The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model

Author Posting. © American Chemical Society, 2020. This is an open access article published under an ACS AuthorChoice License. The definitive version was published in Chemical Research in Toxicology, 33(4), (2020): 860-879, doi:10.1021/acs.chemrestox.9b00476.The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (“dioxins”), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.This review is dedicated in memory of the career of Alan Poland, one of the truly great minds in pharmacology and toxicology. This work was supported by the National Institutes of Health Grants R35-ES028377, T32-ES007015, P30-CA014520, P42-ES007381, and U01-ES1026127, The UW SciMed GRS Program, and The Morgridge Foundation. The authors would like to thank Catherine Stanley of UW Media Solutions for her artwork

UNLV New Horizons Band & The Las Vegas Flute Ensemble & The UNLV Community Band

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Management Implications of Molt Migration by the Atlantic Flyway Resident Population of Canada Geese, Branta canadensis

We used satellite-tracked transmitters in 2001 and 2003 to document the timing, location, and extent of molt migrations by female Canada Geese (Branta canadensis) affiliated with the Atlantic Flyway Resident Population (AFRP) of Canada Geese that breed in the temperate region of eastern North America. Twenty-seven adult females were captured during the nesting period in late May and fitted with a satellite transmitter mounted either on a plastic neck collar or backpack harness. Nests of 24 birds were destroyed late in incubation to prevent renesting and ensure nest failure; three females did not have nests. Twelve of the 27 birds (44%) made a northward migration to molt in northern Quebec, Canada: seven to the eastern coast of Hudson Bay (58°12'N, 76°60'W), three to lowland areas east of James Bay (53°30'N, 79°02'W), and two to interior locations south of Ungava Bay (55°54'N, 68°24'W). Molt migrants were present in northern Quebec from June to September, a period that coincides with breeding ground aerial surveys and banding operations conducted for Atlantic Population (AP) Canada Geese that breed in this same region of northern Quebec. With >1 million AFRP geese estimated in the Atlantic Flyway, the potential exists for substantial numbers of yearling, sub-adult, and nest-failed or non-breeding adults to molt migrate to northern breeding areas and bias efforts to survey and mark AP geese. Within AFRP breeding areas, many local flocks have reached nuisance levels. We hypothesized that by inducing molt migration in breeding adults, through destruction of nests late in incubation, we would lessen recruitment, reduce numbers of summer resident adults with young, and increase adult mortality from hunting. However, molt migration behavior was not uniform throughout our study area. Molt migrants were from rural areas in New York, Pennsylvania, and Vermont, whereas marked birds that did not make molt migrations were from more coastal regions of the flyway. The 14 birds that did not make a molt migration remained within 60 km of their banding site. A genetic comparison of these two groups revealed no detectable differences. We conclude that failure to undergo a molt migration is likely attributed to the historical origin of captive-reared birds of mixed subspecies that comprise AFRP flocks in the eastern regions of the flyway and the availability of quality local habitat, distinct from brood-rearing areas, for molting

Molecular self-organization: Predicting the pattern diversity and lowest energy state of competing ordering motifs

Self-organized monolayers of highly flexible \Frechet dendrons were deposited on graphite surfaces by solution casting. Scanning tunneling microscopy (STM) reveals an unprecedented variety of patterns with up to seven stable hierarchical ordering motifs serving as a versatile model system. The essential molecular properties determined by molecular mechanics simulations are condensed to a coarse grained interaction site model of various chain configurations. In a Monte Carlo approach with random starting configurations the experimental pattern diversity can be reproduced in all facets of the local and global ordering. Based on an energy analysis of the Monte Carlo and molecular mechanics modeling the thermodynamically most stable pattern is predicted coinciding with the pattern, which dominates in the STM images after several hours or upon moderate heating.Comment: 6 pages, 7 figure

How does reviewing the evidence change veterinary surgeons' beliefs regarding the treatment of ovine footrot? A quantitative and qualitative study

Footrot is a widespread, infectious cause of lameness in sheep, with major economic and welfare costs. The aims of this research were: (i) to quantify how veterinary surgeons’ beliefs regarding the efficacy of two treatments for footrot changed following a review of the evidence (ii) to obtain a consensus opinion following group discussions (iii) to capture complementary qualitative data to place their beliefs within a broader clinical context. Grounded in a Bayesian statistical framework, probabilistic elicitation (roulette method) was used to quantify the beliefs of eleven veterinary surgeons during two one-day workshops. There was considerable heterogeneity in veterinary surgeons’ beliefs before they listened to a review of the evidence. After hearing the evidence, seven participants quantifiably changed their beliefs. In particular, two participants who initially believed that foot trimming with topical oxytetracycline was the better treatment, changed to entirely favour systemic and topical oxytetracycline instead. The results suggest that a substantial amount of the variation in beliefs related to differences in veterinary surgeons’ knowledge of the evidence. Although considerable differences in opinion still remained after the evidence review, with several participants having non-overlapping 95% credible intervals, both groups did achieve a consensus opinion. Two key findings from the qualitative data were: (i) veterinary surgeons believed that farmers are unlikely to actively seek advice on lameness, suggesting a proactive veterinary approach is required (ii) more attention could be given to improving the way in which veterinary advice is delivered to farmers. In summary this study has: (i) demonstrated a practical method for probabilistically quantifying how veterinary surgeons’ beliefs change (ii) revealed that the evidence that currently exists is capable of changing veterinary opinion (iii) suggested that improved transfer of research knowledge into veterinary practice is needed (iv) identified some potential obstacles to the implementation of veterinary advice by farmers

The linearization of the Kodama state

We study the question of whether the linearization of the Kodama state around classical deSitter spacetime is normalizable in the inner product of the theory of linearized gravitons on deSitter spacetime. We find the answer is no in the Lorentzian theory. However, in the Euclidean theory the corresponding linearized Kodama state is delta-functional normalizable. We discuss whether this result invalidates the conjecture that the full Kodama state is a good physical state for quantum gravity with positive cosmological constant.Comment: 14 pages, statement on the corresponding Yang-Mills case correcte

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