RAM function is dependent on Kapβ2-mediated nuclear entry

Eukaryotic gene expression is dependent on the modification of the first transcribed nucleotide of pre-mRNA by the addition of the 7-methylguanosine cap. The cap protects transcripts from exonucleases and recruits complexes which mediate transcription elongation, processing and translation initiation. The cap is synthesized by a series of reactions which link 7-methylguanosine to the first transcribed nucleotide via a 5′ to 5′ triphosphate bridge. In mammals, cap synthesis is catalysed by the sequential action of RNGTT (RNA guanylyltransferase and 5′-phosphatase) and RNMT (RNA guanine-7 methyltransferase), enzymes recruited to RNA pol II (polymerase II) during the early stages of transcription. We recently discovered that the mammalian cap methyltransferase is a heterodimer consisting of RNMT and the RNMT-activating subunit RAM (RNMT-activating mini-protein). RAM activates and stabilizes RNMT and thus is critical for cellular cap methylation and cell viability. In the present study we report that RNMT interacts with the N-terminal 45 amino acids of RAM, a domain necessary and sufficient for maximal RNMT activation. In contrast, smaller components of this RAM domain are sufficient to stabilize RNMT. RAM functions in the nucleus and we report that nuclear import of RAM is dependent on PY nuclear localization signals and Kapβ2 (karyopherin β2) nuclear transport protein

Euro-American discussion document on entry and advanced level practice in nuclear medicine

The European Association of Nuclear Medicine Technologist Committee (EANMTC) and the Society of Nuclear Medicine Technologist Section (SNMTS) meet biannually to consider matters of mutual importance. These meetings are held during the SNM and EANM annual conferences. For several years, within these meetings, EANMTC and SNMTS have considered the value of having a Euro-American initiative in defining entry-level and advanced practice competencies for nuclear medicine radiographers (NMRs) and nuclear medicine technologists (NMTs). In June 2009, during the SNM annual conference in Toronto, it was agreed that a Euro-American working party would be established to consider advanced practice. It was recognized that any consideration of a definition for advanced practice would be predicated on an understanding or definition of entry-level practice. As a result, both types of practice would have to be considered. This discussion document outlines some of the background issues associated with advanced practice generally and specifically within nuclear medicine. The primary purpose of this document is to stimulate debate, on a Euro-American level, about the perceived value of advanced practice for NMRs and NMTs within nuclear medicine and to develop an internationally accepted list of entry-level competencies and scope of practice for NMRs and NMTs within nuclear medicine

The William and Flora Hewlett Foundation's Nuclear Security Initiative: Findings from a Summative Evaluation

The Nuclear Security Initiative (NSI) began as an exploratory effort in 2008 and, as with other Foundation initiatives, was intended to be a time-limited effort (though the timeframe for the Foundation's exit was not specified at the outset). The NSI was extended in 2011 and the last grants were made in 2014. Over seven years, the NSI pursued a number of strategies designed to reduce the risk of a nuclear disaster.Although security issues have never been a central element in the Hewlett Foundation's main programs, the Foundation does have a history of funding projects in the peace and security space when these issues touched on the Foundation's main focus areas. Re-entry into the nuclear security space was opportunistic; at the time of the NSI's inception, windows appeared to be opening, signaling that nearterm gains on pressing policy issues were possible. In 2007, four eminent statesmen (Kissinger, Shultz, Nunn and Perry) authored a provocative Wall Street Journal op-ed calling for "a nuclear-free world" and outlining the policy steps required to achieve it. This was the first such articulation by prominent foreign policy and national security leaders from across the political spectrum. Shortly thereafter came the election of Barack Obama who, as a Senator, had taken interest in advancing nuclear security and nonproliferation and who, when newly elected, began making these issues a first-tier national security concern of his Administration. Finally, there was increasing movement by some growing powers, such as Brazil and Turkey, to explore development of nuclear energy domestically, thereby increasing the risk of global nuclear proliferation.The evaluation that is the subject of this report revealed that the NSI set in motion new things in the field—including an increased and more intentional focus on advocacy and communications, increased coordination among funders, and increased attention to building the expertise and capacity of states outside of the P5 (United States, Russia, China, United Kingdom, France) and other established nuclear powers, as opposed to focusing exclusively on US-Russia and US-China relations. The Hewlett Foundation's re-entry into the nuclear security space was seen as bringing "excitement and energy" and "innovation.

The SUMO Ligase Protein Inhibitor of Activated STAT 1 (PIAS1) is a constituent PML-NB protein that contributes to the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1)

Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukaemia (PML)-nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signalling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase Protein Inhibitor of Activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well characterized PML-NB proteins. In contrast to Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation

Detection of radioactive material entering national ports: A Bayesian approach to radiation portal data

Given the potential for illicit nuclear material being used for terrorism, most ports now inspect a large number of goods entering national borders for radioactive cargo. The U.S. Department of Homeland Security is moving toward one hundred percent inspection of all containers entering the U.S. at various ports of entry for nuclear material. We propose a Bayesian classification approach for the real-time data collected by the inline Polyvinyl Toluene radiation portal monitors. We study the computational and asymptotic properties of the proposed method and demonstrate its efficacy in simulations. Given data available to the authorities, it should be feasible to implement this approach in practice.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS334 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Conceptual definition of a 50-100 kWe NEP system for planetary science missions

The Phase 1 objective of this project is to assess the applicability of a common Nuclear Electric Propulsion (NEP) flight system of the 50-100 kWe power class to meet the advanced transportation requirements of a suite of planetary science (robotic) missions, accounting for differences in mission-specific payloads and delivery requirements. The candidate missions are as follows: (1) Comet Nucleus Sample Return; (2) Multiple Mainbelt Asteroid Rendezvous; (3) Jupiter Grand Tour (Galilean satellites and magnetosphere); (4) Uranus Orbiter/Probe (atmospheric entry and landers); (5) Neptune Orbiter/Probe (atmospheric entry and landers); and (6) Pluto-Charon Orbiter/Lander. The discussion is presented in vugraph form

A novel function for the Caenorhabditis elegans torsin OOC-5 in nucleoporin localization and nuclear import.

Torsin proteins are AAA+ ATPases that localize to the endoplasmic reticular/nuclear envelope (ER/NE) lumen. A mutation that markedly impairs torsinA function causes the CNS disorder DYT1 dystonia. Abnormalities of NE membranes have been linked to torsinA loss of function and the pathogenesis of DYT1 dystonia, leading us to investigate the role of the Caenorhabditis elegans torsinA homologue OOC-5 at the NE. We report a novel role for torsin in nuclear pore biology. In ooc-5-mutant germ cell nuclei, nucleoporins (Nups) were mislocalized in large plaques beginning at meiotic entry and persisted throughout meiosis. Moreover, the KASH protein ZYG-12 was mislocalized in ooc-5 gonads. Nups were mislocalized in adult intestinal nuclei and in embryos from mutant mothers. EM analysis revealed vesicle-like structures in the perinuclear space of intestinal and germ cell nuclei, similar to defects reported in torsin-mutant flies and mice. Consistent with a functional disruption of Nups, ooc-5-mutant embryos displayed impaired nuclear import kinetics, although the nuclear pore-size exclusion barrier was maintained. Our data are the first to demonstrate a requirement for a torsin for normal Nup localization and function and suggest that these functions are likely conserved

Corticotropin-releasing hormone interacts with interleukin-1 to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor

Context: The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. Objectives: In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor. Design: Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression. Results: In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6–18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH. Conclusions: CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediator