors (sevenfold) and mattresses (threefold) and more total Der p 1, Fel d 1, and endotoxin in both sites. Floor, but not mattress, Der p 1 concentrations were also significantly higher (threefold) using our reference method. We recommend that, in order to minimize sampling device bias, allergen and endotoxin are expressed as a concentration, and that the bed is considered the major source of allergen exposure. Practical Implications Dust sampling equipment can influence the dust yield. In order to have confidence in comparisons of allergen and endotoxin reservoir levels between centers, standardization in the use of sampling equipment is important.     

Relationship between persistent organic pollutants (POPs) and ranging patterns in common bottlenose dolphins (Tursiops truncatus) from coastal Georgia, USA

Bottlenose dolphins (Tursiops truncatus) are apex predators in coastal southeastern U.S. waters; as such they are indicators of persistent organic pollutants (POPs) in coastal ecosystems. POP concentrations measured in a dolphin's blubber are influenced by a number of factors, including the animal's sex and ranging pattern in relation to POP point sources. This study examined POP concentrations measured in bottlenose dolphin blubber samples (n = 102) from the Georgia, USA coast in relation to individual ranging patterns and specifically, distance of sightings from a polychlorinated biphenyl (PCB) point source near Brunswick, Georgia. Dolphin ranging patterns were determined based upon 5 years of photo-identification data from two field sites approximately 40 km apart: (1) the Brunswick field site, which included the Turtle/Brunswick River Estuary (TBRE), and (2) the Sapelo field site, which included the Sapelo Island National Estuarine Research Reserve (SINERR). Dolphins were categorized into one of three ranging patterns from photo-identification data. Individuals with sighting histories exclusively within one of the defined field sites were considered to have either Brunswick or Sapelo ranging patterns. Individuals sighted in both field sites were classified as having a Mixed ranging pattern. Brunswick males had the highest concentrations of PCBs reported for any marine mammal. The pattern of PCB congeners was consistent with Aroclor 1268, a highly chlorinated PCB mixture associated with a Superfund site in Brunswick. PCB levels in Sapelo males were lower than in Brunswick males, but comparable to the highest levels measured in other dolphin populations along the southeastern U.S. Female dolphins had higher Aroclor 1268 proportions than males, suggesting that the highly chlorinated congeners associated with Aroclor 1268 may not be offloaded through parturition and lactation, as easily as less halogenated POPs. Individuals sighted farther from the Superfund point source had lower Aroclor 1268 proportions.     

Aaron Siskind

Abstract

Scholars have acknowledged the scotsman, hugh Mackay (c. 1824–1857), as the earliest photographer in Hongkong. A resident of the British colony during the late 1840s, he was beleived to have operated a daguerreotype studio in that growing port town. ¹ A recent study of newspapers published in Hongkong between 1845 and 1849, revelas that Mackay's involvement with photography has been overstated and he may never, in fact, have taken a photograph. A review of Mackay's career, as documented in these publications, illustrates how the thoughtful use of primary source material, such as advertisements, can assist the historian of photography and, as demontrated in this case, challenge generally accepted notions.     

Schulze and ranked-pairs voting are fixed-parameter tractable to bribe,manipulate, and control

Schulze and ranked-pairs elections have received much attention recently, and the former has quickly become a quite widely used election system. For many cases these systems have been proven resistant to bribery, control, or manipulation, with ranked pairs being particularly praised for being NP-hard for all three of those. Nonetheless, the present paper shows that with respect to the number of candidates, Schulze and ranked-pairs elections are fixed-parameter tractable to bribe, control, and manipulate: we obtain uniform, polynomial-time algorithms whose running times’ degrees do not depend on the number of candidates. We also provide such algorithms for some weighted variants of these problems.     

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.     

Using conscious reflection,group processes,and AI to facilitate development of expertise

Three experiments investigated procedures derived from research on knowledge acquisition, group processes, and artificial intelligence for facilitating the development of expertise. In each experimental session, subjects learned to control a simulated sugar production factory. Then they formulated written policies for controlling sugar production either alone as individuals or in small groups. An adaptive AI system provided feedback on policy quality. The research also investigated the use of forced reflective practice in which learners attempted to predict what their policy would do while performing the task. The AI system provided feedback about what their policy would have done in each situation and the outcome based on their policy's response or their suggested alternative response. Results indicated that group interaction and feedback from the AI system improved policy quality. However, only when all three procedures were employed, group interaction, AI feedback, and forced reflective practice, was the development of individual expertise on the task enhanced.