Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription.

Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes

Astronomical Distance Determination in the Space Age: Secondary Distance Indicators

The formal division of the distance indicators into primary and secondary leads to difficulties in description of methods which can actually be used in two ways: with, and without the support of the other methods for scaling. Thus instead of concentrating on the scaling requirement we concentrate on all methods of distance determination to extragalactic sources which are designated, at least formally, to use for individual sources. Among those, the Supernovae Ia is clearly the leader due to its enormous success in determination of the expansion rate of the Universe. However, new methods are rapidly developing, and there is also a progress in more traditional methods. We give a general overview of the methods but we mostly concentrate on the most recent developments in each field, and future expectations. © 2018, The Author(s)

The MYCmRNA3'-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels

Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on glutamine, inducing "glutamine addiction". Surprisingly, colon cancer cells that express high levels of MYC due to WNT pathway mutations are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous MYC via the 3'-UTR of the MYC mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine-nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the MYC 3'-UTR is critical for maintaining genome stability when ribonucleotide levels are low

The SCUBA Half-Degree Extragalactic Survey — I. Survey motivation, design and data processing.

The Submillimetre Common-User Bolometer Array (SCUBA) Half-Degree Extragalactic Survey (SHADES) is a major new blank-field extragalactic submillimetre (submm) survey currently underway at the James Clerk Maxwell Telescope (JCMT). Ultimately, SHADES aims to cover half a square degree at 450 and 850 μm to a 4σ depth of ≃ 8 mJy at 850 μm. Two fields are being observed, the Subaru/XMM—Newton Deep Field (SXDF) (02h18m−05°) and the Lockman Hole East (10h52m+ 57°). The survey has three main aims: (i) to investigate the population of high-redshift submm galaxies and the cosmic history of massive dust-enshrouded star formation activity; (ii) to investigate the clustering properties of submm-selected galaxies in order to determine whether these objects could be progenitors of present-day massive ellipticals; and (iii) to investigate the fraction of submm-selected sources that harbour active galactic nuclei. To achieve these aims requires that the submm data be combined with co-spatial information spanning the radio-to-X-ray frequency range. Accordingly, SHADES has been designed to benefit from ultra-deep radio imaging obtained with the Very Large Array (VLA), deep mid-infrared observations from the Spitzer Space Telescope, submm mapping by the Balloon-borne Large Aperture Submillimetre Telescope (BLAST), deep near-infrared imaging with the United Kingdom Infrared Telescope, deep optical imaging with the Subaru Telescope and deep X-ray observations with the XMM—Newton observatory. It is expected that the resulting extensive multiwavelength data set will provide complete photometric redshift information accurate to graphic as well as detailed spectral energy distributions for the vast majority of the submm-selected sources. In this paper, the first of a series on SHADES, we present an overview of the motivation for the survey, describe the SHADES survey strategy, provide a detailed description of the primary data-analysis pipeline and demonstrate the superiority of our adopted matched-filter source-extraction technique over, for example, Emerson-II style methods. We also report on the progress of the survey. As of 2004 February, 720 arcmin2 had been mapped with SCUBA (about 40 per cent of the anticipated final total area) to a median 1σ depth of 2.2 mJy per beam at 850 μm (25 mJy per beam at 450 μm), and the source-extraction routines give a source density of 650 ± 50 sources deg−2 > 3σ at 850 μm. Although uncorrected for Eddington bias, this source density is more than sufficient for providing enough sources to answer the science goals of SHADES, once half a square degree is observed. A refined reanalysis of the original 8-mJy survey Lockman hole data was carried out in order to evaluate the new data-reduction pipeline. Of the 17 most secure sources in the original sample, 12 have been reconfirmed, including 10 of the 11 for which radio identifications were previously secured