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

Connectivity-enhanced diffusion analysis reveals white matter density disruptions in first episode and chronic schizophrenia.

Reduced fractional anisotropy (FA) is a well-established correlate of schizophrenia, but it remains unclear whether these tensor-based differences are the result of axon damage and/or organizational changes and whether the changes are progressive in the adult course of illness. Diffusion MRI data were collected in 81 schizophrenia patients (54 first episode and 27 chronic) and 64 controls. Analysis of FA was combined with "fixel-based" analysis, the latter of which leverages connectivity and crossing-fiber information to assess both fiber bundle density and organizational complexity (i.e., presence and magnitude of off-axis diffusion signal). Compared with controls, patients with schizophrenia displayed clusters of significantly lower FA in the bilateral frontal lobes, right dorsal centrum semiovale, and the left anterior limb of the internal capsule. All FA-based group differences overlapped substantially with regions containing complex fiber architecture. FA within these clusters was positively correlated with principal axis fiber density, but inversely correlated with both secondary/tertiary axis fiber density and voxel-wise fiber complexity. Crossing fiber complexity had the strongest (inverse) association with FA (r = -0.82). When crossing fiber structure was modeled in the MRtrix fixel-based analysis pipeline, patients exhibited significantly lower fiber density compared to controls in the dorsal and posterior corpus callosum (central, postcentral, and forceps major). Findings of lower FA in patients with schizophrenia likely reflect two inversely related signals: reduced density of principal axis fiber tracts and increased off-axis diffusion sources. Whereas the former confirms at least some regions where myelin and or/axon count are lower in schizophrenia, the latter indicates that the FA signal from principal axis fiber coherence is broadly contaminated by macrostructural complexity, and therefore does not necessarily reflect microstructural group differences. These results underline the need to move beyond tensor-based models in favor of acquisition and analysis techniques that can help disambiguate different sources of white matter disruptions associated with schizophrenia

The Origin of Solar Activity in the Tachocline

Solar active regions, produced by the emergence of tubes of strong magnetic field in the photosphere, are restricted to within 35 degrees of the solar equator. The nature of the dynamo processes that create and renew these fields, and are therefore responsible for solar magnetic phenomena, are not well understood. We analyze the magneto-rotational stability of the solar tachocline for general field geometry. This thin region of strong radial and latitudinal differential rotation, between the radiative and convective zones, is unstable at latitudes above 37 degrees, yet is stable closer to the equator. We propose that small-scale magneto-rotational turbulence prevents coherent magnetic dynamo action in the tachocline except in the vicinity of the equator, thus explaining the latitudinal restriction of active regions. Tying the magnetic dynamo to the tachocline elucidates the physical conditions and processes relevant to solar magnetism.Comment: 10 pages, 1 figure, accepted for publication in ApJ

Accurate estimation of angular power spectra for maps with correlated masks

The widely used MASTER approach for angular power spectrum estimation was developed as a fast $C_{\ell}$ estimator on limited regions of the sky. This method expresses the power spectrum of a masked map ("pseudo-$C_\ell$") in terms of the power spectrum of the unmasked map (the true $C_\ell$) and that of the mask or weight map. However, it is often the case that the map and mask are correlated in some way, such as point source masks used in cosmic microwave background (CMB) analyses, which have nonzero correlation with CMB secondary anisotropy fields and other mm-wave sky signals. In such situations, the MASTER approach gives biased results, as it assumes that the unmasked map and mask have zero correlation. While such effects have been discussed before with regard to specific physical models, here we derive a completely general formalism for any case where the map and mask are correlated. We show that our result ("reMASTERed") reconstructs ensemble-averaged pseudo-$C_\ell$ to effectively exact precision, with significant improvements over traditional estimators for cases where the map and mask are correlated. In particular, we obtain an improvement in the mean absolute percent error from 30% with the MASTER result to essentially no error with the reMASTERed result for an integrated Sachs-Wolfe (ISW) field map with a mask built from the thresholded ISW field, and 10% to effectively zero for a Compton-$y$ map combined with an infrared source mask (the latter being directly relevant to actual data analysis). An important consequence of our result is that for maps with correlated masks it is no longer possible to invert a simple equation to obtain the true $C_\ell$ from the pseudo-$C_\ell$. Instead, our result necessitates the use of forward modeling from theory space into the observable domain of the pseudo-$C_\ell$. Our code is publicly available at https://github.com/kmsurrao/reMASTERed.Comment: 14+9 pages, 6+6 figures; matches the version accepted for publication in PRD (https://journals.aps.org/prd/abstract/10.1103/PhysRevD.107.083521); code available at at https://github.com/kmsurrao/reMASTERe

Transdiagnostic treatment of bipolar disorder and comorbid anxiety using the Unified Protocol for Emotional Disorders: A pilot feasibility and acceptability trial

