TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors

The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220.

Regulation of endocytosis, nuclear translocation, and signaling of fibroblast growth factor receptor 1 by E-cadherin

Fibroblast growth factor (FGF) receptors (FGFRs) signal to modulate diverse cellular functions, including epithelial cell morphogenesis. In epithelial cells, E-cadherin plays a key role in cell-cell adhesion, and its function can be regulated through endocytic trafficking. In this study, we investigated the location, trafficking, and function of FGFR1 and E-cadherin and report a novel mechanism, based on endocytic trafficking, for the coregulation of E-cadherin and signaling from FGFR1. FGF induces the internalization of surface FGFR1 and surface E-cadherin, followed by nuclear translocation of FGFR1. The internalization of both proteins is regulated by common endocytic machinery, resulting in cointernalization of FGFR1 and E-cadherin into early endosomes. By blocking endocytosis, we show that this is a requisite, initial step for the nuclear translocation of FGFR1. Overexpression of E-cadherin blocks both the coendocytosis of E-cadherin and FGFR1, the nuclear translocation of FGFR1 and FGF-induced signaling to the mitogen-activated protein kinase pathway. Furthermore, stabilization of surface adhesive E-cadherin, by overexpressing p120(ctn), also blocks internalization and nuclear translocation of FGFR1. These data reveal that conjoint endocytosis and trafficking is a novel mechanism for the coregulation of E-cadherin and FGFR1 during cell signaling and morphogenesis.

Salt diffusion and distribution in meat studied by Na-23 nuclear magnetic resonance imaging and relaxometry

This study introduces the use of combined Na-23 magnetic resonance imaging (MRI) and Na-23 NMR relaxometry for the study of meat curing. The diffusion of sodium ions into the meat was measured using Na-23 MRI on a 1 kg meat sample brined in 10% w/w NaCl for 3-100 h. Calculations revealed a diffusion coefficient of 1 x 10(-5) cm(2)/s after 3 h of curing and subsequently decreasing to 8 x 10(-6) cm(2)/s at longer curing times, suggesting that changes occur in the microscopic structure of the meat during curing. The microscopic mobility and distribution of sodium was measured using Na-23 relaxometry. Two sodium populations were observed, and with increasing length of curing time the relaxation times of these changed, reflecting a salt-induced swelling and increase in myofibrillar pore sizes. Accordingly, the present study demonstrated that pore size and thereby salt-induced swelling in meat can be assessed using Na-23 relaxometry.

History and evolutionary trajectory of the Iranian nuclear program

What actors and processes at what levels of analysis and through what mechanisms have pushed Iran's nuclear program (INP) towards being designated as a proliferation threat (securitization)? What actors and processes at what levels of analysis and through what mechanisms have pushed Iran's nuclear program away from being designated as an existential threat (de-securitization)? What has been the overall balance of power and interaction dynamics of these opposing forces over the last half-century and what is their most likely future trajectory? ^ Iran's nuclear story can be told as the unfolding of constant interaction between state and non-state forces of "nuclear securitization" and "nuclear de-securitization." Tracking the crisscrossing interaction between these different securitizing and de-securitizing actors in a historical context constitutes the central task of this project. ^ A careful tracing of "security events" on different analytical levels reveals the broad contours of the evolutionary trajectory of INP and its possible future path(s). Out of this theoretically conscious historical narrative, one can make informed observations about the overall thrust of INP along the securitization - de-securitization continuum. ^ The main contributions of this work are three fold: First, it brings a fresh theoretical perspective on Iran's proliferation behavior by utilizing the "securitization" theory tracing the initial indications of the threat designation of INP all the way back to the mid 1970s. Second, it gives a solid and thematically grounded historical texture to INP by providing an intimate engagement with the persons, processes, and events of Tehran's nuclear pursuit over half a century. Third, it demonstrates how INP has interacted with and even at times transformed the NPT as the keystone of the non-proliferation regime, and how it has affected and injected urgency to the international discourse on nuclear proliferation specifically in the Middle East.^

Suppression of nuclear factor-��B activity in macrophages by chylomicron remnants: modulation by the fatty acid composition of the particles

Current evidence indicates that chylomicron remnants (CMR) induce macrophage foam cell formation, an early event in atherosclerosis. Inflammation also plays a part in atherogenesis and the transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated. In this study, the influence of CMR on the activity of NF-kappaB in macrophages and its modulation by the fatty acid composition of the particles were investigated using macrophages derived from the human monocyte cell line THP-1 and CMR-like particles (CRLPs). Incubation of THP-1 macrophages with CRLPs caused decreased NF-kappaB activation and downregulated the expression of phospho-p65-NF-kappaB and phospho-IkappaBalpha (pIkappaBalpha). Secretion of the inflammatory cytokines tumour necrosis factor alpha, interleukin-6 and monocyte chemoattractant protein-1, which are under NF-kappaB transcriptional control, was inhibited and mRNA expression for cyclooxygenase-2, an NF-kappaB target gene, was reduced. CRLPs enriched in polyunsaturated fatty acids compared with saturated or monounsaturated fatty acids had a markedly greater inhibitory effect on NF-kappaB binding to DNA and the expression of phospho-p65-NF-kappaB and pIkappaB. Lipid loading of macrophages with CRLPs enriched in polyunsaturated fatty acids compared with monounsaturated fatty acids or saturated fatty acids also increased the subsequent rate of cholesterol efflux, an effect which may be linked to the inhibition of NF-kappaB activity. These findings demonstrate that CMR suppress NF-kappaB activity in macrophages, and that this effect is modulated by their fatty acid composition. This downregulation of inflammatory processes in macrophages may represent a protective effect of CMR which is enhanced by dietary polyunsaturated fatty acids.

Turkish Security Policymaking on Nuclear Issues: Conceptualizing Advanced Cooperative Security Strategies

Turkey is a non-nuclear member of a nuclear alliance in a region where nuclear proliferation is of particular concern. As the only North Atlantic Treaty Organization (NATO) member that has a border with the Middle East, Turkish officials argue that Turkey cannot solely rely on NATO guarantees in addressing the regional security challenges. However, Turkey has not been able to formulate a security policy that reconciles its quest for independence, its NATO membership, the bilateral relationship with the United States, and regional engagement in the Middle East. This dissertation assesses the strategic implications of Turkey���s perceptions of the U.S./NATO nuclear and conventional deterrence on nuclear issues. It explores three case studies by the process tracing of Turkish policymakers��� nuclear-related decisions on U.S. tactical nuclear weapons deployed in Europe, national air and missile defense, and Iran���s nuclear program. The study finds that the principles of Turkish security policymaking do not incorporate a fundamentally different reasoning on nuclear issues than conventional deterrence. Nuclear weapons and their delivery systems do not have a defining role in Turkish security and defense strategy. The decisions are mainly guided by non-nuclear considerations such as Alliance politics, modernization of the domestic defense industry, and regional influence. The dissertation argues that Turkey could formulate more effective and less risky security policies on nuclear issues by emphasizing the cooperative security approaches within the NATO Alliance over confrontational measures. The findings of this dissertation reveal that a major transformation of Turkish security policymaking is required to end the crisis of confidence with NATO, redefinition of the strategic partnership with the US, and a more cautious approach toward the Middle East. The dissertation argues that Turkey should promote proactive measures to reduce, contain, and counter risks before they develop into real threats, as well as contribute to developing consensual confidence-building measures to reduce uncertainty.

MULTI-UNIT ACCIDENT CONTRIBUTIONS TO U.S. NUCLEAR REGULATORY COMMISSION QUANTITATIVE HEALTH OBJECTIVES: A SAFETY GOAL POLICY ANALYSIS USING MODELS FROM STATE-OF-THE-ART REACTOR CONSEQUENCE ANALYSES

The U.S. Nuclear Regulatory Commission implemented a safety goal policy in response to the 1979 Three Mile Island accident. This policy addresses the question ���How safe is safe enough?��� by specifying quantitative health objectives (QHOs) for comparison with results from nuclear power plant (NPP) probabilistic risk analyses (PRAs) to determine whether proposed regulatory actions are justified based on potential safety benefit. Lessons learned from recent operating experience���including the 2011 Fukushima accident���indicate that accidents involving multiple units at a shared site can occur with non-negligible frequency. Yet risk contributions from such scenarios are excluded by policy from safety goal evaluations���even for the nearly 60% of U.S. NPP sites that include multiple units. This research develops and applies methods for estimating risk metrics for comparison with safety goal QHOs using models from state-of-the-art consequence analyses to evaluate the effect of including multi-unit accident risk contributions in safety goal evaluations.

FABRICATION, CHARACTERIZATION, AND IRRADIATION OF AN AUSTENITIC OXIDE DISPERSION STRENGTHENED STEEL SUITED FOR NEXT GENERATION NUCLEAR APPLICATIONS

As nuclear energy systems become more advanced, the materials encompassing them need to perform at higher temperatures for longer periods of time. In this Master���s thesis we experiment with an oxide dispersion strengthened (ODS) austenitic steel that has been recently developed. ODS materials have a small concentration of nano oxide particles dispersed in their matrix, and typically have higher strength and better extreme temperature creep resistance characteristics than ordinary steels. However, no ODS materials have ever been installed in a commercial power reactor to date. Being a newer research material, there are many unanswered phenomena that need to be addressed regarding the performance under irradiation. Furthermore, due to the ODS material traditionally needing to follow a powder metallurgy fabrication route, there are many processing parameters that need to be optimized before achieving a nuclear grade material specification. In this Master���s thesis we explore the development of a novel ODS processing technology conducted in Beijing, China, to produce solutionized bulk ODS samples with ~97% theoretical density. This is done using relatively low temperatures and ultra high pressure (UHP) equipment, to compact the mechanically alloyed (MA) steel powder into bulk samples without any thermal phase change influence or oxide precipitation. By having solutionized bulk ODS samples, transmission electron microscopy (TEM) observation of nano oxide precipitation within the steel material can be studied by applying post heat treatments. These types of samples will be very useful to the science and engineering community, to answer questions regarding material powder compacting, oxide synthesis, and performance. Subsequent analysis performed at Queen���s University included X-ray diffraction (XRD) and inductively coupled plasma optical emission spectrometry (ICP-OES). Additional TEM in-situ 1MeV Kr2+ irradiation experiments coupled with energy dispersive X-ray (EDX) techniques, were also performed on large (200nm+) non-stoichiometric oxides embedded within the austenite steel grains, in an attempt to quantify the elemental compositional changes during high temperature (520oC) heavy ion irradiation.