Synergistic Activation of Cardiac Genes by Myocardin and Tbx5

Myocardial differentiation is associated with the activation and expression of an array of cardiac specific genes. However, the transcriptional networks that control cardiac gene expression are not completely understood. Myocardin is a cardiac and smooth muscle-specific expressed transcriptional coactivator of Serum Response Factor (SRF) and is able to potently activate cardiac and smooth muscle gene expression during development. We hypothesize that myocardin discriminates between cardiac and smooth muscle specific genes by associating with distinct co-factors. Here, we show that myocardin directly interacts with Tbx5, a member of the T-box family of transcription factors involved in the Holt-Oram syndrome. Tbx5 synergizes with myocardin to activate expression of the cardiac specific genes atrial natriuretic factor (ANF) and alpha myosin heavy chain (α-MHC), but not that of smooth muscle specific genes SM22 or smooth muscle myosin heavy chain (SM-MHC). We found that this synergistic activation of shared target genes is dependent on the binding sites for Tbx5, T-box factor-Binding Elements (TBEs). Myocardin and Tbx5 physically interact and their interaction domains were mapped to the basic domain and the coil domain of myocardin and Tbx5, respectively. Our analysis demonstrates that the Tbx5G80R mutation, which leads to the Holt-Oram syndrome in humans, failed to synergize with myocardin to activate cardiac gene expression. These data uncover a key role for Tbx5 and myocardin in establishing the transcriptional foundation for cardiac gene activation and suggest that the interaction of myocardin and Tbx5 maybe involved in cardiac development and diseases

Experimental tests of sub-surface reflectors as an explanation for the ANITA anomalous events

The balloon-borne ANITA [1] experiment is designed to detect ultra-high energy neutrinos via radio emissions produced by in-ice showers. Although initially purposed for interactions within the Antarctic ice sheet, ANITA also demonstrated the ability to self-trigger on radio emissions from ultra-high energy charged cosmic rays [2] (CR) interacting in the Earth's atmosphere. For showers produced above the Antarctic ice sheet, reflection of the down-coming radio signals at the Antarctic surface should result in a polarity inversion prior to subsequent observation at the ~35–40 km altitude ANITA gondola. Based on data taken during the ANITA-1 and ANITA-3 flights, ANITA published two anomalous instances of upcoming cosmic-rays with measured polarity opposite the remaining sample of ~50 UHECR signals [3, 4]. The steep observed upwards incidence angles (25–30 degrees relative to the horizontal) require non-Standard Model physics if these events are due to in-ice neutrino interactions, as the Standard Model cross-section would otherwise prohibit neutrinos from penetrating the long required chord of Earth. Shoemaker et al. [5] posit that glaciological effects may explain the steep observed anomalous events. We herein consider the scenarios offered by Shoemaker et al. and find them to be disfavored by extant ANITA and HiCal experimental data. We note that the recent report of four additional near-horizon anomalous ANITA-4 events [6], at >3σ significance, are incompatible with their model, which requires significant signal transmission into the ice

Physics of Neutron Star Crusts

The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10

Deletion of the N-terminus of SF2/ASF Permits RS-Domain-Independent Pre-mRNA Splicing

Serine/arginine-rich (SR) proteins are essential splicing factors with one or two RNA-recognition motifs (RRMs) and a C-terminal arginine- and serine-rich (RS) domain. SR proteins bind to exonic splicing enhancers via their RRM(s), and from this position are thought to promote splicing by antagonizing splicing silencers, recruiting other components of the splicing machinery through RS-RS domain interactions, and/or promoting RNA base-pairing through their RS domains. An RS domain tethered at an exonic splicing enhancer can function as a splicing activator, and RS domains play prominent roles in current models of SR protein functions. However, we previously reported that the RS domain of the SR protein SF2/ASF is dispensable for in vitro splicing of some pre-mRNAs. We have now extended these findings via the identification of a short inhibitory domain at the SF2/ASF N-terminus; deletion of this segment permits splicing in the absence of this SR protein's RS domain of an IgM pre-mRNA substrate previously classified as RS-domain-dependent. Deletion of the N-terminal inhibitory domain increases the splicing activity of SF2/ASF lacking its RS domain, and enhances its ability to bind pre-mRNA. Splicing of the IgM pre-mRNA in S100 complementation with SF2/ASF lacking its RS domain still requires an exonic splicing enhancer, suggesting that an SR protein RS domain is not always required for ESE-dependent splicing activation. Our data provide additional evidence that the SF2/ASF RS domain is not strictly required for constitutive splicing in vitro, contrary to prevailing models for how the domains of SR proteins function to promote splicing

Characteristics of Four Upward-Pointing Cosmic-Ray-like Events Observed with ANITA

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section

A search for ultrahigh-energy neutrinos associated with astrophysical sources using the third flight of ANITA