BACKGROUND Comorbid anxiety in bipolar disorder (BD) is associated with greater illness severity, reduced treatment response, and greater impairment. Treating anxiety in the context of BD is crucial for improving illness course and outcomes. The current study examined the feasibility, acceptability and preliminary efficacy of the Unified Protocol (UP), a transdiagnostic cognitive behavioral therapy, as an adjunctive treatment to pharmacotherapy for BD and comorbid anxiety disorders. METHODS Twenty-nine patients with BD and at least one comorbid anxiety disorder were randomized to pharmacotherapy treatment-as-usual (TAU) or TAU with 18 sessions of the UP (UP+TAU). All patients completed assessments every four weeks to track symptoms, functioning, emotion regulation and temperament. Linear mixed-model regressions were conducted to track symptom changes over time and to examine the relationship between emotion-related variables and treatment response. RESULTS Satisfaction ratings were equivalent for both treatment groups. Patients in the UP+TAU group evidenced significantly greater reductions over time in anxiety and depression symptoms (Cohen's d's>0.80). Baseline levels of neuroticism, perceived affective control, and emotion regulation ability predicted magnitude of symptom change for the UP+TAU group only. Greater change in perceived control of emotions and emotion regulation skills predicted greater change in anxiety related symptoms. LIMITATIONS This was a pilot feasibility and acceptability trial; results should be interpreted with caution. CONCLUSIONS Treatment with the UP+TAU was rated high in patient satisfaction, and resulted in significantly greater improvement on indices of anxiety and depression relative to TAU. This suggests that the UP may be a feasible treatment approach for BD with comorbid anxiety.This work was supported by a Postdoctoral National Research Service Award from the National Institutes of Health [F32 MH098490] to K. Ellard. (F32 MH098490 - Postdoctoral National Research Service Award from the National Institutes of Health)Accepted manuscrip

Evaluating How Local- and Regional-Scale Processes Interact to Regulate Growth of Age-0 Largemouth Bass

Regional- and local-scale processes may interact to influence early growth and survival, thereby governing cohort strength. During summer through fall 1994–1996, we assessed how precipitation (a regional-scale process) and prey availability (a local-scale process) influenced piscivory and growth of age-0 largemouth bass Micropterus salmoides in five Ohio reservoirs (190–1,145 ha). We expected early growth to vary with the abundance and relative sizes of age- 0 gizzard shad Dorosoma cepedianum. We collected age-0 largemouth bass and prey fishes every 3 weeks in each reservoir. In 1994, May precipitation was low (total = 4 cm), resulting in low mean daily reservoir discharge (x¯5 reservoirs = 3.6 m3/s). In four reservoirs, stable water levels may have led to successful largemouth bass reproduction and perhaps an early hatch. As such, age-0 largemouth bass in these systems were abundant, consumed gizzard shad, and reached large sizes by fall (15.3 g). In 1995 and 1996, high precipitation (total > 12 cm) and high reservoir discharge [x¯5 reservoirs = 13.8 m3/s (1995), 28.8 m3/s (1996)] in some reservoirs in May likely reduced largemouth bass abundances. Growth during these years was density dependent across reservoirs. When age-0 largemouth bass abundance was low, nonshad prey fish were consumed, and mean fall sizes were similar to those in 1994 (12.0 g). Conversely, fall weights (4.5–7.4 g) declined in reservoirs with increasing largemouth bass density. Surveying May precipitation in Ohio across 48 years revealed that conditions like those in 1994 occurred less than 15% of the time. Because gizzard shad should rarely be available and other prey fish species probably are limited, density-dependent processes should often regulate early piscivory, growth, and potentially, cohort strength in these systems.This research was funded by National Science Foundation grant DEB 9407859 to RAS and Federal Aid in Sport Fish Restoration project F-69-P, administered jointly by the U.S. Fish and Wildlife Service and the Ohio Division of Wildlife. A Postdoctoral Fellowship and Presidential Fellowship from The Ohio State University supported RAW and JEG, respectively, during part of this work

Exoplanets Around Red Giants: Distribution and Habitability

As the search for exoplanets continues, more are being discovered orbiting Red Giant stars. We use current data from the NASA Exoplanet Archive to investigate planet distribution around Red Giant stars and their presence in the host's habitable zone. As well, we update the power law relation between planet mass and stellar radius found in previous studies and provide more detailed investigations on this topic. Ten Red Giant-hosted exoplanets are found to be in the optimistically calculated habitable zone, five of which are in a more conservatively calculated habitable zone. We believe additional exoplanets can be found in habitable zones around Red Giants using the direct imaging and other methods, along with more powerful detection instrumentation

Control of Visually Guided Behavior by Distinct Populations of Spinal Projection Neurons

A basic question in the field of motor control is how different actions are represented by activity in spinal projection neurons. We used a new behavioral assay to identify visual stimuli that specifically drive basic motor patterns in zebrafish. These stimuli evoked consistent patterns of neural activity in the neurons projecting to the spinal cord, which we could map throughout the entire population using in vivo two-photon calcium imaging. We found that stimuli that drive distinct behaviors activated distinct subsets of projection neurons, consisting, in some cases, of just a few cells. This stands in contrast to the distributed activation seen for more complex behaviors. Furthermore, targeted cell by cell ablations of the neurons associated with evoked turns abolished the corresponding behavioral response. This description of the functional organization of the zebrafish motor system provides a framework for identifying the complete circuit underlying a vertebrate behavior.Molecular and Cellular Biolog