LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival.

Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier. Human LRH-1 (hLRH-1) rescues epithelial integrity and when overexpressed, mitigates inflammatory damage in murine and human intestinal organoids, including those derived from IBD patients. Finally, hLRH-1 greatly reduces disease severity in T-cell-mediated murine colitis. Together with the failure of a ligand-incompetent hLRH-1 mutant to protect against TNFα-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease

Gemini Planet Imager Observational Calibrations III: Empirical Measurement Methods and Applications of High-Resolution Microlens PSFs

The newly commissioned Gemini Planet Imager (GPI) combines extreme adaptive optics, an advanced coronagraph, precision wavefront control and a lenslet-based integral field spectrograph (IFS) to measure the spectra of young extrasolar giant planets between 0.9-2.5 um. Each GPI detector image, when in spectral model, consists of ~37,000 microspectra which are under or critically sampled in the spatial direction. This paper demonstrates how to obtain high-resolution microlens PSFs and discusses their use in enhancing the wavelength calibration, flexure compensation and spectral extraction. This method is generally applicable to any lenslet-based integral field spectrograph including proposed future instrument concepts for space missions.Comment: 10 pages, 6 figures. Proceedings of the SPIE, 9147-282 v2: reference adde

An affective disorder in zebrafish with mutation of the glucocorticoid receptor

Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants

Modeling and predicting the shape of the far-infrared to submillimeter emission in ultra-compact HII regions and cold clumps

Dust properties are very likely affected by the environment in which dust grains evolve. For instance, some analyses of cold clumps (7 K- 17 K) indicate that the aggregation process is favored in dense environments. However, studying warm (30 K-40 K) dust emission at long wavelength ($\lambda$$>$300 $\mu$m) has been limited because it is difficult to combine far infared-to-millimeter (FIR-to-mm) spectral coverage and high angular resolution for observations of warm dust grains. Using Herschel data from 70 to 500 $\mu$m, which are part of the Herschel infrared Galactic (Hi-GAL) survey combined with 1.1 mm data from the Bolocam Galactic Plane Survey (BGPS), we compared emission in two types of environments: ultra-compact HII (UCHII) regions, and cold molecular clumps (denoted as cold clumps). With this comparison we tested dust emission models in the FIR-to-mm domain that reproduce emission in the diffuse medium, in these two environments (UCHII regions and cold clumps). We also investigated their ability to predict the dust emission in our Galaxy. We determined the emission spectra in twelve UCHII regions and twelve cold clumps, and derived the dust temperature (T) using the recent two-level system (TLS) model with three sets of parameters and the so-called T-$\beta$ (temperature-dust emissvity index) phenomenological models, with $\beta$ set to 1.5, 2 and 2.5. We tested the applicability of the TLS model in warm regions for the first time. This analysis indicates distinct trends in the dust emission between cold and warm environments that are visible through changes in the dust emissivity index. However, with the use of standard parameters, the TLS model is able to reproduce the spectral behavior observed in cold and warm regions, from the change of the dust temperature alone, whereas a T-$\beta$ model requires $\beta$ to be known.Comment: Accepted for publication in A&A. 19 pages, 8 figures, 7 table

Plasma Physics

Contains reports on four research projects.U. S. Atomic Energy Commission (Contract AT(30-1)-1842

Multidisciplinary Optimization of Urban-Air-Mobility Class Aircraft Trajectories with Acoustic Constraints

The design and analysis of on-demand mobility class vehicles will require thorough acoustic analysis to ensure that more numerous aircraft can operate in densely populated areas without causing excessive levels of noise. This work is a step towards a comprehensive ODM vehicle analysis capability. The authors use 6DOF equations of motion to model the electric quad-rotor concept developed by NASA's Revolutionary Vertical Lift Technologies program. As a first step towards acoustic analysis, this trajectory is coupled to an acoustic model that tracks the sound pressure level perceived by an acoustic observer on the ground. The results show that the approach is successful in finding trajectories that minimize total propulsive impulse while obeying limits imposed on the sound pressure level. Future work will involve adding acoustic analysis of increasing fidelity and tying the resulting trajectories to the performance of the electric propulsion system