The ANtarctic Impulsive Transient Antenna (ANITA) long-duration balloon experiment is sensitive to interactions of ultrahigh-energy (E>1018 eV) neutrinos in the Antarctic ice sheet. The third flight of ANITA, lasting 22 days, began in December 2014. We develop a methodology to search for energetic neutrinos spatially and temporally coincident with potential source classes in ANITA data. This methodology is applied to several source classes: the potential IceCube-identified neutrino sources TXS 0506+056 and NGC 1068, flaring high-energy blazars reported by the Fermi All-Sky Variability Analysis, gamma-ray bursts, and supernovae. Among searches within the five source classes, one candidate was identified as associated with SN 2015D, although not at a statistically significant level. We proceed to place upper limits on the source classes. We further comment on potential application of this methodology to more sensitive future instruments

DNA microarray revealed and RNAi plants confirmed key genes conferring low Cd accumulation in barley grains

List of genes down-regulated in both W6nk2 and Zhenong8 after 15 days exposure to 5 ΟM Cd. (DOC 130 kb

An analysis of a tau-neutrino hypothesis for the near-horizon cosmic-ray-like events observed by ANITA-IV

We present the results of a simulation of the acceptance of the Antarctic Impulsive Transient Antenna (ANITA) to possible υτ point source fluxes detected via τ-lepton-induced air showers. This investigation is framed around the detection of four upward-going extensive air shower events observed very close to the horizon in ANITA-IV. These four events as well as the overall diffuse and point source exposure to Earth-skimming υτ are also compared against published ultrahigh-energy neutrino limits from the Pierre Auger Observatory. We find that while these four events were detected at sky coordinates close to ANITA’s maximum υτ sensitivity and were not simultaneously visible by Auger, the implied fluence necessary for ANITA to observe these events is in tension with limits set by Auger across a wide range of energies and is additionally in tension with ANITA’s Askaryan in-ice neutrino channel above 1019 eV

Analysis of a tau neutrino origin for the near-horizon air shower events observed by the fourth flight of the Antarctic Impulsive Transient Antenna

We study in detail the sensitivity of the Antarctic Impulsive Transient Antenna (ANITA) to possible Formula Presented point source fluxes detected via Formula Presented-lepton-induced air showers. This investigation is framed around the observation of four upward-going extensive air shower events very close to the horizon seen in ANITA-IV. We find that these four upgoing events are not observationally inconsistent with Formula Presented-induced EASs from Earth-skimming Formula Presented both in their spectral properties as well as in their observed locations on the sky. These four events as well as the overall diffuse and point source exposure to Earth-skimming Formula Presented are also compared against published ultrahigh-energy neutrino limits from the Pierre Auger Observatory. While none of these four events occurred at sky locations simultaneously visible by Auger, the implied fluence necessary for ANITA to observe these events is in strong tension with limits set by Auger across a wide range of energies and is additionally in tension with ANITA’s Askaryan in-ice neutrino channel above Formula Presented. We conclude by discussing some of the technical challenges with simulating and analyzing these near horizon events and the potential for future observatories to observe similar events

Methyl-donor depletion of head and neck cancer cells in vitro establishes a less aggressive tumour cell phenotype

PURPOSE: DNA methylation plays a fundamental role in the epigenetic control of carcinogenesis and is, in part, influenced by the availability of methyl donors obtained from the diet. In this study, we developed an in-vitro model to investigate whether methyl donor depletion affects the phenotype and gene expression in head and neck squamous cell carcinoma (HNSCC) cells. METHODS: HNSCC cell lines (UD-SCC2 and UPCI-SCC72) were cultured in medium deficient in methionine, folate, and choline or methyl donor complete medium. Cell doubling-time, proliferation, migration, and apoptosis were analysed. The effects of methyl donor depletion on enzymes controlling DNA methylation and the pro-apoptotic factors death-associated protein kinase-1 (DAPK1) and p53 upregulated modulator of apoptosis (PUMA) were examined by quantitative-PCR or immunoblotting. RESULTS: HNSCC cells cultured in methyl donor deplete conditions showed significantly increased cell doubling times, reduced cell proliferation, impaired cell migration, and a dose-dependent increase in apoptosis when compared to cells cultured in complete medium. Methyl donor depletion significantly increased the gene expression of DNMT3a and TET-1, an effect that was reversed upon methyl donor repletion in UD-SCC2 cells. In addition, expression of DAPK1 and PUMA was increased in UD-SCC2 cells cultured in methyl donor deplete compared to complete medium, possibly explaining the observed increase in apoptosis in these cells. CONCLUSION: Taken together, these data show that depleting HNSCC cells of methyl donors reduces the growth and mobility of HNSCC cells, while increasing rates of apoptosis, suggesting that a methyl donor depleted diet may significantly affect the growth of established HNSCC