MicroRNA-224 Targets SMAD Family Member 4 to Promote Cell Proliferation and Negatively Influence Patient Survival

10.1371/journal.pone.0068744PLoS ONE87-POLN

Characterizing 51 Eri b from 1-5 μ\mum: a partly-cloudy exoplanet

We present spectro-photometry spanning 1-5 $\mu$m of 51 Eridani b, a 2-10 M$_\text{Jup}$ planet discovered by the Gemini Planet Imager Exoplanet Survey. In this study, we present new $K1$ (1.90-2.19 $\mu$m) and $K2$ (2.10-2.40 $\mu$m) spectra taken with the Gemini Planet Imager as well as an updated $L_P$ (3.76 $\mu$m) and new $M_S$ (4.67 $\mu$m) photometry from the NIRC2 Narrow camera. The new data were combined with $J$ (1.13-1.35 $\mu$m) and $H$ (1.50-1.80 $\mu$m) spectra from the discovery epoch with the goal of better characterizing the planet properties. 51 Eri b photometry is redder than field brown dwarfs as well as known young T-dwarfs with similar spectral type (between T4-T8) and we propose that 51 Eri b might be in the process of undergoing the transition from L-type to T-type. We used two complementary atmosphere model grids including either deep iron/silicate clouds or sulfide/salt clouds in the photosphere, spanning a range of cloud properties, including fully cloudy, cloud free and patchy/intermediate opacity clouds. Model fits suggest that 51 Eri b has an effective temperature ranging between 605-737 K, a solar metallicity, a surface gravity of $\log$(g) = 3.5-4.0 dex, and the atmosphere requires a patchy cloud atmosphere to model the SED. From the model atmospheres, we infer a luminosity for the planet of -5.83 to -5.93 ($\log L/L_{\odot}$), leaving 51 Eri b in the unique position as being one of the only directly imaged planet consistent with having formed via cold-start scenario. Comparisons of the planet SED against warm-start models indicates that the planet luminosity is best reproduced by a planet formed via core accretion with a core mass between 15 and 127 M$_{\oplus}$.Comment: 27 pages, 19 figures, Accepted for publication in The Astronomical Journa

Phylogenomic Analysis of Salmonella enterica subsp. enterica Serovar Bovismorbificans from Clinical and Food Samples Using Whole Genome Wide Core Genes and kmer Binning Methods to Identify Two Distinct Polyphyletic Genome Pathotypes

Salmonella enterica subsp. enterica serovar Bovismorbificans has caused multiple outbreaks involving the consumption of produce, hummus, and processed meat products worldwide. To elucidate the intra-serovar genomic structure of S. Bovismorbificans, a core-genome analysis with 2690 loci (based on 150 complete genomes representing Salmonella enterica serovars developed as part of this study) and a k-mer-binning based strategy were carried out on 95 whole genome sequencing (WGS) assemblies from Swiss, Canadian, and USA collections of S. Bovismorbificans strains from foodborne infections. Data mining of a digital DNA tiling array of legacy SARA and SARB strains was conducted to identify near-neighbors of S. Bovismorbificans. The core genome analysis and the k-mer-binning methods identified two polyphyletic clusters, each with emerging evolutionary properties. Four STs (2640, 142, 1499, and 377), which constituted the majority of the publicly available WGS datasets from >260 strains analyzed by k-mer-binning based strategy, contained a conserved core genome backbone with a different evolutionary lineage as compared to strains comprising the other cluster (ST150). In addition, the assortment of genotypic features contributing to pathogenesis and persistence, such as antimicrobial resistance, prophage, plasmid, and virulence factor genes, were assessed to understand the emerging characteristics of this serovar that are relevant clinically and for food safety concerns. The phylogenomic profiling of polyphyletic S. Bovismorbificans in this study corresponds to intra-serovar variations observed in S. Napoli and S. Newport serovars using similar high-resolution genomic profiling approaches and contributes to the understanding of the evolution and sequence divergence of foodborne Salmonellae. These intra-serovar differences may have to be thoroughly understood for the accurate classification of foodborne Salmonella strains needed for the uniform development of future food safety mitigation strategies

Reanalysis and Simulation Suggest a Phylogenetic Microarray Does Not Accurately Profile Microbial Communities

The second generation (G2) PhyloChip is designed to detect over 8700 bacteria and archaeal and has been used over 50 publications and conference presentations. Many of those publications reveal that the PhyloChip measures of species richness greatly exceed statistical estimates of richness based on other methods. An examination of probes downloaded from Greengenes suggested that the system may have the potential to distort the observed community structure. This may be due to the sharing of probes by taxa; more than 21% of the taxa in that downloaded data have no unique probes. In-silico simulations using these data showed that a population of 64 taxa representing a typical anaerobic subterranean community returned 96 different taxa, including 15 families incorrectly called present and 19 families incorrectly called absent. A study of nasal and oropharyngeal microbial communities by Lemon et al (2010) found some 1325 taxa using the G2 PhyloChip, however, about 950 of these taxa have, in the downloaded data, no unique probes and cannot be definitively called present. Finally, data from Brodie et al (2007), when re-examined, indicate that the abundance of the majority of detected taxa, are highly correlated with one another, suggesting that many probe sets do not act independently. Based on our analyses of downloaded data, we conclude that outputs from the G2 PhyloChip should be treated with some caution, and that the presence of taxa represented solely by non-unique probes be independently verified

Meridional shifts of the Atlantic intertropical convergence zone since the Last Glacial Maximum

The intertropical convergence zone is a near-equatorial band of intense rainfall and convection. Over the modern Atlantic Ocean, its annual average position is approximately 5° N, and it is associated with low sea surface salinity and high surface temperatures. This average position has varied since the Last Glacial Maximum, in response to changing climate boundary conditions. The nature of this variation is less clear, with suggestions that the intertropical convergence zone migrated north–south away from the colder hemisphere or that it contracted and expanded symmetrically around its present position2. Here we use paired Mg/Ca and δ18O measurements of planktonic foraminifera for a transect of ocean sediment cores to reconstruct past changes in tropical surface ocean temperature and salinity in the Atlantic Ocean over the past 25,000 years. We show that the low-salinity, high-temperature surface waters associated with the intertropical convergence zone migrated southward of their present position during the Last Glacial Maximum, when the Northern Hemisphere cooled, and northward during the warmer early Holocene, by about ±7° of latitude. Our evidence suggests that the intertropical convergence zone moved latitudinally over the ocean, rather than expanding or contracting. We conclude that the marine intertropical convergence zone has migrated significantly away from its present position owing to external climate forcing during the past 25,000 years

Cell Cycle Phase Regulates Glucocorticoid Receptor Function

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase

Outcome and human epidermal growth factor receptor (HER) 1–4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling

BACKGROUND: We have shown previously that whereas overexpression of human epidermal growth factor receptor (HER)1, HER2 and HER3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study, bromodeoxyuridine (BrdU)-derived proliferation indices are correlated with clinical outcome and HER1–4 status for further clarification of the differing roles for the HER family at a biological level. METHODS: Seventy-eight invasive breast cancers had BrdU labelling in vivo to determine the BrdU labelling index (BLI) and the potential tumour doubling time (T(pot)). Long-term clinical follow-up was available for these patients. We used immunohistochemistry to establish the HER1–4 status in 55 patients from the BrdU cohort. RESULTS: We demonstrate a significant correlation between high BLI values and breast cancer-specific death (P = 0.0174). Low T(pot )times were also significantly correlated with breast cancer-specific death (P = 0.0258). However, BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER1, HER2 or HER3 had significantly (P = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (P = 0.024). Conversely, HER4 positivity was significantly correlated (P = 0.013) with low BLI values, in line with previous data associating this receptor with good prognosis tumours. CONCLUSIONS: These results support the hypothesis that HER1–3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role

Identification of novel small molecules that inhibit STAT3-dependent transcription and function

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents