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Sample records for nuclear transport factors

  1. Nuclear Transport Factors: Global Regulation of Mitosis

    PubMed Central

    Forbes, Douglass J.; Travesa, Anna; Nord, Matthew; Bernis, Cyril

    2015-01-01

    The unexpected repurposing of nuclear transport proteins from their function in interphase to an equally vital and very different set of functions in mitosis was very surprising. The multi-talented cast when first revealed included the import receptors, importin alpha and beta, the small regulatory GTPase RanGTP, and a subset of nuclear pore proteins. In this review, we report that recent years have revealed new discoveries in each area of this expanding story in vertebrates: (a) The cast of nuclear transport receptors playing a role in mitotic spindle regulation has expanded: both transportin, a nuclear import receptor, and Crm1/Xpo1, an export receptor, are involved in different aspects of spindle assembly. Importin beta and transportin also regulate nuclear envelope and pore assembly. (b) The role of nucleoporins has grown to include recruiting the key microtubule nucleator the γ-TuRC complex and the exportin Crm1 to the mitotic kinetochores of humans. Together they nucleate microtubule formation from the kinetochores towards the centrosomes. (c) New research finds that the original importin beta/RanGTP team have been further co-opted by evolution to help regulate other cellular and organismal activities, ranging from the actual positioning of the spindle within the cell perimeter, to regulation of a newly discovered spindle microtubule branching activity, to regulation of the interaction of microtubule structures with specific actin structures. (d) Lastly, because of the multitudinous roles of karyopherins throughout the cell cycle, a recent large push toward testing their potential as chemotherapeutic targets has begun to yield burgeoning progress in the clinic. PMID:25982429

  2. Nuclear transport factors: global regulation of mitosis.

    PubMed

    Forbes, Douglass J; Travesa, Anna; Nord, Matthew S; Bernis, Cyril

    2015-08-01

    The unexpected repurposing of nuclear transport proteins from their function in interphase to an equally vital and very different set of functions in mitosis was very surprising. The multi-talented cast when first revealed included the import receptors, importin alpha and beta, the small regulatory GTPase RanGTP, and a subset of nuclear pore proteins. In this review, we report that recent years have revealed new discoveries in each area of this expanding story in vertebrates: (a) The cast of nuclear import receptors playing a role in mitotic spindle regulation has expanded: both transportin, a nuclear import receptor, and Crm1/Xpo1, an export receptor, are involved in different aspects of spindle assembly. Importin beta and transportin also regulate nuclear envelope and pore assembly. (b) The role of nucleoporins has grown to include recruiting the key microtubule nucleator - the γ-TuRC complex - and the exportin Crm1 to the mitotic kinetochores of humans. Together they nucleate microtubule formation from the kinetochores toward the centrosomes. (c) New research finds that the original importin beta/RanGTP team have been further co-opted by evolution to help regulate other cellular and organismal activities, ranging from the actual positioning of the spindle within the cell perimeter, to regulation of a newly discovered spindle microtubule branching activity, to regulation of the interaction of microtubule structures with specific actin structures. (d) Lastly, because of the multitudinous roles of karyopherins throughout the cell cycle, a recent large push toward testing their potential as chemotherapeutic targets has begun to yield burgeoning progress in the clinic.

  3. Reprint of "Nuclear transport factors: global regulation of mitosis".

    PubMed

    Forbes, Douglass J; Travesa, Anna; Nord, Matthew S; Bernis, Cyril

    2015-06-01

    The unexpected repurposing of nuclear transport proteins from their function in interphase to an equally vital and very different set of functions in mitosis was very surprising. The multi-talented cast when first revealed included the import receptors, importin alpha and beta, the small regulatory GTPase RanGTP, and a subset of nuclear pore proteins. In this review, we report that recent years have revealed new discoveries in each area of this expanding story in vertebrates: (a) The cast of nuclear import receptors playing a role in mitotic spindle regulation has expanded: both transportin, a nuclear import receptor, and Crm1/Xpo1, an export receptor, are involved in different aspects of spindle assembly. Importin beta and transportin also regulate nuclear envelope and pore assembly. (b) The role of nucleoporins has grown to include recruiting the key microtubule nucleator – the γ-TuRC complex – and the exportin Crm1 to the mitotic kinetochores of humans. Together they nucleate microtubule formation from the kinetochores toward the centrosomes. (c) New research finds that the original importin beta/RanGTP team have been further co-opted by evolution to help regulate other cellular and organismal activities, ranging from the actual positioning of the spindle within the cell perimeter, to regulation of a newly discovered spindle microtubule branching activity, to regulation of the interaction of microtubule structures with specific actin structures. (d) Lastly, because of the multitudinous roles of karyopherins throughout the cell cycle, a recent large push toward testing their potential as chemotherapeutic targets has begun to yield burgeoning progress in the clinic.

  4. Nuclear transport and transcription.

    PubMed

    Komeili, A; O'Shea, E K

    2000-06-01

    The compartmentalization of DNA in the nucleus of eukaryotic cells establishes a connection between the nuclear transport machinery and the transcriptional apparatus. General transcription factors, as well as specific transcriptional activators and repressors, such as p53 and NF-AT, need to be imported into the nucleus following their translation. In addition, nuclear transport plays a crucial role in regulating the activity of many transcription factors.

  5. Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.

    PubMed

    Read, Jolene; Ingram, Alistair; Al Saleh, Hassan A; Platko, Khrystyna; Gabriel, Kathleen; Kapoor, Anil; Pinthus, Jehonathan; Majeed, Fadwa; Qureshi, Talha; Al-Nedawi, Khalid

    2017-01-01

    Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR. Also, we found that the mutant receptor EGFRvIII could be transported to the nucleus of other cells via EVs. To assess the role of EVs in the regulation of an actual nuclear receptor, we studied the regulation of androgen receptor (AR). We found that full-length AR and mutant variant ARv7 are secreted in EVs derived from prostate cancer cell lines and could be transported to the nucleus of AR-null cells. The EV-derived AR was able to bind the androgen-responsive promoter region of prostate specific antigen, and recruit RNA Pol II, an indication of active transcription. The nuclear-translocated AR via EVs enhanced the proliferation of acceptor cells in the absence of androgen. Finally, we provide evidence that nuclear localisation of AR could occur in vivo via orthotopically-injected EVs in male SCID mice prostate glands. To our knowledge, this is the first study showing the nuclear translocation of nuclear receptors via EVs, which significantly extends the role of EVs as paracrine transcriptional regulators. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Thermodynamics of nuclear transport

    NASA Astrophysics Data System (ADS)

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    Molecular transport across the nuclear envelope is important for eukaryotes for gene expression and signaling. Experimental studies have revealed that nuclear transport is inherently a nonequilibrium process and actively consumes energy. In this work we present a thermodynamics theory of nuclear transport for a major class of nuclear transporters that are mediated by the small GTPase Ran. We identify the molecular elements responsible for powering nuclear transport, which we term the ``Ran battery'' and find that the efficiency of transport, measured by the cargo nuclear localization ratio, is limited by competition between cargo molecules and RanGTP to bind transport receptors, as well as the amount of NTF2 (i.e. RanGDP carrier) available to circulate the energy flow. This picture complements our current understanding of nuclear transport by providing a comprehensive thermodynamics framework to decipher the underlying biochemical machinery. Pm and CHW were supported by a Simons Investigator in the Mathematical Modeling in Living Systems grant (to PM).

  7. Germline and developmental roles of the nuclear transport factor importin alpha3 in C. elegans.

    PubMed

    Geles, K G; Adam, S A

    2001-05-01

    The importin alpha family of transport factors mediates the nuclear import of classical nuclear localization signal-containing proteins. In order to understand how multiple importin alpha proteins are regulated both in individual cells and in a whole organism, the three importin alpha (ima) genes of Caenorhabditis elegans have been identified and studied. All three IMAs are expressed in the germline; however, only IMA-3 is expressed in the soma. RNA interference (RNAi) experiments demonstrate that IMA-3 is required for the progression of meiotic prophase I during oocyte development. Loss of IMA-3 expression leads also to a disruption of the nuclear pore complex accompanied by the mis-localization of P granules. A range of defects occurring in ima-3(RNAi) F1 progeny further supports a role for IMA-3 during embryonic and larval development. The functional association of IMA-3 with distinct cellular events, its expression pattern and intracellular localization indicate that regulation of the nuclear transport machinery is involved in the control of developmental pathways.

  8. Interaction of Sp1 zinc finger with transport factor in the nuclear localization of transcription factor Sp1

    SciTech Connect

    Ito, Tatsuo; Kitamura, Haruka; Uwatoko, Chisana; Azumano, Makiko; Itoh, Kohji; Kuwahara, Jun

    2010-12-10

    Research highlights: {yields} Sp1 zinc fingers themselves interact with importin {alpha}. {yields} Sp1 zinc finger domains play an essential role as a nuclear localization signal. {yields} Sp1 can be transported into the nucleus in an importin-dependent manner. -- Abstract: Transcription factor Sp1 is localized in the nucleus and regulates the expression of many cellular genes, but the nuclear transport mechanism of Sp1 is not well understood. In this study, we revealed that GST-fused Sp1 protein bound to endogenous importin {alpha} in HeLa cells via the Sp1 zinc finger domains, which comprise the DNA binding domain of Sp1. It was found that the Sp1 zinc finger domains directly interacted with a wide range of importin {alpha} including the armadillo (arm) repeat domain and the C-terminal acidic domain. Furthermore, it turned out that all three zinc fingers of Sp1 are essential for binding to importin {alpha}. Taken together, these results suggest that the Sp1 zinc finger domains play an essential role as a NLS and Sp1 can be transported into the nucleus in an importin-dependent manner even though it possesses no classical NLSs.

  9. Nuclear Factor Erythroid 2-Related Factor 2 Facilitates Neuronal Glutathione Synthesis by Upregulating Neuronal Excitatory Amino Acid Transporter 3 Expression

    PubMed Central

    Escartin, Carole; Won, Seok Joon; Malgorn, Carole; Auregan, Gwennaelle; Berman, Ari E.; Chen, Pei-Chun; Déglon, Nicole; Johnson, Jeffrey A.; Suh, Sang Won; Swanson, Raymond A.

    2012-01-01

    Astrocytes support neuronal antioxidant capacity by releasing glutathione, which is cleaved to cysteine in brain extracellular space. Free cysteine is then taken up by neurons through excitatory amino acid transporter 3 [EAAT3; also termed Slc1a1 (solute carrier family 1 member 1)] to support de novo glutathione synthesis. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) pathway by oxidative stress promotes astrocyte release of glutathione, but it remains unknown how this release is coupled to neuronal glutathione synthesis. Here we evaluated transcriptional regulation of the neuronal cysteine transporter EAAT3 by the Nrf2-ARE pathway. Nrf2 activators and Nrf2 overexpression both produced EAAT3 transcriptional activation in C6 cells. A conserved ARE-related sequence was found in the EAAT3 promoter of several mammalian species. This ARE-related sequence was bound by Nrf2 in mouse neurons in vivo as observed by chromatin immunoprecipitation. Chemical activation of the Nrf2-ARE pathway in mouse brain increased both neuronal EAAT3 levels and neuronal glutathione content, and these effects were abrogated in mice genetically deficient in either Nrf2 or EAAT3. Selective overexpression of Nrf2 in brain neurons by lentiviral gene transfer was sufficient to upregulate both neuronal EAAT3 protein and glutathione content. These findings identify a mechanism whereby Nrf2 activation can coordinate astrocyte glutathione release with neuronal glutathione synthesis through transcriptional upregulation of neuronal EAAT3 expression. PMID:21593323

  10. Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression.

    PubMed

    Escartin, Carole; Won, Seok Joon; Malgorn, Carole; Auregan, Gwennaelle; Berman, Ari E; Chen, Pei-Chun; Déglon, Nicole; Johnson, Jeffrey A; Suh, Sang Won; Swanson, Raymond A

    2011-05-18

    Astrocytes support neuronal antioxidant capacity by releasing glutathione, which is cleaved to cysteine in brain extracellular space. Free cysteine is then taken up by neurons through excitatory amino acid transporter 3 [EAAT3; also termed Slc1a1 (solute carrier family 1 member 1)] to support de novo glutathione synthesis. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) pathway by oxidative stress promotes astrocyte release of glutathione, but it remains unknown how this release is coupled to neuronal glutathione synthesis. Here we evaluated transcriptional regulation of the neuronal cysteine transporter EAAT3 by the Nrf2-ARE pathway. Nrf2 activators and Nrf2 overexpression both produced EAAT3 transcriptional activation in C6 cells. A conserved ARE-related sequence was found in the EAAT3 promoter of several mammalian species. This ARE-related sequence was bound by Nrf2 in mouse neurons in vivo as observed by chromatin immunoprecipitation. Chemical activation of the Nrf2-ARE pathway in mouse brain increased both neuronal EAAT3 levels and neuronal glutathione content, and these effects were abrogated in mice genetically deficient in either Nrf2 or EAAT3. Selective overexpression of Nrf2 in brain neurons by lentiviral gene transfer was sufficient to upregulate both neuronal EAAT3 protein and glutathione content. These findings identify a mechanism whereby Nrf2 activation can coordinate astrocyte glutathione release with neuronal glutathione synthesis through transcriptional upregulation of neuronal EAAT3 expression.

  11. Membrane-bound trafficking regulates nuclear transport of integral epidermal growth factor receptor (EGFR) and ErbB-2.

    PubMed

    Wang, Ying-Nai; Lee, Heng-Huan; Lee, Hong-Jen; Du, Yi; Yamaguchi, Hirohito; Hung, Mien-Chie

    2012-05-11

    Nuclear localization of multiple receptor-tyrosine kinases (RTKs), such as EGF receptor (EGFR), ErbB-2, FGF receptor (FGFR), and many others, has been reported by several groups. We previously showed that cell surface EGFR is trafficked to the nucleus through a retrograde pathway from the Golgi to the endoplasmic reticulum (ER) and that EGFR is then translocated to the inner nuclear membrane (INM) through the INTERNET (integral trafficking from the ER to the nuclear envelope transport) pathway. However, the nuclear trafficking mechanisms of other membrane RTKs, apart from EGFR, remain unclear. The purpose of this study was to compare the nuclear transport of EGFR family proteins with that of FGFR-1. Interestingly, we found that digitonin permeabilization, which selectively releases soluble nuclear transporters from the cytoplasm and has been shown to inhibit nuclear transport of FGFR-1, had no effects on EGFR nuclear transport, raising the possibility that EGFR and FGFR-1 use different pathways to be translocated into the nucleus. Using the subnuclear fractionation assay, we further demonstrated that biotinylated cell surface ErbB-2, but not FGFR-1, is targeted to the INM, associating with Sec61β in the INM, similar to the nuclear trafficking of EGFR. Thus, ErbB-2, but not FGFR-1, shows a similar trafficking pathway to EGFR for translocation to the nucleus, indicating that at least two different pathways of nuclear transport exist for cell surface receptors. This finding provides a new direction for investigating the trafficking mechanisms of various nuclear RTKs.

  12. Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA.

    PubMed

    Okuyama, Takahide; Yamagishi, Ryosuke; Shimada, Jiro; Ikeda, Masaaki; Maruoka, Yayoi; Kaneko, Hiroki

    2017-02-17

    Oct4 is a master regulator of the induction and maintenance of cellular pluripotency, and has crucial roles in early stages of differentiation. It is the only factor that cannot be substituted by other members of the same protein family to induce pluripotency. However, although Oct4 nuclear transport and delivery to target DNA are critical events for reprogramming to pluripotency, little is known about the molecular mechanism. Oct4 is imported to the nucleus by the classical nuclear transport mechanism, which requires importin α as an adaptor to bind the nuclear localization signal (NLS). Although there are structures of complexes of the NLS of transcription factors (TFs) in complex with importin α, there are no structures available for complexes involving intact TFs. We have therefore modeled the structure of the complex of the whole Oct4 POU domain and importin α2 using protein-protein docking and molecular dynamics. The model explains how the Ebola virus VP24 protein has a negative effect on the nuclear import of STAT1 by importin α but not on Oct4, and how Nup 50 facilitates cargo release from importin α. The model demonstrates the structural differences between the Oct4 importin α bound and DNA bound crystal states. We propose that the 'expanded linker' between the two DNA-binding domains of Oct4 is an intrinsically disordered region and that its conformational changes have a key role in the recognition/binding to both DNA and importin α. Moreover, we propose that this structural change enables efficient delivery to DNA after release from importin α.

  13. Involvement of Nuclear Factor κB, not Pregnane X Receptor, in Inflammation-Mediated Regulation of Hepatic Transporters.

    PubMed

    Abualsunun, Walaa A; Piquette-Miller, Micheline

    2017-10-01

    Endotoxin-induced inflammation decreases the hepatic expression of several drug transporters, metabolizing enzymes, and nuclear transcription factors, including pregnane X receptor (PXR). As the nuclear factor κB (NF-κB) is a major mediator of inflammation, and reciprocal repression between NF-κB and PXR signaling has been reported, the objective of this study was to examine whether NF-κB directly regulates the expression of transporters or exerts its effect indirectly via PXR. PXR-deficient (-/-) or wild-type (+/+) male mice were dosed with the selective NF-κB inhibitor PHA408 (40 mg/kg i.p.) or vehicle (n = 5-8/group), followed by endotoxin (5 mg/kg) or saline 30 minutes later. Animals were sacrificed at 6 hours; samples were analyzed using quantitative reverse-transcription polymerase chain reaction and Western blots. Endotoxin induced tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and inducible nitric oxide synthase in PXR (+/+) and (-/-) mice. As compared with saline controls, endotoxin administration imposed 30%-70% significant decreases in the expression of Abcb1a, Abcb11, Abcc2, Abcc3, Abcg2, Slc10a1, Slco2b1, and Slco1a4 in PXR (+/+) and (-/-) mice to a similar extent. Preadministration of PHA408 attenuated endotoxin-mediated changes in both PXR (+/+) and (-/-) mice (P < 0.05). Our findings demonstrate that endotoxin activates NF-κB and imposes a downregulation of numerous ATP-binding cassette and solute carrier transporters through NF-κB in liver and is independent of PXR. Moreover, inhibition of NF-κB attenuates the impact of endotoxin on transporter expression. As NF-κB activation is involved in many acute and chronic disease states, disease-induced changes in transporter function may be an important source of variability in drug response. This information may be useful in predicting potential drug-disease interactions. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Effects of natural nuclear factor-kappa B inhibitors on anticancer drug efflux transporter human P-glycoprotein.

    PubMed

    Nabekura, Tomohiro; Hiroi, Takashi; Kawasaki, Tatsuya; Uwai, Yuichi

    2015-03-01

    Drug efflux transporter P-glycoprotein plays an important role in cancer chemotherapy. The nuclear factor-κB (NF-κB) transcription factors play critical roles in development and progression of cancer. In this study, the effects of natural compounds that can inhibit NF-κB activation on the function of P-glycoprotein were investigated using human MDR1 gene-transfected KB/MDR1 cells. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-glycoprotein, in KB/MDR1 cells increased in the presence of caffeic acid phenetyl ester (CAPE), licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol in a concentration-dependent manner. In contrast, lupeol, zerumbone, thymoquinone, emodin, and anethol had no effects. The ATPase activities of P-glycoprotein were stimulated by CAPE, licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol. Tumor necrosis factor (TNF)-α stimulated NF-κB activation was inhibited by CAPE, licochalcone A, anacardic acid, and xanthohumol. KB/MDR1 cells were sensitized to vinblastine cytotoxicity by CAPE, licochalcone A, anacardic acid, xanthohumol, magnolol, and honokiol, showing that these natural NF-κB inhibitors reverse multidrug resistance. These results suggest that natural compounds, such as CAPE, licochalcone A, and anacardic acid, have dual inhibitory effects on the anticancer drug efflux transporter P-glycoprotein and NF-κB activation, and may become useful to enhance the efficacy of cancer chemotherapy.

  15. Transport Properties in Nuclear Pasta

    NASA Astrophysics Data System (ADS)

    Caplan, Matthew; Horowitz, Charles; Berry, Donald; da Silva Schneider, Andre

    2016-09-01

    At the base of the inner crust of neutron stars, where matter is near the nuclear saturation density, nuclear matter arranges itself into exotic shapes such as cylinders and slabs, called `nuclear pasta.' Lepton scattering from these structures may govern the transport properties of the inner crust; electron scattering from protons in the pasta determines the thermal and electrical conductivity, as well as the shear viscosity of the inner crust. These properties may vary in pasta structures which form at various densities, temperatures, and proton fractions. In this talk, we report on our calculations of lepton transport in nuclear pasta and the implication for neutron star observables.

  16. Intrinsic and extrinsic negative regulators of nuclear protein transport processes

    PubMed Central

    Sekimoto, Toshihiro; Yoneda, Yoshihiro

    2012-01-01

    The nuclear–cytoplasmic protein transport is a critical process in cellular events. The identification of transport signals (nuclear localization signal and nuclear export signal) and their receptors has facilitated our understanding of this expanding field. Nuclear transport must be appropriately regulated to deliver proteins through the nuclear pore when their functions are required in the nucleus, and to export them into the cytoplasm when they are not needed in the nucleus. Altered nuclear transport processes have been observed in stressed cells, which would change gene expressions. Some viruses interfere with nuclear transport in host cells to evade immune defense. Moreover, certain transport factors negatively regulate nuclear protein transport in cells. Understanding the regulatory mechanisms of nuclear–cytoplasmic trafficking not only provides important information about cellular processes, but also is of use for developing specific inhibitors for transport pathways. PMID:22672474

  17. Processivity factor of KSHV contains a nuclear localization signal and binding domains for transporting viral DNA polymerase into the nucleus

    SciTech Connect

    Chen Yali; Ciustea, Mihai; Ricciardi, Robert P. . E-mail: ricciardi@biochem.dental.upenn.edu

    2005-09-30

    Kaposi's sarcoma-associated human herpesvirus (KSHV) encodes a processivity factor (PF-8, ORF59) that forms homodimers and binds to viral DNA polymerase (Pol-8, ORF9). PF-8 is essential for stabilizing Pol-8 on template DNA so that Pol-8 can incorporate nucleotides continuously. Here, the intracellular interaction of these two viral proteins was examined by confocal immunofluorescence microscopy. When individually expressed, PF-8 was observed exclusively in the nucleus, whereas Pol-8 was found only in the cytoplasm. However, when co-expressed, Pol-8 was co-translocated with PF-8 into the nucleus. Mutational analysis revealed that PF-8 contains a nuclear localization signal (NLS) as well as domains located at the N-terminus and the C-proximal regions that are required for Pol-8 binding. This study suggests that the mechanism that enables PF-8 to transport Pol-8 into the nucleus is the first critical step required for Pol-8 and PF-8 to function processively in KSHV DNA synthesis.

