The Phonology of the Miyako Dialects : Phonological Systems and Comparisons

French National Centre for Scientific ResearchKyoto UniversityFirst Published: August 1, 2012 (in Japanese

Tissue specific induction of p62/sqstm1 by farnesoid X receptor

Background: Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism. Methods and Results: This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice. Conclusions: Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR. © 2012 Williams et al

Resolving Orbital and Climate Keys of Earth and Extraterrestrial Environments with Dynamics 1.0: A General Circulation Model for Simulating the Climates of Rocky Planets

Resolving Orbital and Climate Keys of Earth and Extraterrestrial Environments with Dynamics (ROCKE-3D) is a 3-Dimensional General Circulation Model (GCM) developed at the NASA Goddard Institute for Space Studies for the modeling of atmospheres of Solar System and exoplanetary terrestrial planets. Its parent model, known as ModelE2 (Schmidt et al. 2014), is used to simulate modern and 21st Century Earth and near-term paleo-Earth climates. ROCKE-3D is an ongoing effort to expand the capabilities of ModelE2 to handle a broader range of atmospheric conditions including higher and lower atmospheric pressures, more diverse chemistries and compositions, larger and smaller planet radii and gravity, different rotation rates (slowly rotating to more rapidly rotating than modern Earth, including synchronous rotation), diverse ocean and land distributions and topographies, and potential basic biosphere functions. The first aim of ROCKE-3D is to model planetary atmospheres on terrestrial worlds within the Solar System such as paleo-Earth, modern and paleo-Mars, paleo-Venus, and Saturn's moon Titan. By validating the model for a broad range of temperatures, pressures, and atmospheric constituents we can then expand its capabilities further to those exoplanetary rocky worlds that have been discovered in the past and those to be discovered in the future. We discuss the current and near-future capabilities of ROCKE-3D as a community model for studying planetary and exoplanetary atmospheres.Comment: Revisions since previous draft. Now submitted to Astrophysical Journal Supplement Serie

Research Report on Miyako Ryukyuan : General Study for Research and Conservation of Endangered Dialects in Japan

National Institute for Japanese Language and LinguisticsFrench National Centre for Scientific ResearchKyoto UniversityHiroshima UniversityUniversity of the RyukyusHokusei Gakuen UniversityHitotsubashi UniversityHitotsubashi UniversityHitotsubashi UniversityFirst Published: August 1, 2012 (in Japanese

tRNA methylation resolves codon usage bias at the limit of cell viability.

Codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N1-methylation of guanosine at position 37 (m1G37) on the 3'-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable Escherichia coli strain, lacking m1G37, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m1G37 neutralizes differential translation of proline codons by the major isoacceptor. Lack of m1G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial species that exclusively use the major isoacceptor for survival

Novel Arenavirus, Zambia

To investigate arenavirus in Zambia, we characterized virus from the kidneys of 5 arenavirus RNA–positive rodents (Mastomys natalensis) among 263 captured. Full-genome sequences of the viruses suggested that they were new strains similar to Lassa virus–related arenaviruses. Analyzing samples from additional rodents and other species can elucidate epizootiologic aspects of arenaviruses

Identification of Small-Molecule Inhibitors of Neutral Ceramidase (nCDase) via Target-Based High-Throughput Screening

There is interest in developing inhibitors of human neutral ceramidase (nCDase) because this enzyme plays a critical role in colon cancer. There are currently no potent or clinically effective inhibitors for nCDase reported to date, so we adapted a fluorescence-based enzyme activity method to a high-throughput screening format. We opted to use an assay whereby nCDase hydrolyzes the substrate RBM 14-16, and the addition of NaIO4 acts as an oxidant that releases umbelliferone, resulting in a fluorescent signal. As designed, test compounds that act as ceramidase inhibitors will prevent the hydrolysis of RBM 14-16, thereby decreasing fluorescence. This assay uses a 1536-well plate format with excitation in the blue spectrum of light energy, which could be a liability, so we incorporated a counterscreen that allows for rapid selection against fluorescence artifacts to minimize false-positive hits. The high-throughput screen of >650,000 small molecules found several lead series of hits. Multiple rounds of chemical optimization ensued with improved potency in terms of IC50 and selectivity over counterscreen assays. This study describes the first large-scale high-throughput optical screening assay for nCDase inhibitors that has resulted in leads that are now being pursued in crystal docking studies and in vitro drug metabolism and pharmacokinetics (DMPK).National Cancer Institute https://doi.org/10.13039/100000054Stony Brook Cancer CenterPeer Reviewe