The airway epithelia initiate and modulate the inflammatory responses to various pathogens. The cystic fibrosis transmembrane conductance regulator-mediated Cl(-) secretion system plays a key role in mucociliary clearance of inhaled pathogens. We have explored the effects of Toxoplasma gondii, an opportunistic intracellular protozoan parasite, on Cl(-) secretion of the mouse tracheal epithelia. In this study, ATP-induced Cl(-) secretion indicated the presence of a biphasic short-circuit current (Isc) response, which was mediated by a Ca(2+)-activated Cl(-) channel (CaCC) and the cystic fibrosis transmembrane conductance regulator. However, the ATP-evoked Cl(-) secretion in T. gondii-infected mouse tracheal epithelia and the elevation of [Ca(2+)]i in T. gondii-infected human airway epithelial cells were suppressed. Quantitative reverse transcription-PCR revealed that the mRNA expression level of the P2Y2 receptor (P2Y2-R) increased significantly in T. gondii-infected mouse tracheal cells. This revealed the influence that pathological changes in P2Y2-R had on the downstream signal, suggesting that P2Y2-R was involved in the mechanism underlying T. gondii infection in airways. These results link T. gondii infection as well as other pathogen infections to Cl(-) secretion, via P2Y2-R, which may provide new insights for the treatment of pneumonia caused by pathogens including T. gondii.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

We present the first release of the MaNGA Stellar Library (MaStar), which is a large, well-calibrated, high-quality empirical library covering the wavelength range 3622-10354 Å at a resolving power of R ∼ 1800. The spectra were obtained using the same instrument as used by the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) project, by piggybacking on the Sloan Digital Sky Survey (SDSS-IV)/Apache Point Observatory Galaxy Evolution Experiment 2-N (APOGEE-2N) observations. Compared to previous empirical libraries, the MaStar library will have a higher number of stars and a more comprehensive stellar-parameter coverage, especially of cool dwarfs, low-metallicity stars, and stars with different [α/Fe], achieved by a sophisticated target-selection strategy that takes advantage of stellar-parameter catalogs from the literature. This empirical library will provide a new basis for stellar-population synthesis and is particularly well suited for stellar-population analysis of MaNGA galaxies. The first version of the library contains 8646 high-quality per-visit spectra for 3321 unique stars. Compared to photometry, the relative flux calibration of the library is accurate to 3.9% in g-r, 2.7% in r-i, and 2.2% in i-z. The data are released as part of SDSS Data Release 15. We expect the final release of the library to contain more than 10,000 stars.