  18. Fasting Induces Nuclear Factor E2-Related Factor 2 and ATP-Binding Cassette Transporters via Protein Kinase A and Sirtuin-1 in Mouse and Human

    PubMed Central

    Kulkarni, Supriya R.; Donepudi, Ajay C.; Xu, Jialin; Wei, Wei; Cheng, Qiuqiong C.; Driscoll, Maureen V.; Johnson, Delinda A.; Johnson, Jeffrey A.; Li, Xiaoling

    2014-01-01

    Abstract Aims: The purpose of this study was to determine whether 3′-5′-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2–4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear factor-E2 related-factor 2 (NRF2) is a transcription factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. Results: Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1–dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, which was decreased by the PKA inhibitor, H-89. Moreover, fasting induced NRF2 target gene expression was decreased in liver and hepatocytes of SIRT1 liver-specific null mice and NRF2-null mice. Lastly, NRF2 and SIRT1 were recruited to MAREs and Antioxidant Response Elements (AREs) in the human ABCC2 promoter. Innovation: Oxidative stress mediated NRF2 activation is well described, yet the influence of basic metabolic processes on NRF2 activation is just emerging. Conclusion: The current data point toward a novel role of nutrient status in regulation of NRF2 activity and the antioxidant response, and indicates that cAMP/PKA and SIRT1 are upstream regulators for fasting-induced activation of the NRF2-ARE pathway. Antioxid. Redox Signal. 20, 15–30. PMID:23725046

  19. The molecular mechanism for nuclear transport and its application.

    PubMed

    Kim, Yun Hak; Han, Myoung-Eun; Oh, Sae-Ock

    2017-06-01

    Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus.

  20. GSK-3 mediated phosphorylation couples ER-Golgi transport and nuclear stabilisation of the CREB-H transcription factor to mediate Apolipoprotein secretion.

    PubMed

    Barbosa, Sónia; Carreira, Suzanne; O'Hare, Peter

    2017-04-05

    CREB-H, an ER-anchored transcription factor plays a key role in regulating secretion in metabolic pathways, particularly triglyceride homeostasis. It controls the production both of secretory pathway components and cargoes including apolipoproteins ApoA-IV and ApoC-II, contributing to VLDL/HDL distribution and lipolysis. The key mechanism controlling CREB-H activity involves its ER retention and forward transport to the Golgi, where it is cleaved by Golgi-resident proteases releasing the N-terminal product which traffics to the nucleus to effect transcriptional responses. Here we show that a serine-rich motif, termed the P-motif located in the N-terminus between serines 73 to 90, controls release of the precursor transmembrane form from the ER and its forward transport to the Golgi. This motif is subject to GSK-3 phosphorylation promoting ER-retention while mutation of target serines or drug inhibition of GSK-3 activity, co-ordinately induces both forward transport of the precursor and cleavage, resulting in nuclear import. We previously showed that for the nuclear product, the P-motif is subject to multiple phosphorylations which regulate stability by targeting the protein to the SCF(Fbw1a) E3 ubiquitin ligase. Thus phosphorylation at the P-motif provides integrated control of CREB-H function, coupling intercompartmental transport in the cytoplasm with stabilisation of the active form in the nucleus.

  1. Tritium transport around nuclear facilities

    SciTech Connect

    Murphy, C.E. Jr.; Sweet, C.W.

    1981-01-01

    The transport and cycling of tritium around nuclear facilities is reviewed with special emphasis on studies at the Savannah River Laboratory, Aiken, South Carolina. These studies have shown that the rate of deposition from the atmosphere, the site of deposition, and the subsequent cycling are strongly influenced by the compound with which the tritium is associated. Tritiated hydrogen is largely deposited in the soil, while tritiated water is deposited in the greatest quantity in the vegetation. Tritiated hydrogen is converted in the soil to tritiated water that leaves the soil slowly, through drainage and transpiration. Tritiated water deposited directly to the vegetation leaves the vegetation more rapidly after exposure. Only a small part of the tritium entering the vegetation becomes bound in organic molecules. However, it appears tht the existence of soil organic compounds with tritium concentrations greater than the equilibrium concentration in the associated water can be explained by direct metabolism of tritiated hydrogen in vegetation.

  2. Role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the transcriptional regulation of brain ABC transporters during acute acetaminophen (APAP) intoxication in mice.

    PubMed

    Ghanem, Carolina I; Rudraiah, Swetha; Bataille, Amy M; Vigo, María B; Goedken, Michael J; Manautou, José E

    2015-04-01

    Changes in expression of liver ABC transporters have been described during acute APAP intoxication. However, the effect of APAP on brain ABC transporters is poorly understood. The aim of this study was to evaluate the effect of APAP on brain ABC transporters expression and the role of the oxidative stress sensor Nrf2. Male C57BL/6J mice were administered APAP (400mg/kg) for analysis of brain mRNA and protein expression of Mrp1-6, Bcrp and P-gp. The results show induction of P-gp, Mrp2 and Mrp4 proteins, with no changes in Bcrp, Mrp1 or Mrp5-6. The protein values were accompanied by corresponding changes in mRNA levels. Additionally, brain Nrf2 nuclear translocation and expression of two Nrf2 target genes, quinone oxidoreductase 1 (Nqo1) and Hemoxygenase 1 (Ho-1), was evaluated at 6, 12 and 24h after APAP treatment. Nrf2 nuclear content increased by 58% at 12h after APAP along with significant increments in mRNA and protein expression of Nqo1 and Ho-1. Furthermore, APAP treated Nrf2 knockout mice did not increase mRNA or protein expression of Mrp2 and Mrp4 as observed in wildtypes. In contrast, P-gp induction by APAP was observed in both genotypes. In conclusion, acute APAP intoxication induces protein expression of brain P-gp, Mrp2 and Mrp4. This study also suggests that brain changes in Mrp2 and Mrp4 expression may be due to in situ Nrf2 activation by APAP, while P-gp induction is independent of Nrf2 function. The functional consequences of these changes in brain ABC transporters by APAP deserve further attention. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Cloning, expression and characterization of the putative nuclear transport factor 2 (NTF2) gene from moss Conocephalum conicum(L.) Dum.

    PubMed

    Bian, Chunxiang; Ruan, Qiping; Peng, Zhengsong; Ji, Hongchun; Jiang, Lichun; Li, Jintao; Yuan, Lijuan

    2011-03-01

    Biomacromolecules import into the nucleus is a complex progress which requires the participation of several cytosolic factors, and nuclear transport factor 2 (NTF2) is one of essential components in nuclear trafficking. Its main role is to transport RanGDP from cytoplasm to nucleus by interacting with FxFG nucleoporin repeats. In the study a putative new gene, designated as CcNTF2, was obtained from the moss (Conocephalum conicum) cDNA library we have constructed. The full-length cDNA sequence is 913 bp in size contains a 372 bp open reading frame (ORF) flanked by a 195 bp 5'-untranslated sequence and a long 346 bp 3'-non-coding region, encoding 123 amino acids of 13,575.3 Da. Part of the genomic sequence was also cloned and sequenced, which is 1,602 bp long and possesses two exons and one intron. Alignment analysis showed that the CcNTF2 protein is high conserved among plant NTF2 and shares 81% similarity with the ones from Arabidopsis thaliana and Brassica rapa. The expression of wild-type CcNTF2 was detected by immunoblotting of extraction of C. conicum and it indicated the putative protein is integral. Through functional expression of CcNTF2-green fluorescent protein (GFP) in tobacco, it was demonstrated that CcNTF2 can accumulate at the nuclear rim. Site-directed mutagenesis analysis confirmed CcNTF2 P71K has influence on the protein import into nucleus. In addition, overexpression of CcNTF2 P71K was observed to be deleterious for the plant cell. It is the first illumination of NTF2 in moss, and our study established the primary foundation for further research on moss NTF2.

  4. Elliptic flow and nuclear modification factor in ultrarelativistic heavy-ion collisions within a partonic transport model.

    PubMed

    Uphoff, Jan; Senzel, Florian; Fochler, Oliver; Wesp, Christian; Xu, Zhe; Greiner, Carsten

    2015-03-20

    The quark gluon plasma produced in ultrarelativistic heavy-ion collisions exhibits remarkable features. It behaves like a nearly perfect liquid with a small shear viscosity to entropy density ratio and leads to the quenching of highly energetic particles. We show that both effects can be understood for the first time within one common framework. Employing the parton cascade Boltzmann approach to multiparton scatterings, the microscopic interactions and the space-time evolution of the quark gluon plasma are calculated by solving the relativistic Boltzmann equation. Based on cross sections obtained from perturbative QCD with explicitly taking the running coupling into account, we calculate the nuclear modification factor and elliptic flow in ultrarelativistic heavy-ion collisions. With only one single parameter associated with coherence effects of medium-induced gluon radiation, the experimental data of both observables can be understood on a microscopic level. Furthermore, we show that perturbative QCD interactions with a running coupling lead to a sufficiently small shear viscosity to entropy density ratio of the quark gluon plasma, which provides a microscopic explanation for the observations stated by hydrodynamic calculations.

  5. Non-FG mediated transport of the large pre-ribosomal subunit through the nuclear pore complex by the mRNA export factor Gle2

    PubMed Central

    Occhipinti, Laura; Chang, Yiming; Altvater, Martin; Menet, Anna M.; Kemmler, Stefan; Panse, Vikram G.

    2013-01-01

    Multiple export receptors passage bound pre-ribosomes through nuclear pore complexes (NPCs) by transiently interacting with the Phe-Gly (FG) meshwork of their transport channels. Here, we reveal how the non-FG interacting yeast mRNA export factor Gly-Leu-FG lethal 2 (Gle2) functions in the export of the large pre-ribosomal subunit (pre-60S). Structure-guided studies uncovered conserved platforms used by Gle2 to export pre-60S: an uncharacterized basic patch required to bind pre-60S, and a second surface that makes non-FG contacts with the nucleoporin Nup116. A basic patch mutant of Gle2 is able to function in mRNA export, but not pre-60S export. Thus, Gle2 provides a distinct interaction platform to transport pre-60S to the cytoplasm. Notably, Gle2’s interaction platforms become crucial for pre-60S export when FG-interacting receptors are either not recruited to pre-60S or are impaired. We propose that large complex cargos rely on non-FG as well as FG-interactions for their efficient translocation through the nuclear pore complex channel. PMID:23907389

  6. Non-FG mediated transport of the large pre-ribosomal subunit through the nuclear pore complex by the mRNA export factor Gle2.

    PubMed

    Occhipinti, Laura; Chang, Yiming; Altvater, Martin; Menet, Anna M; Kemmler, Stefan; Panse, Vikram G

    2013-09-01

    Multiple export receptors passage bound pre-ribosomes through nuclear pore complexes (NPCs) by transiently interacting with the Phe-Gly (FG) meshwork of their transport channels. Here, we reveal how the non-FG interacting yeast mRNA export factor Gly-Leu-FG lethal 2 (Gle2) functions in the export of the large pre-ribosomal subunit (pre-60S). Structure-guided studies uncovered conserved platforms used by Gle2 to export pre-60S: an uncharacterized basic patch required to bind pre-60S, and a second surface that makes non-FG contacts with the nucleoporin Nup116. A basic patch mutant of Gle2 is able to function in mRNA export, but not pre-60S export. Thus, Gle2 provides a distinct interaction platform to transport pre-60S to the cytoplasm. Notably, Gle2's interaction platforms become crucial for pre-60S export when FG-interacting receptors are either not recruited to pre-60S or are impaired. We propose that large complex cargos rely on non-FG as well as FG-interactions for their efficient translocation through the nuclear pore complex channel.

  7. The pro-inflammatory cytokine tumor necrosis factor α stimulates expression of the carnitine transporter OCTN2 (novel organic cation transporter 2) and carnitine uptake via nuclear factor-κB in Madin-Darby bovine kidney cells.

    PubMed

    Zhou, X; Ringseis, R; Wen, G; Eder, K

    2015-06-01

    Carnitine uptake into tissues is mediated mainly by the novel organic cation transporter 2 (OCTN2), whose expression is upregulated in the liver of early-lactating dairy cows. It has been shown recently that pro-inflammatory cytokines, including tumor necrosis factor α (TNFα), stimulate OCTN2 expression and carnitine uptake in intestinal cells and inflamed intestinal mucosa. Given that many early-lactating dairy cows show typical signs of hepatic and systemic inflammation, such as elevated concentrations of circulating TNFα and activation of the key regulator of inflammation, nuclear factor κB (NF-κB), in tissues, it is possible that upregulation of OCTN2 and increase of carnitine uptake by TNFα is mediated by NF-κB, a mechanism that might contribute to the upregulation of OCNT2 in the liver of early-lactating dairy cows. Thus, in the present study, we tested the hypothesis that TNFα stimulates OCTN2 gene expression and carnitine uptake via NF-κB in the bovine Madin-Darby bovine kidney (MDBK) cell line. Treatment with TNFα caused activation of NF-κB, increased the mRNA and protein concentration of OCTN2, and stimulated the uptake of carnitine in MDBK cells. In contrast, combined treatment of MDBK cells with TNFα and the NF-κB inhibitor BAY 11-7085 completely blocked the effect of TNFα on OCTN2 mRNA and protein concentration and uptake of carnitine. These findings suggest that the bovine OCTN2 gene and carnitine uptake are regulated by NF-κB. Future studies are required to show the in vivo relevance of this regulatory mechanism in cattle.

  8. The Yeast Nuclear Pore Complex and Transport Through It

    PubMed Central

    Aitchison, John D.; Rout, Michael P.

    2012-01-01

    Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell’s genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or “Nups”), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC’s role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins. PMID:22419078

  9. Nuclear transportation: The global vision

    SciTech Connect

    Lowry, D.; Blowers, A.

    1996-12-31

    The movement of nuclear materials - spent fuel, plutonium and uranium and radioactive wastes - has become an issue of international political significance. It has generated considerable attention from a developing network of NGOs focussing on movements between France and Japan. The paper discusses the conflicts and their implications for six basic principles of radioactive waste management.

  10. Hepatocyte nuclear factor 1 regulates the expression of the organic cation transporter 1 via binding to an evolutionary conserved region in intron 1 of the OCT1 gene.

    PubMed

    O'Brien, Valerie P; Bokelmann, Kristin; Ramírez, Jacqueline; Jobst, Karoline; Ratain, Mark J; Brockmöller, Jürgen; Tzvetkov, Mladen V

    2013-10-01

    The organic cation transporter 1 (OCT1), also known as solute carrier family 22 member 1, is strongly and specifically expressed in the human liver. Here we show that the hepatocyte nuclear factor 1 (HNF1) regulates OCT1 transcription and contributes to the strong, liver-specific expression of OCT1. Bioinformatic analyses revealed strong conservation of HNF1 binding motifs in an evolutionary conserved region (ECR) in intron 1 of the OCT1 gene. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the specific binding of HNF1 to the intron 1 ECR. In reporter gene assays performed in HepG2 cells, the intron 1 ECR increased SV40 promoter activity by 22-fold and OCT1 promoter activity by 13-fold. The increase was reversed when the HNF1 binding sites in the intron 1 ECR were mutated or the endogenous HNF1α expression was downregulated with small interfering RNA. Following HNF1α overexpression in Huh7 cells, the intron 1 ECR increased SV40 promoter activity by 11-fold and OCT1 promoter activity by 6-fold. Without HNF1α overexpression, the increases were only 3- and 2-fold, respectively. Finally, in human liver samples, high HNF1 expression was significantly correlated with high OCT1 expression (r = 0.48, P = 0.002, n = 40). In conclusion, HNF1 is a strong regulator of OCT1 expression. It remains to be determined whether genetic variants, disease conditions, or drugs that affect HNF1 activity may affect the pharmacokinetics and efficacy of OCT1-transported drugs such as morphine, tropisetron, ondansetron, tramadol, and metformin. Beyond OCT1, this study demonstrates the validity and usefulness of interspecies comparisons in the discovery of functionally relevant genomic sequences.

  11. Atoms on the Move: Transporting Nuclear Material.

    ERIC Educational Resources Information Center

    Dukert, Joseph M.

    This is an Energy Research and Development Administration pamphlet outlining in detail the many aspects involved in safe transportation of all types of nuclear materials. The detailed safety regulations and designs of various shipping packages and containers are emphasized. Included are maps of waste burial sites and fuel production facilities, an…

  12. Energetics of Transport through the Nuclear Pore Complex

    PubMed Central

    Ghavami, Ali; van der Giessen, Erik; Onck, Patrick R.

    2016-01-01

    Molecular transport across the nuclear envelope in eukaryotic cells is solely controlled by the nuclear pore complex (NPC). The NPC provides two types of nucleocytoplasmic transport: passive diffusion of small molecules and active chaperon-mediated translocation of large molecules. It has been shown that the interaction between intrinsically disordered proteins that line the central channel of the NPC and the transporting cargoes is the determining factor, but the exact mechanism of transport is yet unknown. Here, we use coarse-grained molecular dynamics simulations to quantify the energy barrier that has to be overcome for molecules to pass through the NPC. We focus on two aspects of transport. First, the passive transport of model cargo molecules with different sizes is studied and the size selectivity feature of the NPC is investigated. Our results show that the transport probability of cargoes is significantly reduced when they are larger than ∼5 nm in diameter. Secondly, we show that incorporating hydrophobic binding spots on the surface of the cargo effectively decreases the energy barrier of the pore. Finally, a simple transport model is proposed which characterizes the energy barrier of the NPC as a function of diameter and hydrophobicity of the transporting particles. PMID:26894898

  13. Spent Nuclear Fuel Transport Reliability Study

    SciTech Connect

    Wang, Jy-An John; Wang, Hong; Jiang, Hao

    2016-01-01

    This conference paper was orignated and shorten from the following publisehd PTS documents: 1. Jy-An Wang, Hao Jiang, and Hong Wang, Dynamic Deformation Simulation of Spent Nuclear Fuel Assembly and CIRFT Deformation Sensor Stability Investigation, ORNL/SPR-2015/662, November 2015. 2. Jy-An Wang, Hong Wang, Mechanical Fatigue Testing of High-Burnup Fuel for Transportation Applications, NUREG/CR-7198, ORNL/TM-2014/214, May 2015. 3. Jy-An Wang, Hong Wang, Hao Jiang, Yong Yan, Bruce Bevard, Spent Nuclear Fuel Vibration Integrity Study 16332, WM2016 Conference, March 6 10, 2016, Phoenix, Arizona.

  14. Crocodylian nuclear factor kappa B.

    PubMed

    Merchant, Mark; Morkotinis, Vasileios; Hale, Amber; White, Mary; Moran, Chris

    2017-11-01

    We deduced the amino acid (aa) sequence of the nuclear factor kappa B (NFκB) protein from genomic data for the American alligator (Alligator mississippiensis), the estuarine crocodile (Crocodylus porosus), and the Indian gharial (Gavialis gangeticus). A 105kDa protein, NFκB1 exhibits complex post-translational processing, multiple mechanisms of activation, and acts as precursor for a p50, a Rel homology transcription factor which influences the expression of key genes for developmental processes, apoptosis, and immune function. The aa sequences of the crocodylian proteins share very high identity with each other (97.2±0.7%), birds (81.0±1.1%, n=6), mammals (75.3±1.6%, n=4), reptiles (80.3±5.1%, n=2), and less identity with fish (55.5±5.5%, n=4) and one amphibian (66.1±0.8%). The crocodylian protein has a well-conserved Rel homology domain, a nuclear localization signal, and a glycine-rich region which facilitates proteasome-mediated generation of p50. The Rel homology domain contains sequences responsible for dimerization, DNA-binding, and nuclear translocation. In addition, seven ankyrin repeats were located, which putatively allow for inhibition of transcriptional regulation by mediating interaction with Inhibitor kappa B. Other features include a death domain, and conserved serine residues, near the C-terminal end, which act as potential phosphorylation sites for activation of the proteolytic generation of p50. Western blot analysis showed both the 105kDa precursor and the 50kDa mature NFκB were expressed in the alligator liver. Nuclear factor κB exhibited diffuse cytoplasmic distribution in alligator hepatocytes, and almost no cytoplasmic localization in infected animals. In addition, nuclear NFκB exhibited specific binding to the consensus NFκB promoter element. Published by Elsevier Inc.

  15. Ran-binding protein 5 (RanBP5) is related to the nuclear transport factor importin-beta but interacts differently with RanBP1.

    PubMed Central

    Deane, R; Schäfer, W; Zimmermann, H P; Mueller, L; Görlich, D; Prehn, S; Ponstingl, H; Bischoff, F R

    1997-01-01

    We report the identification and characterization of a novel 124-kDa Ran binding protein, RanBP5. This protein is related to importin-beta, the key mediator of nuclear localization signal (NLS)-dependent nuclear transport. RanBP5 was identified by two independent methods: it was isolated from HeLa cells by using its interaction with RanGTP in an overlay assay to monitor enrichment, and it was also found by the yeast two-hybrid selection method with RanBP1 as bait. RanBP5 binds to RanBP1 as part of a trimeric RanBP1-Ran-RanBP5 complex. Like importin-beta, RanBP5 strongly binds the GTP-bound form of Ran, stabilizing it against both intrinsic and RanGAP1-induced GTP hydrolysis and also against nucleotide exchange. The GAP resistance of the RanBP5-RanGTP complex can be relieved by RanBP1, which might reflect an in vivo role for RanBP1. RanBP5 is a predominantly cytoplasmic protein that can bind to nuclear pore complexes. We propose that RanBP5 is a mediator of a nucleocytoplasmic transport pathway that is distinct from the importin-alpha-dependent import of proteins with a classical NLS. PMID:9271386

  16. Ran-binding protein 5 (RanBP5) is related to the nuclear transport factor importin-beta but interacts differently with RanBP1.

    PubMed

    Deane, R; Schäfer, W; Zimmermann, H P; Mueller, L; Görlich, D; Prehn, S; Ponstingl, H; Bischoff, F R

    1997-09-01

    We report the identification and characterization of a novel 124-kDa Ran binding protein, RanBP5. This protein is related to importin-beta, the key mediator of nuclear localization signal (NLS)-dependent nuclear transport. RanBP5 was identified by two independent methods: it was isolated from HeLa cells by using its interaction with RanGTP in an overlay assay to monitor enrichment, and it was also found by the yeast two-hybrid selection method with RanBP1 as bait. RanBP5 binds to RanBP1 as part of a trimeric RanBP1-Ran-RanBP5 complex. Like importin-beta, RanBP5 strongly binds the GTP-bound form of Ran, stabilizing it against both intrinsic and RanGAP1-induced GTP hydrolysis and also against nucleotide exchange. The GAP resistance of the RanBP5-RanGTP complex can be relieved by RanBP1, which might reflect an in vivo role for RanBP1. RanBP5 is a predominantly cytoplasmic protein that can bind to nuclear pore complexes. We propose that RanBP5 is a mediator of a nucleocytoplasmic transport pathway that is distinct from the importin-alpha-dependent import of proteins with a classical NLS.

  17. Transport description of damped nuclear reactions

    SciTech Connect

    Randrup, J.

    1983-04-01

    Part I is an elementary introduction to the general transport theory of nuclear dynamics. It can be read without any special knowledge of the field, although basic quantum mechanics is required for the formal derivation of the general expression for the transport coefficients. The results can also be used in a wider context than the present one. Part II gives the student an up-to-date orientation about recent progress in the understanding of the angular-momentum variables in damped reactions. The emphasis is here on the qualitative understanding of the physics rather than the, at times somewhat tedious, formal derivations. (WHK)

  18. Tertiary-butylhydroquinone upregulates expression of ATP-binding cassette transporter A1 via nuclear factor E2-related factor 2/heme oxygenase-1 signaling in THP-1 macrophage-derived foam cells.

    PubMed

    Lu, Qian; Tang, Shi-Lin; Liu, Xiao-Yan; Zhao, Guo-Jun; Ouyang, Xin-Ping; Lv, Yun-Cheng; He, Ping-Ping; Yao, Feng; Chen, Wu-Jun; Tang, Yan-Yan; Zhang, Min; Zhang, Da-Wei; Yin, Kai; Tang, Chao-Ke

    2013-01-01

    Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis. tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity. Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested.

  19. Air Transport of Spent Nuclear Fuel (SNF) Assemblies

    SciTech Connect

    Haire, M.J.; Moses, S.D.; Shapovalov, V.I.; Morenko, A.

    2007-07-01

    Sometimes the only feasible means of shipping research reactor spent nuclear fuel (SNF) among countries is via air transport because of location or political conditions. The International Atomic Energy Agency (IAEA) has established a regulatory framework to certify air transport Type C casks. However, no such cask has been designed, built, tested, and certified. In lieu of an air transport cask, research reactor SNF has been transported using a Type B cask under an exemption with special arrangements for administrative and security controls. This work indicates that it may be feasible to transport commercial power reactor SNF assemblies via air, and that the cost is only about three times that of shipping it by railway. Optimization (i.e., reduction) of this cost factor has yet to be done. (authors)

  20. Nuclear Transport Modulation Reduces Hypercholesterolemia, Atherosclerosis, and Fatty Liver

    PubMed Central

    Liu, Yan; Major, Amy S.; Zienkiewicz, Jozef; Gabriel, Curtis L.; Veach, Ruth Ann; Moore, Daniel J.; Collins, Robert D.; Hawiger, Jacek

    2013-01-01

    Background Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide. Methods and Results A cell‐penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low‐density lipoprotein receptor‐deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline‐treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM‐treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress‐responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element‐binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM‐modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia. Conclusions Two‐pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications. PMID:23563994

  1. Single-Molecule Imaging of Nuclear Transport

    PubMed Central

    Goryaynov, Alexander; Sarma, Ashapurna; Ma, Jiong; Yang, Weidong

    2010-01-01

    The utility of single molecule fluorescence microscopy approaches has been proven to be of a great avail in understanding biological reactions over the last decade. The investigation of molecular interactions with high temporal and spatial resolutions deep within cells has remained challenging due to the inherently weak signals arising from individual molecules. Recent works by Yang et al. demonstrated that narrow-field epifluorescence microscopy allows visualization of nucleocytoplasmic transport at the single molecule level. By the single molecule approach, important kinetics, such as nuclear transport time and efficiency, for signal-dependent and independent cargo molecules have been obtained. Here we described a protocol for the methodological approach with an improved spatiotemporal resolution of 0.4 ms and 12 nm. The improved resolution enabled us to capture transient active transport and passive diffusion events through the nuclear pore complexes (NPC) in semi-intact cells. We expect this method to be used in elucidating other binding and trafficking events within cells. PMID:20548283

  2. Nevada commercial spent nuclear fuel transportation experience

    SciTech Connect

    1991-09-01

    The purpose of this report is to present an historic overview of commercial reactor spent nuclear fuel (SNF) shipments that have occurred in the state of Nevada, and to review the accident and incident experience for this type of shipments. Results show that between 1964 and 1990, 309 truck shipments covering approximately 40,000 miles moved through Nevada; this level of activity places Nevada tenth among the states in the number of truck shipments of SNF. For the same period, 15 rail shipments moving through the State covered approximately 6,500 miles, making Nevada 20th among the states in terms of number of rail shipments. None of these shipments had an accident or an incident associated with them. Because the data for Nevada are so limited, national data on SNF transportation and the safety of truck and rail transportation in general were also assessed.

  3. Human Factors Research and Nuclear Safety.

    ERIC Educational Resources Information Center

    Moray, Neville P., Ed.; Huey, Beverly M., Ed.

    The Panel on Human Factors Research Needs in Nuclear Regulatory Research was formed by the National Research Council in response to a request from the Nuclear Regulatory Commission (NRC). The NRC asked the research council to conduct an 18-month study of human factors research needs for the safe operation of nuclear power plants. This report…

  4. Nuclear Energy and Synthetic Liquid Transportation Fuels

    NASA Astrophysics Data System (ADS)

    McDonald, Richard

    2012-10-01

    This talk will propose a plan to combine nuclear reactors with the Fischer-Tropsch (F-T) process to produce synthetic carbon-neutral liquid transportation fuels from sea water. These fuels can be formed from the hydrogen and carbon dioxide in sea water and will burn to water and carbon dioxide in a cycle powered by nuclear reactors. The F-T process was developed nearly 100 years ago as a method of synthesizing liquid fuels from coal. This process presently provides commercial liquid fuels in South Africa, Malaysia, and Qatar, mainly using natural gas as a feedstock. Nuclear energy can be used to separate water into hydrogen and oxygen as well as to extract carbon dioxide from sea water using ion exchange technology. The carbon dioxide and hydrogen react to form synthesis gas, the mixture needed at the beginning of the F-T process. Following further refining, the products, typically diesel and Jet-A, can use existing infrastructure and can power conventional engines with little or no modification. We can then use these carbon-neutral liquid fuels conveniently long into the future with few adverse environmental impacts.

  5. Ion transport of Fr nuclear reaction products

    SciTech Connect

    Behr, J.A.; Cahn, S.B.; Dutta, S.B.

    1993-04-01

    Experiments planned for fundamental studies of radioactive atoms in magneto-optic traps require efficient deceleration and transport of nuclear reaction products to energies and locations where they can be trapped. The authors have built a low-energy ion transport system for Francium and other alkalis. A thick Au target is held on a W rod at 45{degrees} to the accelerator beam direction. The heavy-ion fusion reaction 115 MeV {sup 18}O + {sup 197}Au produces {sup 211,210,209}Fr recoil products which are stopped in the target. The target is heated to close to the melting point of Au to allow the Fr to diffuse to the surface, where it is ionized due to Au`s high work function, and is directly extracted by an electrode at 90{degrees} to the accelerator beam direction. The Fr is transported by electrostatic optics {approximately}1 m to a catcher viewed by an {alpha} detector: {ge}15% of the Fr produced in the target reaches the catcher. 2{times}10{sup 5} Fr/sec have been produced at the catcher, yielding at equilibrium a sample of 3x10{sup 7}Fr nuclei. This scheme physically decouples the target diffusion from the surface neutralization process, which can occur at a lower temperature more compatible with the neutral-atom trap.

  6. Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential.

    PubMed

    Stelma, Tamara; Chi, Alicia; van der Watt, Pauline J; Verrico, Annalisa; Lavia, Patrizia; Leaner, Virna D

    2016-04-01

    The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets.

  7. Nuclear transport erupts on the slopes of Mount Etna.

    PubMed

    Powers, Maureen A; Dasso, Mary

    2004-02-01

    Nuclear pore complexes (NPCs) mediate the active transport of large substrates and allow the passive diffusion of small molecules into the nucleus of eukaryotic cells. The EMBO Workshop on the Mechanisms of Nuclear Transport focused on NPCs and on the soluble nucleocytoplasmic transport machinery. This meeting, organized by Valérie Doye (Institut Curie, Paris) and Ed Hurt (University of Heidelberg), was held within view of Mount Etna at Taormina, Sicily (November 1-5, 2003). Presentations emphasized the dynamic properties of the nuclear trafficking machinery, and demonstrated the continuity of nuclear transport with processes in the nucleus and cytoplasm.

  8. Transverse-momentum spectra and nuclear modification factor using Boltzmann Transport Equation with flow in Pb+Pb collisions at √{s_{NN}} = 2.76 TeV

    NASA Astrophysics Data System (ADS)

    Tripathy, Sushanta; Khuntia, Arvind; Tiwari, Swatantra Kumar; Sahoo, Raghunath

    2017-05-01

    In the continuation of our previous work, the transverse-momentum (pT) spectra and nuclear modification factor (R_{AA}) are derived using the relaxation time approximation of Boltzmann Transport Equation (BTE). The initial pT-distribution used to describe p + p collisions has been studied with the perturbative-Quantum Chromodynamics (pQCD) inspired power-law distribution, Hagedorn's empirical formula and with the Tsallis non-extensive statistical distribution. The non-extensive Tsallis distribution is observed to describe the complete range of the transverse-momentum spectra. The Boltzmann-Gibbs Blast Wave (BGBW) distribution is used as the equilibrium distribution in the present formalism, to describe the pT-distribution and nuclear modification factor in nucleus-nucleus collisions. The experimental data for Pb+Pb collisions at √{s_{NN}} = 2.76 TeV at the Large Hadron Collider at CERN have been analyzed for pions, kaons, protons, K^{\\ast0} and φ. It is observed that the present formalism while explaining the transverse-momentum spectra up to 5 GeV/ c, explains the nuclear modification factor very well up to 8 GeV/ c in pT for all these particles except for protons. R_{AA} is found to be independent of the degree of non-extensivity, q_{pp} after pT ˜ 8 GeV/ c.

  9. Nuclear transport: shifting gears in fungal nuclear and cytoplasmic organization.

    PubMed

    Casey, Amanda K; Wente, Susan R

    2012-10-09

    In fungi, nuclear pore complexes are free to move through the nuclear envelope; however, little is known about how movement is regulated. New evidence reveals roles for molecular motors and potential impacts on genomic organization.

  10. Astrocyte Elevated Gene-1 Is a Novel Modulator of HIV-1-associated Neuroinflammation via Regulation of Nuclear Factor-κB Signaling and Excitatory Amino Acid Transporter-2 Repression*

    PubMed Central

    Vartak-Sharma, Neha; Gelman, Benjamin B.; Joshi, Chaitanya; Borgamann, Kathleen; Ghorpade, Anuja

    2014-01-01

    Astrocyte elevated gene-1 (AEG-1), a novel human immunodeficiency virus (HIV)-1 and tumor necrosis factor (TNF)-α-inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic aggressive tumors. However, little is known about its role in astrocyte responses during HIV-1 central nervous system (CNS) infection and whether it contributes toward the development of HIV-associated neurocognitive disorders (HAND). Therefore, in this study, we investigated changes in AEG-1 CNS expression in HIV-1-infected brain tissues and elucidated a potential mechanism of AEG-1-mediated regulation of HAND. Immunoblotting and immunohistochemical analyses of HIV-1 seropositive and HIV-1 encephalitic human brain tissues revealed significantly elevated levels of AEG-1 protein. Immunohistochemical analyses of HIV-1 Tat transgenic mouse brain tissues also showed a marked increase in AEG-1 staining. Similar to in vivo observations, cultured astrocytes expressing HIV-1 Tat also revealed AEG-1 and cytokine up-regulation. Astrocytes treated with HAND-relevant stimuli, TNF-α, interleukin (IL)-1β, and HIV-1, also significantly induced AEG-1 expression and nuclear translocation via activation of the nuclear factor (NF)-κB pathway. Co-immunoprecipitation studies demonstrated IL-1β- or TNF-α-induced AEG-1 interaction with NF-κB p65 subunit. AEG-1 knockdown decreased NF-κB activation, nuclear translocation, and transcriptional output in TNF-α-treated astrocytes. Moreover, IL-1β treatment of AEG-1-overexpressing astrocytes significantly lowered expression of excitatory amino acid transporter 2, increased expression of excitatory amino acid transporter 2 repressor ying yang 1, and reduced glutamate clearance, a major transducer of excitotoxic neuronal damage. Findings from this study identify a novel transcriptional co-factor function of AEG-1 and further implicate AEG-1 in HAND-associated neuroinflammation. PMID:24855648

  11. Modulation of nuclear pore topology by transport modifiers.

    PubMed

    Jäggi, Rainer D; Franco-Obregón, Alfredo; Mühlhäusser, Petra; Thomas, Franziska; Kutay, Ulrike; Ensslin, Klaus

    2003-01-01

    The nuclear pore complex (NPC) represents the only pathway for macromolecular communication between the nuclear and cytoplasmic compartments of the cell. Nucleocytoplasmic transport requires the interaction of transport receptors with phenylalanine-glycine (FG)-repeats that line the transport pathway through the NPC. Here we examine the effects of transport receptors and amphipathic alcohols on NPC topology using scanning force microscopy. We show that transport receptors that irreversibly bind FG-repeats increase NPC vertical aspect, whereas transport receptors that weakly interact with FG-repeats increase NPC diameter. Interestingly, small polar alcohols likewise increase NPC diameter. These opposing effects agree with the inhibition or enhancement of nuclear transport, respectively, previously ascribed to these agents.

  12. Enzymatically driven transport: a kinetic theory for nuclear export.

    PubMed

    Kim, Sanghyun; Elbaum, M

    2013-11-05

    Nuclear import and export are often considered inverse processes whereby transport receptors ferry protein cargo through the nuclear pore. In contrast to import, where the reversible binding of receptor to nuclear RanGTP leads to a balanced bidirectional exchange, termination of export by physiologically irreversible hydrolysis of the Ran-bound GTP leads to unidirectional transport. We present a concise mathematical model that predicts protein distributions and kinetic rates for receptor-mediated nuclear export, which further exhibit an unexpected pseudolinear relation one to the other. Predictions of the model are verified with permeabilized and live cell measurements. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  13. Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor kappaB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells.

    PubMed

    Jové, Mireia; Planavila, Anna; Laguna, Juan Carlos; Vázquez-Carrera, Manuel

    2005-07-01

    The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. Here, we report that exposure of C2C12 skeletal muscle cells to 0.5 mm palmitate results in increased mRNA levels (3.5-fold induction; P < 0.05) and secretion (control 375 +/- 57 vs. palmitate 1129 +/- 177 pg/ml; P < 0.001) of the proinflammatory cytokine IL-6. Palmitate increased nuclear factor-kappaB activation and coincubation of the cells with palmitate and the nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate prevented both IL-6 expression and secretion. Furthermore, incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C, and phorbol myristate acetate, that down-regulates protein kinase C in long-term incubations, abolished induction of IL-6 production. Finally, exposure of skeletal muscle cells to palmitate caused a fall in the mRNA levels of glucose transporter 4 and insulin-stimulated glucose uptake, whereas in the presence of anti-IL-6 antibody, which neutralizes the biological activity of mouse IL-6 in cell culture, these reductions were prevented. These findings suggest that IL-6 may mediate several of the prodiabetic effects of palmitate.

  14. Kpna7 interacts with egg-specific nuclear factors in rainbow trout (Oncorhynchus mykiss)

    USDA-ARS?s Scientific Manuscript database

    Nuclear proteins are required for initiation of transcription in early embryos before embryonic genome activation. The regulation of transportation of nuclear proteins is mediated by transport factors known as importins (karyopherins). Kpna7 is a newly discovered member of the importin a family, whi...

  15. Electron transport through nuclear pasta in magnetized neutron stars

    NASA Astrophysics Data System (ADS)

    Yakovlev, D. G.

    2015-10-01

    We present a simple model for electron transport in a possible layer of exotic nuclear clusters (in the so-called nuclear pasta layer) between the crust and liquid core of a strongly magnetized neutron star. The electron transport there can be strongly anisotropic and gyrotropic. The anisotropy is produced by different electron effective collision frequencies along and across local symmetry axis in domains of exotic ordered nuclear clusters and by complicated effects of the magnetic field. We also calculate averaged kinetic coefficients in case local domains are freely oriented. Possible applications of the obtained results and open problems are outlined.

  16. Effects of Nuclear Interactions in Space Radiation Transport

    NASA Technical Reports Server (NTRS)

    Lin, Zi-Wei; Barghouty, A. F.

    2004-01-01

    Space radiation transport codes have been developed to calculate radiation effects behind materials in human missions to the Moon, Mars or beyond. We study how nuclear fragmentation processes affect predictions from such radiation transport codes. In particular, we investigate the effects of fragmentation cross sections at different energies on fluxes, dose and dose-equivalent from galactic cosmic rays behind typical shielding materials.

  17. Effects of Nuclear Interactions in Space Radiation Transport

    NASA Technical Reports Server (NTRS)

    Lin, Zi-Wei; Barghouty, A. F.

    2005-01-01

    Space radiation transport codes have been developed to calculate radiation effects behind materials in human mission to the Moon, Mars or beyond. We study how nuclear fragmentation processes affect predictions from such radiation transport codes. In particular, we investigate the effects of fragmentation cross sections at different energies on fluxes, dose and dose-equivalent from galactic cosmic rays behind typical shielding materials.

  18. Artificial nanopores that mimic the transport selectivity of the nuclear pore complex.

    PubMed

    Jovanovic-Talisman, Tijana; Tetenbaum-Novatt, Jaclyn; McKenney, Anna Sophia; Zilman, Anton; Peters, Reiner; Rout, Michael P; Chait, Brian T

    2009-02-19

    Nuclear pore complexes (NPCs) act as effective and robust gateways between the nucleus and the cytoplasm, selecting for the passage of particular macromolecules across the nuclear envelope. NPCs comprise an elaborate scaffold that defines a approximately 30 nm diameter passageway connecting the nucleus and the cytoplasm. This scaffold anchors proteins termed 'phenylalanine-glycine' (FG)-nucleoporins, the natively disordered domains of which line the passageway and extend into its lumen. Passive diffusion through this lined passageway is hindered in a size-dependent manner. However, transport factors and their cargo-bound complexes overcome this restriction by transient binding to the FG-nucleoporins. To test whether a simple passageway and a lining of transport-factor-binding FG-nucleoporins are sufficient for selective transport, we designed a functionalized membrane that incorporates just these two elements. Here we demonstrate that this membrane functions as a nanoselective filter, efficiently passing transport factors and transport-factor-cargo complexes that specifically bind FG-nucleoporins, while significantly inhibiting the passage of proteins that do not. This inhibition is greatly enhanced when transport factor is present. Determinants of selectivity include the passageway diameter, the length of the nanopore region coated with FG-nucleoporins, the binding strength to FG-nucleoporins, and the antagonistic effect of transport factors on the passage of proteins that do not specifically bind FG-nucleoporins. We show that this artificial system faithfully reproduces key features of trafficking through the NPC, including transport-factor-mediated cargo import.

  19. Comparative analyses of spent nuclear fuel transport modal options: Transport options under existing site constraints

    SciTech Connect

    Brentlinger, L.A.; Hofmann, P.L.; Peterson, R.W.

    1989-08-01

    The movement of nuclear waste can be accomplished by various transport modal options involving different types of vehicles, transport casks, transport routes, and intermediate intermodal transfer facilities. A series of systems studies are required to evaluate modal/intermodal spent fuel transportation options in a consistent fashion. This report provides total life-cycle cost and life-cycle dose estimates for a series of transport modal options under existing site constraints. 14 refs., 7 figs., 28 tabs.

  20. Transportation capabilities study of DOE-owned spent nuclear fuel

    SciTech Connect

    Clark, G.L.; Johnson, R.A.; Smith, R.W.; Abbott, D.G.; Tyacke, M.J.

    1994-10-01

    This study evaluates current capabilities for transporting spent nuclear fuel owned by the US Department of Energy. Currently licensed irradiated fuel shipping packages that have the potential for shipping the spent nuclear fuel are identified and then matched against the various spent nuclear fuel types. Also included are the results of a limited investigation into other certified packages and new packages currently under development. This study is intended to support top-level planning for the disposition of the Department of Energy`s spent nuclear fuel inventory.

  1. RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors.

    PubMed

    Bischoff, F R; Görlich, D

    1997-12-15

    Nucleocytoplasmic transport appears mediated by shuttling transport receptors that bind RanGTP as a means to regulate interactions with their cargoes. The receptor-RanGTP complexes are kinetically very stable with nucleotide exchange and GTP hydrolysis being blocked, predicting that a specific disassembly mechanism exists. Here we show in three cases receptor RanGTP x RanBP1 complexes to be the key disassembly intermediates, where RanBP1 stimulates the off-rate at the receptor/RanGTP interface by more than two orders of magnitude. The transiently released RanGTP x RanBP1 complex is then induced by RanGAP to hydrolyse GTP, preventing the receptor to rebind RanGTP. The efficient release of importin beta from RanGTP requires importin alpha, in addition to RanBP1.

  2. Investigation of nuclear pore complex protein interactions and the implications for nuclear transport

    NASA Astrophysics Data System (ADS)

    Isgro, Timothy A.

    The nucleus of the cell is of central importance to an organism, serving to store and organize genetic material, while separating and protecting this very important information from the host of other cellular components. While the nucleus requires this protective isolation, it also needs to communicate with the rest of the cell, exchanging proteins and RNA, for a variety of nuclear and cytoplasmic processes which act in concert. The nuclear pore complex is responsible for controlling the transport of large molecules into and out of the cell nucleus. It is perhaps the largest protein structure in eukaryotic cells, and because of its size, pointed experimental study has been difficult. As a result, the mechanism by which the nuclear pore complex selectively allows "good" material across the nuclear envelope, while preventing the transit of "bad", remains unknown. Here, the computer has been used to study interactions between the transport receptors that shuttle material across the nuclear pore complex and FG-nucleoporins, proteins which compose the complex itself and are of great importance in allowing protected nuclear transport. Molecular dynamics simulations have been performed on transport complexes formed by the transport receptors importin-beta, NTF2, and Cse1p. The simulations confirm nearly all interactions previously known about from experimental data, while serving, in some cases, to provide greater detail about these interactions. Furthermore, the simulations uncover a host of previously unknown interactions between each transport receptor and FG-nups. When the interactions are compared across all three transport receptors, a novel binding pattern is revealed that indicates how the nuclear pore complex may recognize the difference between the macromolecules destined to cross the nuclear envelope and the host of other proteins for which it must protect against transport.

  3. Factorized molecular wave functions: Analysis of the nuclear factor

    SciTech Connect

    Lefebvre, R.

    2015-06-07

    The exact factorization of molecular wave functions leads to nuclear factors which should be nodeless functions. We reconsider the case of vibrational perturbations in a diatomic species, a situation usually treated by combining Born-Oppenheimer products. It was shown [R. Lefebvre, J. Chem. Phys. 142, 074106 (2015)] that it is possible to derive, from the solutions of coupled equations, the form of the factorized function. By increasing artificially the interstate coupling in the usual approach, the adiabatic regime can be reached, whereby the wave function can be reduced to a single product. The nuclear factor of this product is determined by the lowest of the two potentials obtained by diagonalization of the potential matrix. By comparison with the nuclear wave function of the factorized scheme, it is shown that by a simple rectification, an agreement is obtained between the modified nodeless function and that of the adiabatic scheme.

  4. The transport of nuclear power plant components. [via airships

    NASA Technical Reports Server (NTRS)

    Keating, S. J., Jr.

    1975-01-01

    The problems of transporting nuclear power plant components to landlocked sites where the usual mode of transport by barge cannot be used are considered. Existing methods of ground-based overland transport are discussed and their costs presented. Components are described and traffic density projections made to the year 2000. Plots of units transported versus distance transported are provided for units booked in 1973 and booked and proposed in 1974. It is shown that, for these cases, overland transport requirements for the industry will be over 5,000,000 ton-miles/year while a projection based on increasing energy demands shows that this figure will increase significantly by the year 2000. The payload size, distances, and costs of existing overland modes are significant enough to consider development of a lighter than air (LTA) mode for transporting NSSS components.

  5. Effects of Nuclear Interactions on Accuracy of Space Radiation Transport

    NASA Technical Reports Server (NTRS)

    Lin, Zi-Wei; Barghouty, A. F.

    2005-01-01

    Space radiation risk to astronauts and electronic equipments is one major obstacle in long term human space explorations. Space radiation transport codes have been developed to calculate radiation effects behind materials in human missions to the Moon, Mars or beyond. We study how nuclear fragmentation processes affect the accuracy of predictions from such radiation transport. In particular, we investigate the effects of fragmentation cross sections at different energies on fluxes, dose and dose-equivalent from galactic cosmic rays behind typical shielding materials. These results tell us at what energies nuclear cross sections are the most important for radiation risk evaluations, and how uncertainties in our knowledge about nuclear fragmentations relate to uncertainties in space transport predictions.

  6. Effects of Nuclear Interactions on Accuracy of Space Radiation Transport

    NASA Technical Reports Server (NTRS)

    Lin, Zi-Wei; Barghouty, A. F.

    2005-01-01

    Space radiation risk to astronauts and electronic equipments is one major obstacle in long term human space explorations. Space radiation transport codes have been developed to calculate radiation effects behind materials in human missions to the Moon, Mars or beyond. We study how nuclear fragmentation processes affect the accuracy of predictions from such radiation transport. In particular, we investigate the effects of fragmentation cross sections at different energies on fluxes, dose and dose-equivalent from galactic cosmic rays behind typical shielding materials. These results tell us at what energies nuclear cross sections are the most important for radiation risk evaluations, and how uncertainties in our knowledge about nuclear fragmentations relate to uncertainties in space transport predictions.

  7. Role of nuclear receptors in the regulation of drug transporters in the brain.

    PubMed

    Chan, Gary N Y; Hoque, Md Tozammel; Bendayan, Reina

    2013-07-01

    ATP-binding cassette membrane-associated drug efflux transporters and solute carrier influx transporters, expressed at the blood-brain barrier, blood-cerebrospinal fluid barrier, and in brain parenchyma, are important determinants of drug disposition in the central nervous system. Targeting the regulatory pathways that govern the expression of these transporters could provide novel approaches to selectively alter drug permeability into the brain. Nuclear receptors are ligand-activated transcription factors which regulate the gene expression of several metabolic enzymes and drug efflux/influx transporters. Although efforts have primarily been focused on investigating these regulatory pathways in peripheral organs (i.e., liver and intestine), recent findings demonstrate their significance in the brain. This review addresses the role of nuclear receptors in the regulation of drug transporter functional expression in the brain. An in-depth understanding of these pathways could guide the development of novel pharmacotherapy with either enhanced efficacy in the central nervous system or minimal associated neurotoxicity.

  8. Review of EPRI Nuclear Human Factors Program

    SciTech Connect

    Hanes, L.F.; O`Brien, J.F.

    1996-03-01

    The Electric Power Research Institute (EPRI) Human Factors Program, which is part of the EPRI Nuclear Power Group, was established in 1975. Over the years, the Program has changed emphasis based on the shifting priorities and needs of the commercial nuclear power industry. The Program has produced many important products that provide significant safety and economic benefits for EPRI member utilities. This presentation will provide a brief history of the Program and products. Current projects and products that have been released recently will be mentioned.

  9. Towards Quantum Transport for Central Nuclear Reactions

    NASA Astrophysics Data System (ADS)

    Danielewicz, Pawel; Rios, Arnau; Barker, Brent

    2016-03-01

    Nonequilibrium Green's functions represent a promising tool for describing central nuclear reactions. Even at the single-particle level, though, the Green's functions contain more information that computers may handle in the foreseeable future. In this study, we explore slab collisions in one dimension, first in the mean field approximation and demonstrate that only function elements close to the diagonal in arguments are relevant, in practice, for the reaction calculations. This bodes well for the application of the Green's functions to the reactions. Moreover we demonstrate that an initial state for a reaction calculation may be generated through adiabatic transformation of interactions. Finally, we report on our progress in incorporating correlations into the dynamic calculations.

  10. Neutron transport analysis for nuclear reactor design

    DOEpatents

    Vujic, Jasmina L.

    1993-01-01

    Replacing regular mesh-dependent ray tracing modules in a collision/transfer probability (CTP) code with a ray tracing module based upon combinatorial geometry of a modified geometrical module (GMC) provides a general geometry transfer theory code in two dimensions (2D) for analyzing nuclear reactor design and control. The primary modification of the GMC module involves generation of a fixed inner frame and a rotating outer frame, where the inner frame contains all reactor regions of interest, e.g., part of a reactor assembly, an assembly, or several assemblies, and the outer frame, with a set of parallel equidistant rays (lines) attached to it, rotates around the inner frame. The modified GMC module allows for determining for each parallel ray (line), the intersections with zone boundaries, the path length between the intersections, the total number of zones on a track, the zone and medium numbers, and the intersections with the outer surface, which parameters may be used in the CTP code to calculate collision/transfer probability and cross-section values.

  11. Neutron transport analysis for nuclear reactor design

    DOEpatents

    Vujic, J.L.

    1993-11-30

    Replacing regular mesh-dependent ray tracing modules in a collision/transfer probability (CTP) code with a ray tracing module based upon combinatorial geometry of a modified geometrical module (GMC) provides a general geometry transfer theory code in two dimensions (2D) for analyzing nuclear reactor design and control. The primary modification of the GMC module involves generation of a fixed inner frame and a rotating outer frame, where the inner frame contains all reactor regions of interest, e.g., part of a reactor assembly, an assembly, or several assemblies, and the outer frame, with a set of parallel equidistant rays (lines) attached to it, rotates around the inner frame. The modified GMC module allows for determining for each parallel ray (line), the intersections with zone boundaries, the path length between the intersections, the total number of zones on a track, the zone and medium numbers, and the intersections with the outer surface, which parameters may be used in the CTP code to calculate collision/transfer probability and cross-section values. 28 figures.

  12. Vulnerability Analysis Considerations for the Transportation of Special Nuclear Material

    SciTech Connect

    Nicholson, Lary G.; Purvis, James W.

    1999-07-21

    The vulnerability analysis methodology developed for fixed nuclear material sites has proven to be extremely effective in assessing associated transportation issues. The basic methods and techniques used are directly applicable to conducting a transportation vulnerability analysis. The purpose of this paper is to illustrate that the same physical protection elements (detection, delay, and response) are present, although the response force plays a dominant role in preventing the theft or sabotage of material. Transportation systems are continuously exposed to the general public whereas the fixed site location by its very nature restricts general public access.

  13. Charge transport in disordered semiconducting polymers driven by nuclear tunneling

    NASA Astrophysics Data System (ADS)

    van der Kaap, N. J.; Katsouras, I.; Asadi, K.; Blom, P. W. M.; Koster, L. J. A.; de Leeuw, D. M.

    2016-04-01

    The current density-voltage (J -V ) characteristics of hole-only diodes based on poly(2-methoxy, 5-(2' ethyl-hexyloxy)-p -phenylene vinylene) (MEH-PPV) were measured at a wide temperature and field range. At high electric fields the temperature dependence of the transport vanishes, and all J -V sweeps converge to a power law. Nuclear tunneling theory predicts a power law at high fields that scales with the Kondo parameter. To model the J -V characteristics we have performed master-equation calculations to determine the dependence of charge carrier mobility on electric field, charge carrier density, temperature, and Kondo parameter, using nuclear tunneling transfer rates. We demonstrate that nuclear tunneling, unlike other semiclassical models, provides a consistent description of the charge transport for a large bias, temperature, and carrier density range.

  14. Classic Nuclear Localization Signals and a Novel Nuclear Localization Motif Are Required for Nuclear Transport of Porcine Parvovirus Capsid Proteins

    PubMed Central

    Boisvert, Maude; Bouchard-Lévesque, Véronique; Fernandes, Sandra

    2014-01-01

    ABSTRACT Nuclear targeting of capsid proteins (VPs) is important for genome delivery and precedes assembly in the replication cycle of porcine parvovirus (PPV). Clusters of basic amino acids, corresponding to potential nuclear localization signals (NLS), were found only in the unique region of VP1 (VP1up, for VP1 unique part). Of the five identified basic regions (BR), three were important for nuclear localization of VP1up: BR1 was a classic Pat7 NLS, and the combination of BR4 and BR5 was a classic bipartite NLS. These NLS were essential for viral replication. VP2, the major capsid protein, lacked these NLS and contained no region with more than two basic amino acids in proximity. However, three regions of basic clusters were identified in the folded protein, assembled into a trimeric structure. Mutagenesis experiments showed that only one of these three regions was involved in VP2 transport to the nucleus. This structural NLS, termed the nuclear localization motif (NLM), is located inside the assembled capsid and thus can be used to transport trimers to the nucleus in late steps of infection but not for virions in initial infection steps. The two NLS of VP1up are located in the N-terminal part of the protein, externalized from the capsid during endosomal transit, exposing them for nuclear targeting during early steps of infection. Globally, the determinants of nuclear transport of structural proteins of PPV were different from those of closely related parvoviruses. IMPORTANCE Most DNA viruses use the nucleus for their replication cycle. Thus, structural proteins need to be targeted to this cellular compartment at two distinct steps of the infection: in early steps to deliver viral genomes to the nucleus and in late steps to assemble new viruses. Nuclear targeting of proteins depends on the recognition of a stretch of basic amino acids by cellular transport proteins. This study reports the identification of two classic nuclear localization signals in the minor

  15. Safety analysis of irradiated nuclear fuel transportation container

    SciTech Connect

    Uspuras, E.; Rimkevicius, S.

    2007-07-01

    Ignalina NPP comprises two Units with RBMK-1500 reactors. After the Unit 1 of the Ignalina Nuclear Power Plant was shut down in 2004, approximately 1000 fuel assemblies from Unit were available for further reuse in Unit 2. The fuel-transportation container, vehicle, protection shaft and other necessary equipment were designed in order to implement the process for on-site transportation of Unit 1 fuel for reuse in the Unit 2. The Safety Analysis Report (SAR) was developed to demonstrate that the proposed set of equipment performs all functions and assures the required level of safety for both normal operation and accident conditions. The purpose of this paper is to introduce the content and main results of SAR, focusing attention on the container used to transport spent fuel assemblies from Unit I on Unit 2. In the SAR, the structural integrity, thermal, radiological and nuclear safety calculations are performed to assess the acceptance of the proposed set of equipment. The safety analysis demonstrated that the proposed nuclear fuel transportation container and other equipment are in compliance with functional, design and regulatory requirements and assure the required safety level. (authors)

  16. Three Distinct Domains Contribute to Nuclear Transport of Murine Foxp3

    PubMed Central

    Hancock, Wayne W.; Özkaynak, Engin

    2009-01-01

    Foxp3, a 47-kDa transcription factor, is necessary for the function of CD4+CD25+ regulatory T cells (Tregs), with an essential role in the control of self-reactive T cells and in preventing autoimmunity. Activation of Tregs by TCR engagement results in upregulation of Foxp3 expression, followed by its rapid nuclear transport and binding to chromatin. Here, we identify three distinct Foxp3 domains that contribute to nuclear transport. The first domain (Domain 1) comprises the C-terminal 12 amino acids. The second domain (Domain 2) is located immediately N-terminal to the forkhead domain (FHD), recently reported to be a binding site for the runt-related transcription factor 1/acute myeloid leukemia 1 (Runx1/AML1). The third domain (Domain 3) is located within the N-terminal first 51 amino acids. Unlike the known nuclear localization signals (NLSs), none of these three regions are rich in basic residues and do not bear any similarity to known monopartite or bipartite NLSs that have one or more clusters of basic amino acids. The basic arginine-lysine-lysine-arginine (RKKR) sequence, located 12-aa from the C-terminal end of Foxp3 was previously reported to be a nuclear localization signal (NLS) for several proteins, including for a GFP-Foxp3 hybrid. Evidence is provided here that in the full-length native Foxp3 RKKR does not function as an NLS. The data reported in this study indicates that Foxp3 achieves nuclear transport by binding to other nuclear factors and co-transporting with them to the nucleus. PMID:19924293

  17. In vivo analysis of the stability and transport of nuclear poly(A)+ RNA

    PubMed Central

    1994-01-01

    We have studied the distribution of poly(A)+ RNA in the mammalian cell nucleus and its transport through nuclear pores by fluorescence and electron microscopic in situ hybridization. Poly(A)+ RNA was detected in the nucleus as a speckled pattern which includes interchromatin granule clusters and perichromatin fibrils. When cells are fractionated by detergent and salt extraction as well as DNase I digestion, the majority of the nuclear poly(A)+ RNA was found to remain associated with the nonchromatin RNP-enriched fraction of the nucleus. After inhibition of RNA polymerase II transcription for 5-10 h, a stable population of poly(A)+ RNA remained in the nucleus and was reorganized into fewer and larger interchromatin granule clusters along with pre- mRNA splicing factors. This stable population of nuclear RNA may play an important role in nuclear function. Furthermore, we have observed that, in actively transcribing cells, the regions of poly(A)+ RNA which reached the nuclear pore complexes appeared as narrow concentrations of RNA suggesting a limited or directed pathway of movement. All of the observed nuclear pores contained poly(A)+ RNA staining suggesting that they are all capable of exporting RNA. In addition, we have directly visualized, for the first time in mammalian cells, the transport of poly(A)+ RNA through the nuclear pore complexes. PMID:7519622

  18. Isotopic tracing of hydrogen transport and trapping in nuclear materials

    NASA Astrophysics Data System (ADS)

    Chêne, Jacques; Martin, Frantz

    2017-06-01

    Some illustrations of the use of deuterium or tritium for isotopic tracing of hydrogen absorption, transport and trapping in nuclear materials are presented. Isotopic tracing of hydrogen has been shown to be successful for the determination of the boundaries conditions for hydrogen desorption or absorption in a material exposed to a hydrogen source. Also, the unique capabilities of isotopic tracing and related techniques to characterize H interactions with point defects and dislocations acting as moving traps has been demonstrated. Such transport mechanisms are considered to play a major role in some stress corrosion cracking and hydrogen embrittlement mechanisms. This article is part of the themed issue 'The challenges of hydrogen and metals'.

  19. Global transport of atmospheric smoke following a major nuclear exchange

    NASA Technical Reports Server (NTRS)

    Haberle, R. M.; Ackerman, T. P.; Toon, O. B.; Hollingsworth, J. L.

    1985-01-01

    A fully interactive zonally symmetric general circulation model is used to simulate the transport and evolution of a massive smoke cloud that is likely to form in the atmosphere following a major nuclear war. The presence of such a cloud significantly alters the simulated circulation and the subsequent transport of the smoke particles themselves. While the model indicates a tendency for interhemispheric exchange, the most immediate effect is that the radiatively active particles are carried into the stratosphere by the generation of strong vertical motions and intense convection regardless of their initial injection altitudes.

  20. Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles.

    PubMed

    Schmidt, H Broder; Görlich, Dirk

    2016-01-01

    Nuclear pore complexes (NPCs) provide a selective passageway for receptor-mediated active transport between nucleus and cytoplasm, while maintaining the distinct molecular compositions of both compartments at large. In this review we discuss how NPCs gain a remarkable sorting selectivity from non-globular FG domains and their phase separation into dense polymer meshworks. The resulting sieve-like FG hydrogels are effective barriers to normal macromolecules but are at the same time highly permeable to shuttling nuclear transport receptors, which bind to FG motifs as well as to their designated cargoes. Phase separation driven by disordered protein domains was recently also recognized as being pivotal to the formation of membraneless organelles, making it an important emerging principle in cell biology. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. A Transport Model for Nuclear Reactions Induced by Radioactive Beams

    SciTech Connect

    Li Baoan; Chen Liewen; Das, Champak B.; Das Gupta, Subal; Gale, Charles; Ko, C.M.; Yong, G.-C.; Zuo Wei

    2005-10-14

    Major ingredients of an isospin and momentum dependent transport model for nuclear reactions induced by radioactive beams are outlined. Within the IBUU04 version of this model we study several experimental probes of the equation of state of neutron-rich matter, especially the density dependence of the nuclear symmetry energy. Comparing with the recent experimental data from NSCL/MSU on isospin diffusion, we found a nuclear symmetry energy of Esym({rho}) {approx_equal} 31.6({rho}/{rho}0)1.05 at subnormal densities. Predictions on several observables sensitive to the density dependence of the symmetry energy at supranormal densities accessible at GSI and the planned Rare Isotope Accelerator (RIA) are also made.

  2. Retinoblastoma-binding Protein 4-regulated Classical Nuclear Transport Is Involved in Cellular Senescence*

    PubMed Central

    Tsujii, Akira; Miyamoto, Yoichi; Moriyama, Tetsuji; Tsuchiya, Yuko; Obuse, Chikashi; Mizuguchi, Kenji; Oka, Masahiro; Yoneda, Yoshihiro

    2015-01-01

    Nucleocytoplasmic trafficking is a fundamental cellular process in eukaryotic cells. Here, we demonstrated that retinoblastoma-binding protein 4 (RBBP4) functions as a novel regulatory factor to increase the efficiency of importin α/β-mediated nuclear import. RBBP4 accelerates the release of importin β1 from importin α via competitive binding to the importin β-binding domain of importin α in the presence of RanGTP. Therefore, it facilitates importin α/β-mediated nuclear import. We showed that the importin α/β pathway is down-regulated in replicative senescent cells, concomitant with a decrease in RBBP4 level. Knockdown of RBBP4 caused both suppression of nuclear transport and induction of cellular senescence. This is the first report to identify a factor that competes with importin β1 to bind to importin α, and it demonstrates that the loss of this factor can trigger cellular senescence. PMID:26491019

  3. An optimal transportation approach for nuclear structure-based pathology

    PubMed Central

    Wang, Wei; Ozolek, John A.; Slepčev, Dejan; Lee, Ann B.; Chen, Cheng; Rohde, Gustavo K.

    2012-01-01

    Nuclear morphology and structure as visualized from histopathology microscopy images can yield important diagnostic clues in some benign and malignant tissue lesions. Precise quantitative information about nuclear structure and morphology, however, is currently not available for many diagnostic challenges. This is due, in part, to the lack of methods to quantify these differences from image data. We describe a method to characterize and contrast the distribution of nuclear structure in different tissue classes (normal, benign, cancer, etc.). The approach is based on quantifying chromatin morphology in different groups of cells using the optimal transportation (Kantorovich-Wasserstein) metric in combination with the Fisher discriminant analysis and multidimensional scaling techniques. We show that the optimal transportation metric is able to measure relevant biological information as it enables automatic determination of the class (e.g. normal vs. cancer) of a set of nuclei. We show that the classification accuracies obtained using this metric are, on average, as good or better than those obtained utilizing a set of previously described numerical features. We apply our methods to two diagnostic challenges for surgical pathology: one in the liver and one in the thyroid. Results automatically computed using this technique show potentially biologically relevant differences in nuclear structure in liver and thyroid cancers. PMID:20977984

  4. Non-nuclear Electron Transport Channels in Hollow Molecules

    SciTech Connect

    Zhao, Jin; Petek, Hrvoje

    2014-08-15

    Electron transport in inorganic semiconductors and metals occurs through delocalized bands formed by overlapping electron orbitals. Strong correlation of electronic wave functions with the ionic cores couples the electron and lattice motions, leading to efficient interaction and scattering that degrades coherent charge transport. By contrast, unoccupied electronic states at energies near the vacuum level with diffuse molecular orbitals may form nearly-free-electron bands with density maxima in non-nuclear interstitial voids, which are subject to weaker electron-phonon interaction. The position of such bands typically above the frontier orbitals, however, renders them unstable with respect to electronic interband relaxation and therefore unsuitable for charge transport. Through electronic-structure calculations, we engineer stable, non-nuclear, nearly-free-electron conduction channels in low-dimensional molecular materials by tailoring their electrostatic and polarization potentials. We propose quantum structures of graphane-derived Janus molecular sheets with spatially isolated conducting and insulating regions that potentially exhibit emergent electronic properties, as a paradigm for molecular-scale non-nuclear charge conductors; we also describe tuning of their electronic properties by application of external fields and calculate their electron–acoustic-phonon interaction.

  5. Non-nuclear electron transport channels in hollow molecules

    NASA Astrophysics Data System (ADS)

    Zhao, Jin; Petek, Hrvoje

    2014-08-01

    Electron transport in inorganic semiconductors and metals occurs through delocalized bands formed by overlapping electron orbitals. Strong correlation of electronic wave functions with the ionic cores couples the electron and lattice motions, leading to efficient interaction and scattering that degrades coherent charge transport. By contrast, unoccupied electronic states at energies near the vacuum level with diffuse molecular orbitals may form nearly-free-electron bands with density maxima in non-nuclear interstitial voids, which are subject to weaker electron-phonon interaction. The position of such bands typically above the frontier orbitals, however, renders them unstable with respect to electronic interband relaxation and therefore unsuitable for charge transport. Through electronic-structure calculations, we engineer stable, non-nuclear, nearly-free-electron conduction channels in low-dimensional molecular materials by tailoring their electrostatic and polarization potentials. We propose quantum structures of graphane-derived Janus molecular sheets with spatially isolated conducting and insulating regions that potentially exhibit emergent electronic properties, as a paradigm for molecular-scale non-nuclear charge conductors; we also describe tuning of their electronic properties by application of external fields and calculate their electron-acoustic-phonon interaction.

  6. Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.

    PubMed

    Gasset-Rosa, Fatima; Chillon-Marinas, Carlos; Goginashvili, Alexander; Atwal, Ranjit Singh; Artates, Jonathan W; Tabet, Ricardos; Wheeler, Vanessa C; Bang, Anne G; Cleveland, Don W; Lagier-Tourenne, Clotilde

    2017-04-05

    Onset of neurodegenerative disorders, including Huntington's disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington's disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington's disease.

  7. The Storage, Transportation, and Disposal of Nuclear Waste

    NASA Astrophysics Data System (ADS)

    Younker, J. L.

    2002-12-01

    The U.S. Congress established a comprehensive federal policy to dispose of wastes from nuclear reactors and defense facilities, centered on deep geologic disposal of high-level radioactive waste. Site screening led to selection of three potential sites and in 1987, Congress directed the Secretary of Energy to characterize only one site: Yucca Mountain in Nevada. For more than 20 years, teams of scientists and engineers have been evaluating the potential suitability of the site. On the basis of their work, the U.S. Secretary of Energy, Spencer Abraham, concluded in February 2002 that a safe repository can be sited at Yucca Mountain. On July 23, 2002, President Bush signed Joint Resolution 87 approving the site at Yucca Mountain for development of a repository, which allows the U.S. Department of Energy (DOE) to prepare and submit a license application to the U.S. Nuclear Regulatory Commission (NRC). Concerns have been raised relative to the safe transportation of nuclear materials. The U.S. history of transportation of nuclear materials demonstrates that high-level nuclear materials can be safely transported. Since the 1960s, over 1.6 million miles have been traveled by more than 2,700 spent nuclear fuel shipments, and there has never been an accident severe enough to cause a release of radioactive materials. The DOE will use NRC-certified casks that must be able to withstand very stringent tests. The same design features that allow the casks to survive severe accidents also limit their vulnerability to sabotage. In addition, the NRC will approve all shipping routes and security plans. With regard to long-term safety, the Yucca Mountain disposal system has five key attributes. First, the arid climate and geology of Yucca Mountain combine to ensure that limited water will enter the emplacement tunnels. Second, the DOE has designed a waste package and drip shield that are expected to have very long lifetimes in the repository environment. Third, waste form

  8. Isotopic Effects in Nuclear Fragmentation and GCR Transport Problems

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.

    2002-01-01

    Improving the accuracy of the galactic cosmic ray (GCR) environment and transport models is an important goal in preparing for studies of the projected risks and the efficiency of potential mitigations methods for space exploration. In this paper we consider the effects of the isotopic composition of the primary cosmic rays and the isotopic dependence of nuclear fragmentation cross sections on GCR transport models. Measurements are used to describe the isotopic composition of the GCR including their modulation throughout the solar cycle. The quantum multiple-scattering approach to nuclear fragmentation (QMSFRG) is used as the data base generator in order to accurately describe the odd-even effect in fragment production. Using the Badhwar and O'Neill GCR model, the QMSFRG model and the HZETRN transport code, the effects of the isotopic dependence of the primary GCR composition and on fragment production for transport problems is described for a complete GCR isotopic-grid. The principle finding of this study is that large errors ( 100%) will occur in the mass-flux spectra when comparing the complete isotopic-grid (141 ions) to a reduced isotopic-grid (59 ions), however less significant errors 30%) occur in the elemental-flux spectra. Because the full isotopic-grid is readily handled on small computer work-stations, it is recommended that they be used for future GCR studies.

  9. Manned space flight nuclear system safety. Volume 4: Space shuttle nuclear system transportation. Part 1: Space shuttle nuclear safety

    NASA Technical Reports Server (NTRS)

    1972-01-01

    An analysis of the nuclear safety aspects (design and operational considerations) in the transport of nuclear payloads to and from earth orbit by the space shuttle is presented. Three representative nuclear payloads used in the study were: (1) the zirconium hydride reactor Brayton power module, (2) the large isotope Brayton power system and (3) small isotopic heat sources which can be a part of an upper stage or part of a logistics module. Reference data on the space shuttle and nuclear payloads are presented in an appendix. Safety oriented design and operational requirements were identified to integrate the nuclear payloads in the shuttle mission. Contingency situations were discussed and operations and design features were recommended to minimize the nuclear hazards. The study indicates the safety, design and operational advantages in the use of a nuclear payload transfer module. The transfer module can provide many of the safety related support functions (blast and fragmentation protection, environmental control, payload ejection) minimizing the direct impact on the shuttle.

  10. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.

    PubMed

    Jovičić, Ana; Paul, Joseph W; Gitler, Aaron D

    2016-08-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.

  11. The motion commotion: Human factors in transportation

    NASA Technical Reports Server (NTRS)

    Millar, A. E., Jr. (Editor); Rosen, R. L. (Editor); Gibson, J. D. (Editor); Crum, R. G. (Editor)

    1972-01-01

    The program for a systems approach to the problem of incorporating human factors in designing transportation systems is summarized. The importance of the human side of transportation is discussed along with the three major factors related to maintaining a mobile and quality life. These factors are (1) people, as individuals and groups, (2) society as a whole, and (3) the natural environment and man-made environs. The problems and bottlenecks are presented along with approaches to their solutions through systems analysis. Specific recommendations essential to achieving improved mobility within environmental constraints are presented.

  12. Azimuthal anisotropies as stringent test for nuclear transport models

    NASA Astrophysics Data System (ADS)

    Crochet, P.; Rami, F.; Donà, R.; Coffin, J. P.; Fintz, P.; Guillaume, G.; Jundt, F.; Kuhn, C.; Roy, C.; de Schauenburg, B.; Tizniti, L.; Wagner, P.; Alard, J. P.; Andronic, A.; Basrak, Z.; Bastid, N.; Belyaev, I.; Bendarag, A.; Berek, G.; Best, D.; Biegansky, J.; Buta, A.; Čaplar, R.; Cindro, N.; Dupieux, P.; Dželalija, M.; Fan, Z. G.; Fodor, Z.; Fraysse, L.; Freifelder, R. P.; Gobbi, A.; Herrmann, N.; Hildenbrand, K. D.; Hong, B.; Jeong, S. C.; Kecskemeti, J.; Kirejczyk, M.; Koncz, P.; Korolija, M.; Kotte, R.; Lebedev, A.; Leifels, Y.; Manko, V.; Moisa, D.; Mösner, J.; Neubert, W.; Pelte, D.; Petrovici, M.; Pinkenburg, C.; Reisdorf, W.; Ritman, J. L.; Sadchikov, A. G.; Schüll, D.; Seres, Z.; Sikora, B.; Simion, V.; Siwek-Wilczyńska, K.; Sodan, U.; Teh, K. M.; Trzaska, M.; Wang, G. S.; Wessels, J. P.; Wienold, T.; Wisniewski, K.; Wohlfarth, D.; Zhilin, A.; Hartnack, C.; FOPI Collaboration

    1997-02-01

    Azimuthal distributions of charged particles and intermediate mass fragments emitted in Au+Au collisions at 600 A MeV have been measured using the FOPI facility at GSI-Darmstadt. Data show a strong increase of the in-plane azimuthal anisotropy ratio with the charge of the detected fragment. Intermediate mass fragments are found to exhibit a strong momentum-space alignment with respect of the reaction plane. The experimental results are presented as a function of the polar centre-of-mass angle and over a broad range of impact parameters. They are compared to the predictions of the Isospin Quantum Molecular Dynamics model using three different parametrisations of the equation of state. We show that such highly accurate data provide stringent test for microscopic transport models and can potentially constrain separately the stiffness of the nuclear equation of state and the momentum dependence of the nuclear interaction.

  13. Isotopic tracing of hydrogen transport and trapping in nuclear materials.

    PubMed

    Chêne, Jacques; Martin, Frantz

    2017-07-28

    Some illustrations of the use of deuterium or tritium for isotopic tracing of hydrogen absorption, transport and trapping in nuclear materials are presented. Isotopic tracing of hydrogen has been shown to be successful for the determination of the boundaries conditions for hydrogen desorption or absorption in a material exposed to a hydrogen source. Also, the unique capabilities of isotopic tracing and related techniques to characterize H interactions with point defects and dislocations acting as moving traps has been demonstrated. Such transport mechanisms are considered to play a major role in some stress corrosion cracking and hydrogen embrittlement mechanisms.This article is part of the themed issue 'The challenges of hydrogen and metals'. © 2017 The Author(s).

  14. 10 CFR 150.21 - Transportation of special nuclear material by aircraft.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Transportation of special nuclear material by aircraft. 150.21 Section 150.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED... Transportation of special nuclear material by aircraft. Except as specifically approved by the Commission no...

  15. 10 CFR 150.21 - Transportation of special nuclear material by aircraft.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false Transportation of special nuclear material by aircraft. 150.21 Section 150.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED... Transportation of special nuclear material by aircraft. Except as specifically approved by the Commission no...

  16. 10 CFR 150.21 - Transportation of special nuclear material by aircraft.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false Transportation of special nuclear material by aircraft. 150.21 Section 150.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED... Transportation of special nuclear material by aircraft. Except as specifically approved by the Commission no...

  17. 25 CFR 170.900 - What is the purpose of the provisions relating to transportation of hazardous and nuclear waste?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... transportation of hazardous and nuclear waste? 170.900 Section 170.900 Indians BUREAU OF INDIAN AFFAIRS... and Nuclear Waste Transportation § 170.900 What is the purpose of the provisions relating to transportation of hazardous and nuclear waste? Sections 170.900 through 170.907 on transportation of nuclear...

  18. Transportable nuclear power plant TEC-M with two reactor plants of improved safety

    SciTech Connect

    Ogloblin, B.G.; Sazonov, A.G.; Svishchev, A.M.; Gromov, B.F.; Zelensky, V.N.; Komkova, O.I.; Sidorov, V.I.; Tolstopyatov, V.P.; Toshinsky, G.I.

    1993-12-31

    Liquid metals are the best to meet the requirements of inherently safety nuclear power plants among the coolants used. A great experience has been gained in lead coolant power plant development and operation as applied to transportable power set-ups. Low chemical activity of this coolant with respect to air-water interaction is a determining factor for this coolant. The transportable nuclear power plant is described. It is intended to generate electric power for populated areas placed a long distance from the main electric power supply sources where it is difficult or not economical to deliver the conventional types of fuel. There are several remote areas in Siberia, Kamchatka in need of this type of power plant.

  19. Karyopherins regulate nuclear pore complex barrier and transport function.

    PubMed

    Kapinos, Larisa E; Huang, Binlu; Rencurel, Chantal; Lim, Roderick Y H

    2017-09-01

    Nucleocytoplasmic transport is sustained by karyopherins (Kaps) and a Ran guanosine triphosphate (RanGTP) gradient that imports nuclear localization signal (NLS)-specific cargoes (NLS-cargoes) into the nucleus. However, how nuclear pore complex (NPC) barrier selectivity, Kap traffic, and NLS-cargo release are systematically linked and simultaneously regulated remains incoherent. In this study, we show that Kapα facilitates Kapβ1 turnover and occupancy at the NPC in a RanGTP-dependent manner that is directly coupled to NLS-cargo release and NPC barrier function. This is underpinned by the binding affinity of Kapβ1 to phenylalanine-glycine nucleoporins (FG Nups), which is comparable with RanGTP·Kapβ1, but stronger for Kapα·Kapβ1. On this basis, RanGTP is ineffective at releasing standalone Kapβ1 from NPCs. Depleting Kapα·Kapβ1 by RanGTP further abrogates NPC barrier function, whereas adding back Kapβ1 rescues it while Kapβ1 turnover softens it. Therefore, the FG Nups are necessary but insufficient for NPC barrier function. We conclude that Kaps constitute integral constituents of the NPC whose barrier, transport, and cargo release functionalities establish a continuum under a mechanism of Kap-centric control. © 2017 Kapinos et al.

  20. Nuclear thermal propulsion transportation systems for lunar/Mars exploration

    NASA Technical Reports Server (NTRS)

    Clark, John S.; Borowski, Stanley K.; Mcilwain, Melvin C.; Pellaccio, Dennis G.

    1992-01-01

    Nuclear thermal propulsion technology development is underway at NASA and DoE for Space Exploration Initiative (SEI) missions to Mars, with initial near-earth flights to validate flight readiness. Several reactor concepts are being considered for these missions, and important selection criteria will be evaluated before final selection of a system. These criteria include: safety and reliability, technical risk, cost, and performance, in that order. Of the concepts evaluated to date, the Nuclear Engine for Rocket Vehicle Applications (NERVA) derivative (NDR) is the only concept that has demonstrated full power, life, and performance in actual reactor tests. Other concepts will require significant design work and must demonstrate proof-of-concept. Technical risk, and hence, development cost should therefore be lowest for the concept, and the NDR concept is currently being considered for the initial SEI missions. As lighter weight, higher performance systems are developed and validated, including appropriate safety and astronaut-rating requirements, they will be considered to support future SEI application. A space transportation system using a modular nuclear thermal rocket (NTR) system for lunar and Mars missions is expected to result in significant life cycle cost savings. Finally, several key issues remain for NTR's, including public acceptance and operational issues. Nonetheless, NTR's are believed to be the 'next generation' of space propulsion systems - the key to space exploration.

  1. 10 CFR 70.20a - General license to possess special nuclear material for transport.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false General license to possess special nuclear material for transport. 70.20a Section 70.20a Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DOMESTIC LICENSING OF SPECIAL NUCLEAR MATERIAL General Licenses § 70.20a General license to possess special nuclear material for...

  2. 10 CFR 70.20a - General license to possess special nuclear material for transport.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false General license to possess special nuclear material for transport. 70.20a Section 70.20a Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DOMESTIC LICENSING OF SPECIAL NUCLEAR MATERIAL General Licenses § 70.20a General license to possess special nuclear material for...

  3. 10 CFR 70.20a - General license to possess special nuclear material for transport.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false General license to possess special nuclear material for transport. 70.20a Section 70.20a Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DOMESTIC LICENSING OF SPECIAL NUCLEAR MATERIAL General Licenses § 70.20a General license to possess special nuclear material for...

  4. 10 CFR 70.20a - General license to possess special nuclear material for transport.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false General license to possess special nuclear material for transport. 70.20a Section 70.20a Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DOMESTIC LICENSING OF SPECIAL NUCLEAR MATERIAL General Licenses § 70.20a General license to possess special nuclear material for...

  5. 10 CFR 70.20a - General license to possess special nuclear material for transport.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false General license to possess special nuclear material for transport. 70.20a Section 70.20a Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DOMESTIC LICENSING OF SPECIAL NUCLEAR MATERIAL General Licenses § 70.20a General license to possess special nuclear material...

  6. 75 FR 64720 - Blue Ribbon Commission on America's Nuclear Future, Transportation and Storage Subcommittee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-20

    ... spent nuclear fuel and nuclear waste. The Co-chairs of the Commission requested the formation of the T&S... Ribbon Commission on America's Nuclear Future, Transportation and Storage Subcommittee AGENCY: Office of Nuclear Energy, Department of Energy. ACTION: Notice of Open Meeting. SUMMARY: This notice announces...

  7. Public opinion factors regarding nuclear power

    SciTech Connect

    Benson, B.

    1991-12-31

    This paper is an effort to identify, as comprehensively as possible, public concerns about nuclear power, and to assess, where possible, the relative importance of these concerns as they relate to government regulation of and policy towards nuclear power. It is based on some two dozen in-depth interviews with key communicators representing the nuclear power industry, the environmental community, and government, as well as on the parallel efforts in our research project: (1) review of federal court case law, (2) a selective examination of the Nuclear Regulatory Commission (NRC) administrative process, and (3) the preceding George Mason University research project in this series. The paper synthesizes our findings about public attitudes towards nuclear power as expressed through federal court case law, NRC administrative law, public opinion surveys, and direct personal interviews. In so doing, we describe the public opinion environment in which the nuclear regulatory process must operate. Our premise is that public opinion ultimately underlies the approaches government agencies take towards regulating nuclear power, and that, to the degree that the nuclear power industry`s practices are aligned with public opinion, a more favorable regulatory climate is possible.

  8. Public opinion factors regarding nuclear power

    SciTech Connect

    Benson, B.

    1991-01-01

    This paper is an effort to identify, as comprehensively as possible, public concerns about nuclear power, and to assess, where possible, the relative importance of these concerns as they relate to government regulation of and policy towards nuclear power. It is based on some two dozen in-depth interviews with key communicators representing the nuclear power industry, the environmental community, and government, as well as on the parallel efforts in our research project: (1) review of federal court case law, (2) a selective examination of the Nuclear Regulatory Commission (NRC) administrative process, and (3) the preceding George Mason University research project in this series. The paper synthesizes our findings about public attitudes towards nuclear power as expressed through federal court case law, NRC administrative law, public opinion surveys, and direct personal interviews. In so doing, we describe the public opinion environment in which the nuclear regulatory process must operate. Our premise is that public opinion ultimately underlies the approaches government agencies take towards regulating nuclear power, and that, to the degree that the nuclear power industry's practices are aligned with public opinion, a more favorable regulatory climate is possible.

  9. Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

    PubMed Central

    Raveh, Barak; Karp, Jerome M.; Sparks, Samuel; Rout, Michael P.; Sali, Andrej; Cowburn, David

    2016-01-01

    Nucleocytoplasmic transport is mediated by the interaction of transport factors (TFs) with disordered phenylalanine-glycine (FG) repeats that fill the central channel of the nuclear pore complex (NPC). However, the mechanism by which TFs rapidly diffuse through multiple FG repeats without compromising NPC selectivity is not yet fully understood. In this study, we build on our recent NMR investigations showing that FG repeats are highly dynamic, flexible, and rapidly exchanging among TF interaction sites. We use unbiased long timescale all-atom simulations on the Anton supercomputer, combined with extensive enhanced sampling simulations and NMR experiments, to characterize the thermodynamic and kinetic properties of FG repeats and their interaction with a model transport factor. Both the simulations and experimental data indicate that FG repeats are highly dynamic random coils, lack intrachain interactions, and exhibit significant entropically driven resistance to spatial confinement. We show that the FG motifs reversibly slide in and out of multiple TF interaction sites, transitioning rapidly between a strongly interacting state and a weakly interacting state, rather than undergoing a much slower transition between strongly interacting and completely noninteracting (unbound) states. In the weakly interacting state, FG motifs can be more easily displaced by other competing FG motifs, providing a simple mechanism for rapid exchange of TF/FG motif contacts during transport. This slide-and-exchange mechanism highlights the direct role of the disorder within FG repeats in nucleocytoplasmic transport, and resolves the apparent conflict between the selectivity and speed of transport. PMID:27091992

  10. The molecular mechanism of nuclear transport revealed by atomic-scale measurements

    PubMed Central

    Hough, Loren E; Dutta, Kaushik; Sparks, Samuel; Temel, Deniz B; Kamal, Alia; Tetenbaum-Novatt, Jaclyn; Rout, Michael P; Cowburn, David

    2015-01-01

    Nuclear pore complexes (NPCs) form a selective filter that allows the rapid passage of transport factors (TFs) and their cargoes across the nuclear envelope, while blocking the passage of other macromolecules. Intrinsically disordered proteins (IDPs) containing phenylalanyl-glycyl (FG)-rich repeats line the pore and interact with TFs. However, the reason that transport can be both fast and specific remains undetermined, through lack of atomic-scale information on the behavior of FGs and their interaction with TFs. We used nuclear magnetic resonance spectroscopy to address these issues. We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment. Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the NPC. DOI: http://dx.doi.org/10.7554/eLife.10027.001 PMID:26371551

  11. Nuclear transport of galectin-3 and its therapeutic implications

    PubMed Central

    Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima

    2014-01-01

    Galectin-3, a member of β-galactoside-binding gene family is a multi-functional protein, which regulates pleiotropic biological functions such as cell growth, cell adhesion, cell-cell interactions, apoptosis, angiogenesis and mRNA processing. Its unique structure enables it to interact with a plethora of ligands in a carbohydrate dependent or independent manner. Galectin-3 is mainly a cytosolic protein, but can easily traverse the intracellular and plasma membranes to translocate into the nucleus, mitochondria or get externalized. Depending on the cell type, specific experimental conditions in vitro, cancer type and stage, galectin-3 has been reported to be exclusively cytoplasmic, predominantly nuclear or distributed between the two compartments. In this review we have summarized the dynamics of galectin-3 shuttling between the nucleus and the cytoplasm, the nuclear transport mechanisms of galectin-3, how its specific interactions with the members of β-catenin signaling pathways affect tumor progression, and its implications as a therapeutic target. PMID:24657939

  12. Evaluation of the transport and resuspension of a simulated nuclear waste slurry: Nuclear Waste Treatment Program

    SciTech Connect

    Carleson, T.E.; Drown, D.C.; Hart, R.E.; Peterson, M.E.

    1987-09-01

    The Department of Chemical Engineering at the University of Idaho conducted research on the transport and resuspension of a simulated high-level nuclear waste slurry. In the United States, the reference process for treating both defense and civilian HLLW is vitrification using the liquid-fed ceramic melter process. The non-Newtonian behavior of the slurry complicates the evaluation of the transport and resuspension characteristics of the slurry. The resuspension of a simulated (nonradioactive) melter feed slurry was evaluated using a slurry designated as WV-205. The simulated slurry was developed for the West Valley Demonstration Project and was used during a pilot-scale ceramic melter (PSCM) experiment conducted at PNL in July 1985 (PSCM-21). This study involved determining the transport characteristics of a fully suspended slurry and the resuspension characteristics of settled solids in a pilot-scale pipe loop. The goal was to predict the transport and resuspension of a full-scale system based on rheological data for a specific slurry. The rheological behavior of the slurry was evaluated using a concentric cylinder rotational viscometer, a capillary tube viscometer, and the pilot-scale pipe loop. The results obtained from the three approaches were compared. 40 refs., 74 figs., 15 tabs.

  13. The rate of nuclear cytoplasmic protein transport is determined by the casein kinase II site flanking the nuclear localization sequence of the SV40 T-antigen.

    PubMed Central

    Rihs, H P; Jans, D A; Fan, H; Peters, R

    1991-01-01

    We have previously demonstrated [Rihs, H.-P. and Peters, R. (1989) EMBO J., 8, 1479-1484] that the nuclear transport of recombinant proteins in which short fragments of the SV40 T-antigen are fused to the amino terminus of Escherichia coli beta-galactosidase is dependent on both the nuclear localization sequence (NLS, T-antigen residues 126-132) and a phosphorylation-site-containing sequence (T-antigen residues 111-125). While the NLS determines the specificity, the rate of transport is controlled by the phosphorylation-site-containing sequence. The present study furthers this observation and examines the role of the various phosphorylation sites. Purified, fluorescently labeled recombinant proteins were injected into the cytoplasm of Vero or hepatoma (HTC) cells and the kinetics of nuclear transport measured by laser microfluorimetry. By replacing serine and threonine residues known to be phosphorylated in vivo, we identified the casein kinase II (CK-II) site S111/S112 to be the determining factor in the enhancement of the transport. Either of the residues 111 or 112 was sufficient to elicit the maximum transport enhancement. The other phosphorylation sites (S120, S123, T124) had no influence on the transport rate. Examination of the literature suggested that many proteins harboring a nuclear localization sequence also contain putative CK-II sites at a distance of approximately 10-30 amino acid residues from the NLS. CK-II has been previously implicated in the transmission of growth signals to the nucleus. Our results suggest that CK-II may exert this role by controlling the rate of nuclear protein transport. Images PMID:1848177

  14. The Arabidopsis thaliana Nuclear Factor Y Transcription Factors

    PubMed Central

    Zhao, Hang; Wu, Di; Kong, Fanying; Lin, Ke; Zhang, Haishen; Li, Gang

    2017-01-01

    Nuclear factor Y (NF-Y) is an evolutionarily conserved trimeric transcription factor complex present in nearly all eukaryotes. The heterotrimeric NF-Y complex consists of three subunits, NF-YA, NF-YB, and NF-YC, and binds to the CCAAT box in the promoter regions of its target genes to regulate their expression. Yeast and mammal genomes generally have single genes with multiple splicing isoforms that encode each NF-Y subunit. By contrast, plant genomes generally have multi-gene families encoding each subunit and these genes are differentially expressed in various tissues or stages. Therefore, different subunit combinations can lead to a wide variety of NF-Y complexes in various tissues, stages, and growth conditions, indicating the potentially diverse functions of this complex in plants. Indeed, many recent studies have proved that the NF-Y complex plays multiple essential roles in plant growth, development, and stress responses. In this review, we highlight recent progress on NF-Y in Arabidopsis thaliana, including NF-Y protein structure, heterotrimeric complex formation, and the molecular mechanism by which NF-Y regulates downstream target gene expression. We then focus on its biological functions and underlying molecular mechanisms. Finally, possible directions for future research on NF-Y are also presented. PMID:28119722

  15. The Arabidopsis thaliana Nuclear Factor Y Transcription Factors.

    PubMed

    Zhao, Hang; Wu, Di; Kong, Fanying; Lin, Ke; Zhang, Haishen; Li, Gang

    2016-01-01

    Nuclear factor Y (NF-Y) is an evolutionarily conserved trimeric transcription factor complex present in nearly all eukaryotes. The heterotrimeric NF-Y complex consists of three subunits, NF-YA, NF-YB, and NF-YC, and binds to the CCAAT box in the promoter regions of its target genes to regulate their expression. Yeast and mammal genomes generally have single genes with multiple splicing isoforms that encode each NF-Y subunit. By contrast, plant genomes generally have multi-gene families encoding each subunit and these genes are differentially expressed in various tissues or stages. Therefore, different subunit combinations can lead to a wide variety of NF-Y complexes in various tissues, stages, and growth conditions, indicating the potentially diverse functions of this complex in plants. Indeed, many recent studies have proved that the NF-Y complex plays multiple essential roles in plant growth, development, and stress responses. In this review, we highlight recent progress on NF-Y in Arabidopsis thaliana, including NF-Y protein structure, heterotrimeric complex formation, and the molecular mechanism by which NF-Y regulates downstream target gene expression. We then focus on its biological functions and underlying molecular mechanisms. Finally, possible directions for future research on NF-Y are also presented.

  16. Radionuclide Gas Transport through Nuclear Explosion-Generated Fracture Networks

    NASA Astrophysics Data System (ADS)

    Jordan, Amy B.; Stauffer, Philip H.; Knight, Earl E.; Rougier, Esteban; Anderson, Dale N.

    2015-12-01

    Underground nuclear weapon testing produces radionuclide gases which may seep to the surface. Barometric pumping of gas through explosion-fractured rock is investigated using a new sequentially-coupled hydrodynamic rock damage/gas transport model. Fracture networks are produced for two rock types (granite and tuff) and three depths of burial. The fracture networks are integrated into a flow and transport numerical model driven by surface pressure signals of differing amplitude and variability. There are major differences between predictions using a realistic fracture network and prior results that used a simplified geometry. Matrix porosity and maximum fracture aperture have the greatest impact on gas breakthrough time and window of opportunity for detection, with different effects between granite and tuff simulations highlighting the importance of accurately simulating the fracture network. In particular, maximum fracture aperture has an opposite effect on tuff and granite, due to different damage patterns and their effect on the barometric pumping process. From stochastic simulations using randomly generated hydrogeologic parameters, normalized detection curves are presented to show differences in optimal sampling time for granite and tuff simulations. Seasonal and location-based effects on breakthrough, which occur due to differences in barometric forcing, are stronger where the barometric signal is highly variable.

  17. Radionuclide gas transport through nuclear explosion-generated fracture networks

    DOE PAGES

    Jordan, Amy B.; Stauffer, Philip H.; Knight, Earl E.; ...

    2015-12-17

    Underground nuclear weapon testing produces radionuclide gases which may seep to the surface. Barometric pumping of gas through explosion-fractured rock is investigated using a new sequentially-coupled hydrodynamic rock damage/gas transport model. Fracture networks are produced for two rock types (granite and tuff) and three depths of burial. The fracture networks are integrated into a flow and transport numerical model driven by surface pressure signals of differing amplitude and variability. There are major differences between predictions using a realistic fracture network and prior results that used a simplified geometry. Matrix porosity and maximum fracture aperture have the greatest impact on gasmore » breakthrough time and window of opportunity for detection, with different effects between granite and tuff simulations highlighting the importance of accurately simulating the fracture network. In particular, maximum fracture aperture has an opposite effect on tuff and granite, due to different damage patterns and their effect on the barometric pumping process. From stochastic simulations using randomly generated hydrogeologic parameters, normalized detection curves are presented to show differences in optimal sampling time for granite and tuff simulations. In conclusion, seasonal and location-based effects on breakthrough, which occur due to differences in barometric forcing, are stronger where the barometric signal is highly variable.« less

  18. Radionuclide gas transport through nuclear explosion-generated fracture networks

    SciTech Connect

    Jordan, Amy B.; Stauffer, Philip H.; Knight, Earl E.; Rougier, Esteban; Anderson, Dale N.

    2015-12-17

    Underground nuclear weapon testing produces radionuclide gases which may seep to the surface. Barometric pumping of gas through explosion-fractured rock is investigated using a new sequentially-coupled hydrodynamic rock damage/gas transport model. Fracture networks are produced for two rock types (granite and tuff) and three depths of burial. The fracture networks are integrated into a flow and transport numerical model driven by surface pressure signals of differing amplitude and variability. There are major differences between predictions using a realistic fracture network and prior results that used a simplified geometry. Matrix porosity and maximum fracture aperture have the greatest impact on gas breakthrough time and window of opportunity for detection, with different effects between granite and tuff simulations highlighting the importance of accurately simulating the fracture network. In particular, maximum fracture aperture has an opposite effect on tuff and granite, due to different damage patterns and their effect on the barometric pumping process. From stochastic simulations using randomly generated hydrogeologic parameters, normalized detection curves are presented to show differences in optimal sampling time for granite and tuff simulations. In conclusion, seasonal and location-based effects on breakthrough, which occur due to differences in barometric forcing, are stronger where the barometric signal is highly variable.

  19. Radionuclide Gas Transport through Nuclear Explosion-Generated Fracture Networks.

    PubMed

    Jordan, Amy B; Stauffer, Philip H; Knight, Earl E; Rougier, Esteban; Anderson, Dale N

    2015-12-17

    Underground nuclear weapon testing produces radionuclide gases which may seep to the surface. Barometric pumping of gas through explosion-fractured rock is investigated using a new sequentially-coupled hydrodynamic rock damage/gas transport model. Fracture networks are produced for two rock types (granite and tuff) and three depths of burial. The fracture networks are integrated into a flow and transport numerical model driven by surface pressure signals of differing amplitude and variability. There are major differences between predictions using a realistic fracture network and prior results that used a simplified geometry. Matrix porosity and maximum fracture aperture have the greatest impact on gas breakthrough time and window of opportunity for detection, with different effects between granite and tuff simulations highlighting the importance of accurately simulating the fracture network. In particular, maximum fracture aperture has an opposite effect on tuff and granite, due to different damage patterns and their effect on the barometric pumping process. From stochastic simulations using randomly generated hydrogeologic parameters, normalized detection curves are presented to show differences in optimal sampling time for granite and tuff simulations. Seasonal and location-based effects on breakthrough, which occur due to differences in barometric forcing, are stronger where the barometric signal is highly variable.

  20. Radionuclide Gas Transport through Nuclear Explosion-Generated Fracture Networks

    PubMed Central

    Jordan, Amy B.; Stauffer, Philip H.; Knight, Earl E.; Rougier, Esteban; Anderson, Dale N.

    2015-01-01

    Underground nuclear weapon testing produces radionuclide gases which may seep to the surface. Barometric pumping of gas through explosion-fractured rock is investigated using a new sequentially-coupled hydrodynamic rock damage/gas transport model. Fracture networks are produced for two rock types (granite and tuff) and three depths of burial. The fracture networks are integrated into a flow and transport numerical model driven by surface pressure signals of differing amplitude and variability. There are major differences between predictions using a realistic fracture network and prior results that used a simplified geometry. Matrix porosity and maximum fracture aperture have the greatest impact on gas breakthrough time and window of opportunity for detection, with different effects between granite and tuff simulations highlighting the importance of accurately simulating the fracture network. In particular, maximum fracture aperture has an opposite effect on tuff and granite, due to different damage patterns and their effect on the barometric pumping process. From stochastic simulations using randomly generated hydrogeologic parameters, normalized detection curves are presented to show differences in optimal sampling time for granite and tuff simulations. Seasonal and location-based effects on breakthrough, which occur due to differences in barometric forcing, are stronger where the barometric signal is highly variable. PMID:26676058

  1. Nuclear fragmentation database for GCR transport code development

    NASA Astrophysics Data System (ADS)

    Zeitlin, C.; Guetersloh, S.; Heilbronn, L.; Miller, J.; Fukumura, A.; Iwata, Y.; Murakami, T.; Sihver, L.

    2010-09-01

    A critical need for NASA is the ability to accurately model the transport of heavy ions in the Galactic Cosmic Rays (GCR) through matter, including spacecraft walls, equipment racks, etc. Nuclear interactions are of great importance in the GCR transport problem, as they can cause fragmentation of the incoming ion into lighter ions. Since the radiation dose delivered by a particle is proportional to the square of (charge/velocity), fragmentation reduces the dose delivered by incident ions. The other mechanism by which dose can be reduced is ionization energy loss, which can lead to some particles stopping in the shielding. This is the conventional notion of shielding, but it is not applicable to human spaceflight since the particles in the GCR tend to be too energetic to be stopped in the relatively thin shielding that is possible within payload mass constraints. Our group has measured a large number of fragmentation cross sections, intended to be used as input to, or for validation of, NASA's radiation transport models. A database containing over 200 charge-changing cross sections and over 2000 fragment production cross sections has been compiled. In this report, we examine in detail the contrast between fragment measurements at large acceptance and small acceptance. We use output from the PHITS Monte Carlo code to test our assumptions using as an example 40Ar data (and simulated data) at a beam energy of 650 MeV/nucleon. We also present preliminary analysis in which isotopic resolution was attained for beryllium fragments produced by beams of 10B and 11B. Future work on the experimental data set will focus on extracting and interpreting production cross sections for light fragments.

  2. A karyopherin alpha2 nuclear transport pathway is regulated by glucose in hepatic and pancreatic cells.

    PubMed

    Cassany, Aurélia; Guillemain, Ghislaine; Klein, Christophe; Dalet, Véronique; Brot-Laroche, Edith; Leturque, Armelle

    2004-01-01

    We studied the role of the karyopherin alpha2 nuclear import carrier (also known as importin alpha2) in glucose signaling. In mhAT3F hepatoma cells, GFP-karyopherin alpha2 accumulated massively in the cytoplasm within minutes of glucose extracellular addition and returned to the nucleus after glucose removal. In contrast, GFP-karyopherin alpha1 distribution was unaffected regardless of glucose concentration. Glucose increased GFP-karyopherin alpha2 nuclear efflux by a factor 80 and its shuttling by a factor 4. These glucose-induced movements were not due to glycolytic ATP production. The mechanism involved was leptomycin B-insensitive, but phosphatase- and energy-dependent. HepG2 and COS-7 cells displayed no glucose-induced GFP-karyopherin alpha2 movements. In pancreatic MIN-6 cells, the glucose-induced movements of karyopherin alpha2 and the stimulation of glucose-induced gene transcription were simultaneously lost between passages 28 and 33. Thus, extracellular glucose regulates a nuclear transport pathway by increasing the nuclear efflux and shuttling of karyopherin alpha2 in cells in which glucose can stimulate the transcription of sugar-responsive genes.

  3. Variance Reduction Factor of Nuclear Data for Integral Neutronics Parameters

    SciTech Connect

    Chiba, G. Tsuji, M.; Narabayashi, T.

    2015-01-15

    We propose a new quantity, a variance reduction factor, to identify nuclear data for which further improvements are required to reduce uncertainties of target integral neutronics parameters. Important energy ranges can be also identified with this variance reduction factor. Variance reduction factors are calculated for several integral neutronics parameters. The usefulness of the variance reduction factors is demonstrated.

  4. Receptors and ionic transporters in nuclear membranes: new targets for therapeutical pharmacological interventions.

    PubMed

    Bkaily, Ghassan; Avedanian, Levon; Al-Khoury, Johny; Ahmarani, Lena; Perreault, Claudine; Jacques, Danielle

    2012-08-01

    Work from our group and other laboratories showed that the nucleus could be considered as a cell within a cell. This is based on growing evidence of the presence and role of nuclear membrane G-protein coupled receptors and ionic transporters in the nuclear membranes of many cell types, including vascular endothelial cells, endocardial endothelial cells, vascular smooth muscle cells, cardiomyocytes, and hepatocytes. The nuclear membrane receptors were found to modulate the functioning of ionic transporters at the nuclear level, and thus contribute to regulation of nuclear ionic homeostasis. Nuclear membranes of the mentioned types of cells possess the same ionic transporters; however, the type of receptors is cell-type dependent. Regulation of cytosolic and nuclear ionic homeostasis was found to be dependent upon a tight crosstalk between receptors and ionic transporters of the plasma membranes and those of the nuclear membrane. This crosstalk seems to be the basis for excitation-contraction coupling, excitation-secretion coupling, and excitation - gene expression coupling. Further advancement in this field will certainly shed light on the role of nuclear membrane receptors and transporters in health and disease. This will in turn enable the successful design of a new class of drugs that specifically target such highly vital nuclear receptors and ionic transporters.

  5. Role of zinc finger structure in nuclear localization of transcription factor Sp1

    SciTech Connect

    Ito, Tatsuo; Azumano, Makiko; Uwatoko, Chisana; Itoh, Kohji Kuwahara, Jun

    2009-02-27

    Transcription factor Sp1 is localized in the nucleus and regulates gene expression. Our previous study demonstrated that the carboxyl terminal region of Sp1 containing 3-zinc finger region as DNA binding domain can also serve as nuclear localization signal (NLS). However, the nuclear transport mechanism of Sp1 has not been well understood. In this study, we performed a gene expression study on mutant Sp1 genes causing a set of amino acid substitutions in zinc finger domains to elucidate nuclear import activity. Nuclear localization of the GFP-fused mutant Sp1 proteins bearing concomitant substitutions in the first and third zinc fingers was highly inhibited. These mutant Sp1 proteins had also lost the binding ability as to the GC box sequence. The results suggest that the overall tertiary structure formed by the three zinc fingers is essential for nuclear localization of Sp1 as well as dispersed basic amino acids within the zinc fingers region.

  6. Biophysical Coarse-Grained Modeling Provides Insights into Transport through the Nuclear Pore Complex

    PubMed Central

    Moussavi-Baygi, R.; Jamali, Y.; Karimi, R.; Mofrad, M.R.K.

    2011-01-01

    The nuclear pore complex (NPC) is the gatekeeper of the nucleus, capable of actively discriminating between the active and inert cargo while accommodating a high rate of translocations. The biophysical mechanisms underlying transport, however, remain unclear due to the lack of information about biophysical factors playing role in transport. Based on published experimental data, we have established a coarse-grained model of an intact NPC structure to examine nucleocytoplasmic transport with refined spatial and temporal resolutions. Using our model, we estimate the transport time versus cargo sizes. Our findings suggest that the mean transport time of cargos smaller than 15 nm is independent of size, while beyond this size, there is a sharp increase in the mean transport time. The model confirms that kap-FG hydrophobicity is sufficient for active cargo transport. Moreover, our model predicts that during translocation, small and large cargo-complexes are hydrophobically attached to FG-repeat domains for 86 and 96% of their transport time, respectively. Inside the central channel FG-repeats form a thick layer on the wall leaving an open tube. The cargo-complex is almost always attached to this layer and diffuses back and forth, regardless of the cargo size. Finally, we propose a plausible model for transport in which the NPC can be viewed as a lubricated gate. This model incorporates basic assumptions underlying virtual-gate and reduction-of-dimensionality models with the addition of the FG-layer inside the central channel acting as a lubricant. PMID:21402022

  7. 75 FR 53686 - Blue Ribbon Commission on America's Nuclear Future, Transportation and Storage Subcommittee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-01

    ... question: ``[s]hould the US change the way in which it is storing used nuclear fuel and high level waste... Doc No: 2010-21867] DEPARTMENT OF ENERGY Blue Ribbon Commission on America's Nuclear Future, Transportation and Storage Subcommittee AGENCY: Department of Energy, Office of Nuclear Energy. ACTION: Notice...

  8. The transcription factor nuclear factor-kappa B and cancer.

    PubMed

    Escárcega, R O; Fuentes-Alexandro, S; García-Carrasco, M; Gatica, A; Zamora, A

    2007-03-01

    Since the discovery of nuclear factor-kappa B (NF-kappaB) in 1986, many studies have been conducted showing the link between the NF-kappaB signalling pathway and control of the inflammatory response. Today it is well known that control of the inflammatory response and apoptosis is closely related to the activation of NF-kappaB. Three NF-kappaB activation pathways exist. The first (the classical pathway) is normally triggered in response to microbial and viral infections or exposure to pro-inflammatory cytokines that activate the tripartite IKK complex, leading to phosphorylation-induced IkappaB degradation and depends mainly on IKKbeta activity. The second (the alternative pathway), leads to selective activation of p52:RelB dimers by inducing the processing of the NF-kappaB2/p100 precursor protein, which mostly occurs as a heterodimer with RelB in the cytoplasm. This pathway is triggered by certain members of the tumour necrosis factor cytokine family, through selective activation of IKKalpha homodimers by the upstream kinase NIK. The third pathway is named CK2 and is IKK independent. NF-kappaB acts through the transcription of anti-apoptotic proteins, leading to increased proliferation of cells and tumour growth. It is also known that some drugs act directly in the inhibition of NF-kappaB, thus producing regulation of apoptosis; some examples are aspirin and corticosteroids. Here we review the role of NF-kappaB in the control of apoptosis, its link to oncogenesis, the evidence of several studies that show that NF-kappaB activation is closely related to different cancers, and finally the potential target of NF-kappaB as cancer therapy.

  9. Nuclear Decay Factors Crack Up mRNA.

    PubMed

    Tudek, Agnieszka; Schmid, Manfred; Jensen, Torben Heick

    2017-03-02

    In this issue of Molecular Cell, Bresson et al. (2017) show that the nuclear RNA decay factors Nab3 and Mtr4 reshape the coding transcriptome during glucose starvation in budding yeast, placing nuclear mRNA metabolism as an important contributor of gene expression regulation.

  10. Genetic and Dietary Factors Influencing the Progression of Nuclear Cataract.

    PubMed

    Yonova-Doing, Ekaterina; Forkin, Zoe A; Hysi, Pirro G; Williams, Katie M; Spector, Tim D; Gilbert, Clare E; Hammond, Christopher J

    2016-06-01

    To determine the heritability of nuclear cataract progression and to explore prospectively the effect of dietary micronutrients on the progression of nuclear cataract. Prospective cohort study. Cross-sectional nuclear cataract and dietary measurements were available for 2054 white female twins from the TwinsUK cohort. Follow-up cataract measurements were available for 324 of the twins (151 monozygotic and 173 dizygotic twins). Nuclear cataract was measured using a quantitative measure of nuclear density obtained from digital Scheimpflug images. Dietary data were available from EPIC food frequency questionnaires. Heritability was modeled using maximum likelihood structural equation twin modeling. Association between nuclear cataract change and micronutrients was investigated using linear and multinomial regression analysis. The mean interval between baseline and follow-up examination was 9.4 years. Nuclear cataract progression. The best-fitting model estimated that the heritability of nuclear cataract progression was 35% (95% confidence interval [CI], 13-54), and individual environmental factors explained the remaining 65% (95% CI, 46-87) of variance. Dietary vitamin C was protective against both nuclear cataract at baseline and nuclear cataract progression (β = -0.0002, P = 0.01 and β = -0.001, P = 0.03, respectively), whereas manganese and intake of micronutrient supplements were protective against nuclear cataract at baseline only (β = -0.009, P = 0.03 and β = -0.03, P = 0.01, respectively). Genetic factors explained 35% of the variation in progression of nuclear cataract over a 10-year period. Environmental factors accounted for the remaining variance, and in particular, dietary vitamin C protected against cataract progression assessed approximately 10 years after baseline. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  11. Site Specific Analyses of a Spent Nuclear Fuel Transportation Accident

    SciTech Connect

    Biwer, B. M.; Chen, S. Y.

    2003-02-24

    The number of spent nuclear fuel (SNF) shipments is expected to increase significantly during the time period that the United States' inventory of SNF is sent to a final disposal site. Prior work estimated that the highest accident risks of a SNF shipping campaign to the proposed geologic repository at Yucca Mountain were in the corridor states, such as Illinois. The largest potential human health impacts would be expected to occur in areas with high population densities such as urban settings. Thus, our current study examined the human health impacts from the most plausible severe SNF transportation accidents in the Chicago metropolitan area. The RISKIND 2.0 program was used to model site-specific data for an area where the largest impacts might occur. The results have shown that the radiological human health consequences of a severe SNF rail transportation accident on average might be similar to one year of exposure to natural background radiation for those persons living a nd working in the most affected areas downwind of the actual accident location. For maximally exposed individuals, an exposure similar to about two years of exposure to natural background radiation was estimated. In addition to the accident probabilities being very low (approximately 1 chance in 10,000 or less during the entire shipping campaign), the actual human health impacts are expected to be lower if any of the accidents considered did occur, because the results are dependent on the specific location and weather conditions, such as wind speed and direction, that were selected to maximize the results. Also, comparison of the results of longer duration accident scenarios against U.S. Environmental Protection Agency guidelines was made to demonstrate the usefulness of this site-specific analysis for emergency planning purposes.

  12. The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation.

    PubMed

    DiGiandomenico, Antonio; Veach, Ruth Ann; Zienkiewicz, Jozef; Moore, Daniel J; Wylezinski, Lukasz S; Hutchens, Martha A; Hawiger, Jacek

    2014-01-01

    Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by

  13. Examining Factors Affecting Attitudes toward Nuclear Power in Taiwan

    NASA Astrophysics Data System (ADS)

    Chan, Tzu-Jen

    Nuclear power has become a major issue in Taiwan for several decades. The objective of the present study is to obtain evidence about the major determinants contributing to attitudes toward nuclear power, by investigating socioeconomic factors, environmental attitudes, knowledge of issues, trust, and risk perception, in shaping nuclear attitudes. A face-to-face survey was conducted using paper-based questionnaires from July 2014 to September 2014. Finally, 364 surveys were collected, of which 356 met validation requirements. The findings showed (1) knowledge of issues, trust in university scientists, trust in environmental groups, and risk perception directly influence attitudes toward nuclear power. (2) Risk perception is directly influenced by trust in nuclear authorities, trust in environmental groups, environmental attitudes, and party preference. (3) Gender, age, and party preference directly influence knowledge, trust in nuclear authorities, or trust in university scientists. The potential explanations and implications of findings are discussed.

  14. Human factors aspects of advanced instrumentation in the nuclear industry

    SciTech Connect

    Carter, R.J.

    1989-01-01

    An important consideration in regards to the use of advanced instrumentation in the nuclear industry is the interface between the instrumentation system and the human. A survey, oriented towards identifying the human factors aspects of digital instrumentation, was conducted at a number of United States (US) and Canadian nuclear vendors and utilities. Human factors issues, subsumed under the categories of computer-generated displays, controls, organizational support, training, and related topics were identified. 20 refs., 2 tabs.

  15. Aptamers that bind specifically to human KPNA2 (importin-α1) and efficiently interfere with nuclear transport.

    PubMed

    Yasuhara, Noriko; Kumar, Penmetcha K R

    2016-11-01

    The importin-α family of proteins plays an important role in the eukaryotic importin/exportin nuclear transport system. These proteins recognize a nuclear localization signal (NLS) within cargo proteins and import them into the nucleus through nuclear pores, in a process mediated by importin-β. Recent studies have shown that importin-α proteins specifically recognize the NLS of several cellular factors and viral proteins, thus regulating their movement. Dysregulation of importin-α is a common hallmark of many pathologies including, multiple cancers. In this study, we isolated aptamers 76 and 72, which bind specifically and efficiently to KPNA2, a member of a subfamily of importin-α1. Both of these aptamers bind to KPNA2 with an equilibrium dissociation constant (K d) of 150 nM and discriminate between KPNA2 and other sub-family members of importin-α, such as KPNA1 and KPNA3. These aptamers specifically interfere with the nuclear transport of cargo proteins mediated by KPNA2 but neither with KPNA1 nor KPNA3, which belongs to other subfamily of importins. These results suggest that the selected aptamers (76 and 72) warrant further study to explore not only their application in cancer diagnosis but also their use as a specific reagent to potentially block KPNA2-dependent nuclear transport of macromolecules across the nuclear membrane.

  16. Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock

    PubMed Central

    Allemand, Eric; Guil, Sònia; Myers, Michael; Moscat, Jorge; Cáceres, Javier F.; Krainer, Adrian R.

    2005-01-01

    Heterogenous nuclear ribonucleoprotein (hnRNP) A1 is an alternative splicing factor that is mainly nuclear, although it shuttles rapidly between nuclear and cytoplasmic compartments. Cells stressed by osmotic shock (OSM) activate the mitogen-activated protein kinase kinase3/6-p38 signaling pathway, which in turn results in accumulation of hnRNP A1 in the cytoplasm. This effect modulates alternative splicing regulation in vivo and correlates with increased hnRNP A1 phosphorylation. We have characterized the molecular mechanism involved in the cytoplasmic accumulation of hnRNP A1 in NIH 3T3 cells subjected to OSM. This treatment results in serine-specific phosphorylation within a C-terminal peptide, dubbed the “F-peptide,” which is adjacent to the M9 motif that mediates bidirectional transport of hnRNP A1. Analysis of mutants in which the F-peptide serines were replaced by aspartic acids or alanines showed that F-peptide phosphorylation is required for the subcellular redistribution of hnRNP A1 in cells subjected to OSM. Furthermore, F-peptide phosphorylation modulates the interaction of hnRNP A1 with transportin Trn1. Our findings suggest that the phosphorylation of F-peptide by cell-signaling pathways regulates the rate of hnRNP A1 nuclear import. PMID:15738418

  17. Solar modulation and nuclear fragmentation effects in galactic cosmic ray transport through shielding

    NASA Astrophysics Data System (ADS)

    Townsend, L. W.; Cucinotta, C. F.; Wilson, J. W.; Shinn, J. L.; Badhwar, G.

    1994-10-01

    Crews of manned interplanetary missions may accumulate significant radiation exposures from the Galactic Cosmic Ray (GCR) environment in space. Estimates of how these dose levels are affected by the assumed temporal and spatial variations in the composition of the GCR environment, and by the effects of the spacecraft and body self-shielding on the transported fields are presented. In this work, the physical processes through which shielding alters the transported radiation fields are described. We then present estimates of the effects on model calculations of (1) nuclear fragmentation model uncertainties, (2) solar modulation, (3) variations between solar cycles, and (4) proposed changes to the quality factors which relate dose equivalent to absorbed dose.

  18. Solar modulation and nuclear fragmentation effects in galactic cosmic ray transport through shielding

    NASA Technical Reports Server (NTRS)

    Townsend, L. W.; Cucinotta, C. F.; Wilson, J. W.; Shinn, J. L.; Badhwar, G.

    1994-01-01

    Crews of manned interplanetary missions may accumulate significant radiation exposures from the Galactic Cosmic Ray (GCR) environment in space. Estimates of how these dose levels are affected by the assumed temporal and spatial variations in the composition of the GCR environment, and by the effects of the spacecraft and body self-shielding on the transported fields are presented. In this work, the physical processes through which shielding alters the transported radiation fields are described. We then present estimates of the effects on model calculations of (1) nuclear fragmentation model uncertainties, (2) solar modulation, (3) variations between solar cycles, and (4) proposed changes to the quality factors which relate dose equivalent to absorbed dose.

  19. The Dose Rate Conversion Factors for Nuclear Fallout

    SciTech Connect

    Spriggs, G D

    2009-02-13

    In a previous paper, the composite exposure rate conversion factor (ECF) for nuclear fallout was calculated using a simple theoretical photon-transport model. The theoretical model was used to fill in the gaps in the FGR-12 table generated by ORNL. The FGR-12 table contains the individual conversion factors for approximate 1000 radionuclides. However, in order to calculate the exposure rate during the first 30 minutes following a nuclear detonation, the conversion factors for approximately 2000 radionuclides are needed. From a human-effects standpoint, it is also necessary to have the dose rate conversion factors (DCFs) for all 2000 radionuclides. The DCFs are used to predict the whole-body dose rates that would occur if a human were standing in a radiation field of known exposure rate. As calculated by ORNL, the whole-body dose rate (rem/hr) is approximately 70% of the exposure rate (R/hr) at one meter above the surface. Hence, the individual DCFs could be estimated by multiplying the individual ECFs by 0.7. Although this is a handy rule-of-thumb, a more consistent (and perhaps, more accurate) method of estimating the individual DCFs for the missing radionuclides in the FGR-12 table is to use the linear relationship between DCF and total gamma energy released per decay. This relationship is shown in Figure 1. The DCFs for individual organs in the body can also be estimated from the estimated whole-body DCF. Using the DCFs given FGR-12, the ratio of the organ-specific DCFs to the whole-body DCF were plotted as a function of the whole-body DCF. From these plots, the asymptotic ratios were obtained (see Table 1). Using these asymptotic ratios, the organ-specific DCFs can be estimated using the estimated whole-body DCF for each of the missing radionuclides in the FGR-12 table. Although this procedure for estimating the organ-specific DCFs may over-estimate the value for some low gamma-energy emitters, having a finite value for the organ-specific DCFs in the table is

  20. Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

    PubMed Central

    Cigdem, Sadik; Okuwaki, Mitsuru; Nagata, Kyosuke

    2016-01-01

    Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEK-Nup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-κB signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-κB-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IκB, in the nucleus. These results suggest that SET-Nup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system. PMID:27114368

  1. Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway.

    PubMed

    Saito, Shoko; Cigdem, Sadik; Okuwaki, Mitsuru; Nagata, Kyosuke

    2016-07-01

    Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEK-Nup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-κB signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-κB-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IκB, in the nucleus. These results suggest that SET-Nup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  2. Facilitated transport and diffusion take distinct spatial routes through the nuclear pore complex

    PubMed Central

    Fiserova, Jindriska; Richards, Shane A.; Wente, Susan R.; Goldberg, Martin W.

    2010-01-01

    Transport across the nuclear envelope is regulated by nuclear pore complexes (NPCs). Much is understood about the factors that shuttle and control the movement of cargos through the NPC, but less has been resolved about the translocation process itself. Various models predict how cargos move through the channel; however, direct observation of the process is missing. Therefore, we have developed methods to accurately determine cargo positions within the NPC. Cargos were instantly trapped in transit by high-pressure freezing, optimally preserved by low-temperature fixation and then localized by immunoelectron microscopy. A statistical modelling approach was used to identify cargo distribution. We found import cargos localized surprisingly close to the edge of the channel, whereas mRNA export factors were at the very centre of the NPC. On the other hand, diffusion of GFP was randomly distributed. Thus, we suggest that spatially distinguished pathways exist within the NPC. Deletion of specific FG domains of particular NPC proteins resulted in collapse of the peripheral localization and transport defects specific to a certain karyopherin pathway. This further confirms that constraints on the route of travel are biochemical rather than structural and that the peripheral route of travel is essential for facilitated import. PMID:20647373

  3. Facilitated transport and diffusion take distinct spatial routes through the nuclear pore complex.

    PubMed

    Fiserova, Jindriska; Richards, Shane A; Wente, Susan R; Goldberg, Martin W

    2010-08-15

    Transport across the nuclear envelope is regulated by nuclear pore complexes (NPCs). Much is understood about the factors that shuttle and control the movement of cargos through the NPC, but less has been resolved about the translocation process itself. Various models predict how cargos move through the channel; however, direct observation of the process is missing. Therefore, we have developed methods to accurately determine cargo positions within the NPC. Cargos were instantly trapped in transit by high-pressure freezing, optimally preserved by low-temperature fixation and then localized by immunoelectron microscopy. A statistical modelling approach was used to identify cargo distribution. We found import cargos localized surprisingly close to the edge of the channel, whereas mRNA export factors were at the very centre of the NPC. On the other hand, diffusion of GFP was randomly distributed. Thus, we suggest that spatially distinguished pathways exist within the NPC. Deletion of specific FG domains of particular NPC proteins resulted in collapse of the peripheral localization and transport defects specific to a certain karyopherin pathway. This further confirms that constraints on the route of travel are biochemical rather than structural and that the peripheral route of travel is essential for facilitated import.

  4. Negative transcriptional regulation of mitochondrial transcription factor A (TFAM) by nuclear TFAM

    SciTech Connect

    Lee, Eun Jin; Kang, Young Cheol; Park, Wook-Ha; Jeong, Jae Hoon; Pak, Youngmi Kim

    2014-07-18

    Highlights: • TFAM localizes in nuclei and mitochondria of neuronal cells. • Nuclear TFAM does not bind the Tfam promoter. • Nuclear TFAM reduced the Tfam promoter activity via suppressing NRF-1 activity. • A novel self-negative feedback regulation of Tfam gene expression is explored. • FAM may play different roles depending on its subcellular localizations. - Abstract: The nuclear DNA-encoded mitochondrial transcription factor A (TFAM) is synthesized in cytoplasm and transported into mitochondria. TFAM enhances both transcription and replication of mitochondrial DNA. It is unclear, however, whether TFAM plays a role in regulating nuclear gene expression. Here, we demonstrated that TFAM was localized to the nucleus and mitochondria by immunostaining, subcellular fractionation, and TFAM-green fluorescent protein hybrid protein studies. In HT22 hippocampal neuronal cells, human TFAM (hTFAM) overexpression suppressed human Tfam promoter-mediated luciferase activity in a dose-dependent manner. The mitochondria targeting sequence-deficient hTFAM also repressed Tfam promoter activity to the same degree as hTFAM. It indicated that nuclear hTFAM suppressed Tfam expression without modulating mitochondrial activity. The repression required for nuclear respiratory factor-1 (NRF-1), but hTFAM did not bind to the NRF-1 binding site of its promoter. TFAM was co-immunoprecipitated with NRF-1. Taken together, we suggest that nuclear TFAM down-regulate its own gene expression as a NRF-1 repressor, showing that TFAM may play different roles depending on its subcellular localizations.

  5. Nuclear import of a lipid-modified transcription factor

    PubMed Central

    Eisenhaber, Birgit; Sammer, Michaela; Lua, Wai Heng; Benetka, Wolfgang; Liew, Lai Ling; Yu, Weimiao; Lee, Hwee Kuan; Koranda, Manfred; Adhikari, Sharmila

    2011-01-01

    Lipid-modified transcription factors (TFs) are biomolecular oddities, since their reduced mobility and membrane attachment appear to contradict nuclear import required for their gene-regulatory function. NFAT5 isoform a (selected from an in silico screen for predicted lipid-modified TFs) is shown to contribute about half of all endogenous expression of human NFAT5 isoforms in the isotonic state. Wild-type NFAT5a protein is, indeed, myristoylated and palmitoylated on its transport to the plasmalemma via the endoplasmic reticulum and the Golgi. In contrast, its lipid anchor-deficient mutants as well as isoforms NFAT5b/c are diffusely localized in the cytoplasm without preference to vesicular structures. Quantitative/live microscopy shows the plasma membrane-bound fraction of NFAT5a moving into the nucleus upon osmotic stress despite the lipid anchoring. The mobilization mechanism is not based on proteolytic processing of the lipid-anchored N terminus but appears to involve reversible palmitoylation. Thus, NFAT5a is an example of TFs immobilized with lipid anchors at cyotoplasmic membranes in the resting state and that, nevertheless, can translocate into the nucleus upon signal induction. PMID:22071693

  6. BGLF4 Kinase Modulates the Structure and Transport Preference of the Nuclear Pore Complex To Facilitate Nuclear Import of Epstein-Barr Virus Lytic Proteins

    PubMed Central

    Chang, Chou-Wei; Lee, Chung-Pei; Su, Mei-Tzu; Tsai, Ching-Hwa

    2014-01-01

    ABSTRACT BGLF4 kinase, the only Ser/Thr protein kinase encoded by the Epstein-Barr virus (EBV) genome, phosphorylates multiple viral and cellular substrates to optimize the cellular environment for viral DNA replication and the nuclear egress of nucleocapsids. Previously, we found that nuclear targeting of BGLF4 is through direct interaction with the FG repeat-containing nucleoporins (FG-Nups) Nup62 and Nup153 independently of cytosolic transport factors. Here, we investigated the regulatory effects of BGLF4 on the structure and biological functions of the nuclear pore complex (NPC). In EBV-positive NA cells, the distribution of FG-Nups was modified during EBV reactivation. In transfected cells, BGLF4 changed the staining pattern of Nup62 and Nup153 in a kinase activity-dependent manner. Detection with anti-phospho-Ser/Thr-Pro MPM-2 antibody demonstrated that BGLF4 induced the phosphorylation of Nup62 and Nup153. The nuclear targeting of importin β was attenuated in the presence of BGLF4, leading to inhibition of canonical nuclear localization signal (NLS)-mediated nuclear import. An in vitro nuclear import assay revealed that BGLF4 induced the nuclear import of larger molecules. Notably, we found that BGLF4 promoted the nuclear import of several non-NLS-containing EBV proteins, including the viral DNA-replicating enzymes BSLF1, BBLF2/3, and BBLF4 and the major capsid protein (VCA), in cotransfected cells. The data presented here suggest that BGLF4 interferes with the normal functions of Nup62 and Nup153 and preferentially helps the nuclear import of viral proteins for viral DNA replication and assembly. In addition, the nuclear import-promoting activity was found in cells expressing the BGLF4 homologs of another two gammaherpesviruses but not those from alpha- and betaherpesviruses. IMPORTANCE During lytic replication, many EBV genome-encoded proteins need to be transported into the nucleus, not only for viral DNA replication but also for the assembly of

  7. Interactome of the inhibitory isoform of the nuclear transporter Importin 13.

    PubMed

    Fatima, Shadma; Wagstaff, Kylie M; Lieu, Kim G; Davies, Rebecca G; Tanaka, Satomi S; Yamaguchi, Yasuka L; Loveland, Kate L; Tam, Patrick P L; Jans, David A

    2017-03-01

    Importin 13 (Imp13) is a bidirectional nuclear transporter of proteins involved in a range of important cellular processes, with an N-terminally truncated inhibitory isoform (tImp13) specifically expressed in testis. To gain insight into tImp13 function, we performed a yeast-2-hybrid screen from a human testis cDNA library, identifying for the first time a suite of interactors with roles in diverse cellular process. We validated the interaction of tImp13 with Eukaryotic translation initiation factor 4γ2 (EIF4G2) and High mobility group containing protein 20A (HMG20A), benchmarking that with glucocorticoid receptor (GR), a known Imp13 interactor expressed in testis. Coimmunoprecipitation assays indicated association of both tImp13 and Imp13 with EIF4G2, HMG20A and GR. Quantitative confocal microscopic analysis revealed the ability of tImp13 to inhibit the nuclear localisation of EIF4G2, HMG20A and GR, as well as that of Imp13 to act as a nuclear exporter for both EIF4G2 and HMG20A, and as a nuclear importer for GR. The physiological relevance of these results was highlighted by the cytoplasmic localisation of EIF4G2, HMG20A and GR in pachytene spermatocytes/round spermatids in the murine testis where tImp13 is present at high levels, in contrast to the nuclear localisation of HMG20A and GR in spermatogonia, where tImp13 is largely absent. Interestingly, Imp13, EIF4G2, HMG20A and GR were found together in the acrosome vesicle of murine epididymal spermatozoa. Collectively, our findings show, for the first time, that tImp13 may have a functional role in the mature spermatozoa, in addition to that in the meiotic germ cells of the testis.

  8. Normative Factors in U.S. Nuclear Policy

    DTIC Science & Technology

    2016-09-01

    weapons in conflict. There exists large bodies of research and theories that attempt to explain the key variables that have prevented the use of...nuclear weapons in anger, and much research exists on how norms factor in to non-use. Some theorists argue that norms are highly explanatory in preventing ...indiscriminate nature, radiation effects, and so on,”25 which prevented policymakers from choosing nuclear arms over conventional weapons. This theory

  9. Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion.

    PubMed

    Bosse, Jens B; Hogue, Ian B; Feric, Marina; Thiberge, Stephan Y; Sodeik, Beate; Brangwynne, Clifford P; Enquist, Lynn W

    2015-10-20

    The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids.

  10. Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion

    PubMed Central

    Bosse, Jens B.; Hogue, Ian B.; Feric, Marina; Thiberge, Stephan Y.; Sodeik, Beate; Brangwynne, Clifford P.; Enquist, Lynn W.

    2015-01-01

    The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids. PMID:26438852

  11. Development and Analysis of Advanced High-Temperature Technology for Nuclear Heat Transport and Power Conversion

    SciTech Connect

    Per F. Peterson

    2010-03-01

    This project by the Thermal Hydraulics Research Laboratory at U.C. Berkeley Studied advanced high-temperature heat transport and power conversion technology, in support of the Nuclear Hydrogen Initiative and Generation IV.

  12. Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver.

    PubMed

    More, Vijay R; Cheng, Qiuqiong; Donepudi, Ajay C; Buckley, David B; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L

    2013-05-01

    Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism and may result in diabetes, which is why alcoholic liver disease and diabetes often are present together. Because there is a sizable population with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected by alcoholic cirrhosis, diabetes, and alcoholic cirrhosis coexisting with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals and can be determinants of drug-induced liver injury. Drug transporter expression and transcription factor-relative mRNA and protein expression in normal, diabetic, cirrhotic, and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreased SLCO1B3 mRNA expression in the liver. ABCC1, 3-5, and ABCG2 protein expression was also upregulated by alcoholic cirrhosis. ABCC3-5 and ABCG2 protein expression was also upregulated in diabetic cirrhosis. Cirrhosis increased nuclear factor E2-related factor 2 mRNA expression, whereas it decreased pregnane-X-receptor and farnesoid-X-receptor mRNA expression in comparison with normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3, and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcoholic cirrhosis altered transporter expression in human liver.

  13. Economic Conditions and Factors Affecting New Nuclear Power Deployment

    SciTech Connect

    Harrison, Thomas J.

    2014-10-01

    This report documents work performed in support of the US Department of Energy Office of Nuclear Energy’s Advanced Small Modular Reactor (AdvSMR) program. The report presents information and results from economic analyses to describe current electricity market conditions and those key factors that may impact the deployment of AdvSMRs or any other new nuclear power plants. Thus, this report serves as a reference document for DOE as it moves forward with its plans to develop advanced reactors, including AdvSMRs. For the purpose of this analysis, information on electricity markets and nuclear power plant operating costs will be combined to examine the current state of the nuclear industry and the process required to successfully move forward with new nuclear power in general and AdvSMRs in particular. The current electricity market is generally unfavorable to new nuclear construction, especially in deregulated markets with heavy competition from natural gas and subsidized renewables. The successful and profitable operation of a nuclear power plant (or any power plant) requires the rate at which the electricity is sold to be sufficiently greater than the cost to operate. The wholesale rates in most US markets have settled into values that provide profits for most operating nuclear power plants but are too low to support the added cost of capital recovery for new nuclear construction. There is a strong geographic dependence on the wholesale rate, with some markets currently able to support new nuclear construction. However, there is also a strong geographic dependence on pronuclear public opinion; the areas where power prices are high tend to have unfavorable views on the construction of new nuclear power plants. The use of government-backed incentives, such as subsidies, can help provide a margin to help justify construction projects that otherwise may not seem viable. Similarly, low interest rates for the project will also add a positive margin to the economic

  14. Nuclear transport of paxillin depends on focal adhesion dynamics and FAT domains

    PubMed Central

    Sathe, Aneesh R.; Shivashankar, G. V.; Sheetz, Michael P.

    2016-01-01

    ABSTRACT The nuclear transport of paxillin appears to be crucial for paxillin function but the mechanism of transport remains unclear. Here, we show that the nuclear transport of paxillin is regulated by focal adhesion turnover and the presence of FAT domains. Focal adhesion turnover was controlled using triangular or circular fibronectin islands. Circular islands caused higher focal adhesion turnover and increased the nuclear transport of paxillin relative to triangular islands. Mutating several residues of paxillin had no effect on its nuclear transport, suggesting that the process is controlled by multiple domains. Knocking out FAK (also known as PTK2) and vinculin caused an increase in nuclear paxillin. This could be reversed by rescue with wild-type FAK but not by FAK with a mutated FAT domain, which inhibits paxillin binding. Expressing just the FAT domain of FAK not only brought down nuclear levels of paxillin but also caused a large immobile fraction of paxillin to be present at focal adhesions, as demonstrated by fluorescence recovery after photobleaching (FRAP) studies. Taken together, focal adhesion turnover and FAT domains regulate the nuclear localization of paxillin, suggesting a possible role for transcriptional control, through paxillin, by focal adhesions. PMID:27068537

  15. Using Nuclear Theory, Data and Uncertainties in Monte Carlo Transport Applications

    SciTech Connect

    Rising, Michael Evan

    2015-11-03

    These are slides for a presentation on using nuclear theory, data and uncertainties in Monte Carlo transport applications. The following topics are covered: nuclear data (experimental data versus theoretical models, data evaluation and uncertainty quantification), fission multiplicity models (fixed source applications, criticality calculations), uncertainties and their impact (integral quantities, sensitivity analysis, uncertainty propagation).

  16. 10 CFR 150.21 - Transportation of special nuclear material by aircraft.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Transportation of special nuclear material by aircraft. 150.21 Section 150.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED REGULATORY AUTHORITY IN AGREEMENT STATES AND IN OFFSHORE WATERS UNDER SECTION 274 Reciprocity §...

  17. 10 CFR 150.21 - Transportation of special nuclear material by aircraft.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false Transportation of special nuclear material by aircraft. 150.21 Section 150.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED REGULATORY AUTHORITY IN AGREEMENT STATES AND IN OFFSHORE WATERS UNDER SECTION 274 Reciprocity §...

  18. Summary report on transportation of nuclear fuel materials in Japan : transportation infrastructure, threats identified in open literature, and physical protection regulations.

    SciTech Connect

    Cochran, John Russell; Ouchi, Yuichiro; Furaus, James Phillip; Marincel, Michelle K.

    2008-03-01

    This report summarizes the results of three detailed studies of the physical protection systems for the protection of nuclear materials transport in Japan, with an emphasis on the transportation of mixed oxide fuel materials1. The Japanese infrastructure for transporting nuclear fuel materials is addressed in the first section. The second section of this report presents a summary of baseline data from the open literature on the threats of sabotage and theft during the transport of nuclear fuel materials in Japan. The third section summarizes a review of current International Atomic Energy Agency, Japanese and United States guidelines and regulations concerning the physical protection for the transportation of nuclear fuel materials.

  19. Nuclear transport defects and nuclear envelope alterations are associated with mutation of the Saccharomyces cerevisiae NPL4 gene.

    PubMed Central

    DeHoratius, C; Silver, P A

    1996-01-01

    To identify components involved in nuclear protein import, we used a genetic selection to isolate mutants that mislocalized a nuclear-targeted protein. We identified temperature-sensitive mutants that accumulated several different nuclear proteins in the cytoplasm when shifted to the semipermissive temperature of 30 degrees C; these were termed npl (nuclear protein localization) mutants. We now present the properties of yeast strains bearing mutations in the NPL4 gene and report the cloning of the NPL4 gene and the characterization of the Np14 protein. The npl4-1 mutant was isolated by the previously described selection scheme. The second allele, npl4-2, was identified from an independently derived collection of temperature-sensitive mutants. The npl4-1 and npl4-2 strains accumulate nuclear-targeted proteins in the cytoplasm at the nonpermissive temperature consistent with a defect in nuclear protein import. Using an in vitro nuclear import assay, we show that nuclei prepared from temperature-shifted npl4 mutant cells are unable to import nuclear-targeted proteins, even in the presence of cytosol prepared from wild-type cells. In addition, npl4-2 cells accumulate poly(A)+ RNA in the nucleus at the nonpermissive temperature, consistent with a failure to export mRNA from the nucleus. The npl4-1 and npl4-2 cells also exhibit distinct, temperature-sensitive structural defects: npl4-1 cells project extra nuclear envelope into the cytoplasm, whereas npl4-2 cells from nuclear envelope herniations that appear to be filled with poly(A)+ RNA. The NPL4 gene encodes an essential M(r) 64,000 protein that is located at the nuclear periphery and localizes in a pattern similar to nuclear pore complex proteins. Taken together, these results indicate that this gene encodes a novel nuclear pore complex or nuclear pore complex-associated component required for nuclear membrane integrity and nuclear transport. Images PMID:8930904

  20. Novel nuclear hENT2 isoforms regulate cell cycle progression via controlling nucleoside transport and nuclear reservoir.

    PubMed

    Grañé-Boladeras, Natalia; Spring, Christopher M; Hanna, W J Brad; Pastor-Anglada, Marçal; Coe, Imogen R

    2016-12-01

    Nucleosides participate in many cellular processes and are the fundamental building blocks of nucleic acids. Nucleoside transporters translocate nucleosides across plasma membranes although the mechanism by which nucleos(t)ides are translocated into the nucleus during DNA replication is unknown. Here, we identify two novel functional splice variants of equilibrative nucleoside transporter 2 (ENT2), which are present at the nuclear envelope. Under proliferative conditions, these splice variants are up-regulated and recruit wild-type ENT2 to the nuclear envelope to translocate nucleosides into the nucleus for incorporation into DNA during replication. Reduced presence of hENT2 splice variants resulted in a dramatic decrease in cell proliferation and dysregulation of cell cycle due to a lower incorporation of nucleotides into DNA. Our findings support a novel model of nucleoside compartmentalisation at the nuclear envelope and translocation into the nucleus through hENT2 and its variants, which are essential for effective DNA synthesis and cell proliferation.

  1. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2.

    PubMed

    Theodore, Melanie; Kawai, Yumiko; Yang, Jianqi; Kleshchenko, Yuliya; Reddy, Sekhar P; Villalta, Fernando; Arinze, Ifeanyi J

    2008-04-04

    Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the transcriptional response of cells to oxidative stress and is translocated into the nucleus following, or concomitant with, its activation by electrophiles or reactive oxygen species. The mechanism of its translocation into the nucleus is not entirely elucidated. Here we have identified two novel nuclear localization signal (NLS) motifs in murine Nrf2, one located near the N-terminal region (amino acid residues 42-53) and the other (residues 587-593) located near the C-terminal region. Imaging of green fluorescent protein (GFP)-tagged Nrf2 revealed that mutation(s) in any of these sequences resulted in decreased nuclear fluorescence intensity compared with the wild-type Nrf2 when Nrf2 activation was induced with the electrophile tert-butylhydroquinone. The mutations also impaired Nrf2-induced transactivation of antioxidant response element-driven reporter gene expression to the same extent as the Nrf2 construct bearing mutation in a previously identified bipartite NLS that maps at residues 494-511. When linked to GFP or to GFP-PEPCK-C each of the novel NLS motifs was sufficient to drive nuclear translocation of the fusion proteins. Co-immunoprecipitation assays demonstrated that importins alpha5 and beta1 associate with Nrf2, an interaction that was blocked by the nuclear import inhibitor SN50. SN50 also blocked tert-butylhydroquinone-induced nuclear fluorescence of GFP-Nrf2 in cells transfected with wild-type GFP-Nrf2. Overall these results reveal that multiple NLS motifs in Nrf2 function in its nuclear translocation in response to pro-oxidant stimuli and that the importin alpha-beta heterodimer nuclear import receptor system plays a critical role in the import process.

  2. Alcohol Cirrhosis Alters Nuclear Receptor and Drug Transporter Expression in Human Liver

    PubMed Central

    More, Vijay R.; Cheng, Qiuqiong; Donepudi, Ajay C.; Buckley, David B.; Lu, Zhenqiang James; Cherrington, Nathan J.

    2013-01-01

    Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism and may result in diabetes, which is why alcoholic liver disease and diabetes often are present together. Because there is a sizable population with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected by alcoholic cirrhosis, diabetes, and alcoholic cirrhosis coexisting with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals and can be determinants of drug-induced liver injury. Drug transporter expression and transcription factor–relative mRNA and protein expression in normal, diabetic, cirrhotic, and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreased SLCO1B3 mRNA expression in the liver. ABCC1, 3–5, and ABCG2 protein expression was also upregulated by alcoholic cirrhosis. ABCC3-5 and ABCG2 protein expression was also upregulated in diabetic cirrhosis. Cirrhosis increased nuclear factor E2–related factor 2 mRNA expression, whereas it decreased pregnane-X-receptor and farnesoid-X-receptor mRNA expression in comparison with normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3, and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcoholic cirrhosis altered transporter expression in human liver. PMID:23462698

  3. Personality Factors and Nuclear Power Plant Operators: Initial License Success

    NASA Astrophysics Data System (ADS)

    DeVita-Cochrane, Cynthia

    Commercial nuclear power utilities are under pressure to effectively recruit and retain licensed reactor operators in light of poor candidate training completion rates and recent candidate failures on the Nuclear Regulatory Commission (NRC) license exam. One candidate failure can cost a utility over $400,000, making the successful licensing of new operators a critical path to operational excellence. This study was designed to discover if the NEO-PI-3, a 5-factor measure of personality, could improve selection in nuclear utilities by identifying personality factors that predict license candidate success. Two large U.S. commercial nuclear power corporations provided potential participant contact information and candidate results on the 2014 NRC exam from their nuclear power units nation-wide. License candidates who participated (n = 75) completed the NEO-PI-3 personality test and results were compared to 3 outcomes on the NRC exam: written exam, simulated operating exam, and overall exam result. Significant correlations were found between several personality factors and both written and operating exam outcomes on the NRC exam. Further, a regression analysis indicated that personality factors, particularly Conscientiousness, predicted simulated operating exam scores. The results of this study may be used to support the use of the NEO-PI-3 to improve operator selection as an addition to the current selection protocol. Positive social change implications from this study include support for the use of a personality measure by utilities to improve their return-on-investment in candidates and by individual candidates to avoid career failures. The results of this study may also positively impact the public by supporting the safe and reliable operation of commercial nuclear power utilities in the United States.

  4. The role of ligand density and size in mediating quantum dot nuclear transport.

    PubMed

    Tang, Peter S; Sathiamoorthy, Sarmitha; Lustig, Lindsay C; Ponzielli, Romina; Inamoto, Ichiro; Penn, Linda Z; Shin, Jumi A; Chan, Warren C W

    2014-10-29

    Studying the effects of the physicochemical properties of nanomaterials on cellular uptake, toxicity, and exocytosis can provide the foundation for designing safer and more effective nanoparticles for clinical applications. However, an understanding of the effects of these properties on subcellular transport, accumulation, and distribution remains limited. The present study investigates the effects of surface density and particle size of semiconductor quantum dots on cellular uptake as well as nuclear transport kinetics, retention, and accumulation. The current work illustrates that cellular uptake and nuclear accumulation of nanoparticles depend on surface density of the nuclear localization signal (NLS) peptides with nuclear transport reaching a plateau at 20% surface NLS density in as little as 30 min. These intracellular nanoparticles have no effects on cell viability up to 72 h post treatment. These findings will set a foundation for engineering more sophisticated nanoparticle systems for imaging and manipulating genetic targets in the nucleus.

  5. Nuclear reaction effects in use of newly recommended quality factor

    NASA Technical Reports Server (NTRS)

    Shinn, Judy L.; Wilson, John W.

    1991-01-01

    The biological risk for energetic ion exposure cannot be reliably estimated exclusive of the target nuclear reaction products produced within the local tissue. A theoretical basis is derived for evaluating target fragment contributions that are evaluated for the newly proposed quality factor.

  6. Electronic and Nuclear Factors in Charge and Excitation Transfer

    SciTech Connect

    Piotr Piotrowiak

    2004-09-28

    We report the and/or state of several subprojects of our DOE sponsored research on Electronic and Nuclear Factors in Electron and Excitation Transfer: (1) Construction of an ultrafast Ti:sapphire amplifier. (2) Mediation of electronic interactions in host-guest molecules. (3) Theoretical models of electrolytes in weakly polar media. (4) Symmetry effects in intramolecular excitation transfer.

  7. Nuclear Energy for a Low-Carbon-Dioxide-Emission Transportation System with Liquid Fuels

    SciTech Connect

    Forsberg, Charles W

    2007-01-01

    The two major energy challenges for the United States are to replace crude oil in our transportation system and reduce greenhouse gas emissions. A multilayer strategy to replace oil using nuclear energy and various carbon sources (fossil fuels, biomass, or air) is described that (a) allows the continued use of liquid fuels (ethanol, gasoline, diesel, and jet fuel) in the transport sector, (b) does not require major changes in lifestyle by the consumer, and (c) ultimately eliminates carbon dioxide emissions from the transport sector. Nuclear energy is used to provide electricity, heat, and ultimately hydrogen, with the hydrogen produced by either electrolysis or more advanced thermochemical production methods. In the near term, nuclear energy can provide low-temperature heat (steam) for ethanol production and electricity for transportation. Midterm options include low-temperature heat and limited quantities of hydrogen for processing cellulosic biomass into liquid fuels (ethanol and lignin-derived hydrocarbons) and providing high-temperature heat for (a) traditional refining and (b) underground oil production and refining. In the longer term, biomass becomes the feedstock for liquid-fuels production, with nuclear energy providing heat and large quantities of hydrogen for complete biomass conversion to hydrocarbon fuels. Nuclear energy could be used to provide over half the total energy required by the transportation system, and the use of oil in the transport sector could potentially be eliminated within several decades.

  8. Nanoscale stiffness topography reveals structure and mechanics of the transport barrier in intact nuclear pore complexes

    PubMed Central

    Labokha, Aksana A.; Osmanović, Dino; Liashkovich, Ivan; Orlova, Elena V.; Ford, Ian J.; Charras, Guillaume; Fassati, Ariberto; Hoogenboom, Bart W.

    2014-01-01

    The nuclear pore complex (NPC) is the gate for transport between the cell nucleus and the cytoplasm. Small molecules cross the NPC by passive diffusion, but molecules larger than ~5 nm must bind to nuclear transport receptors to overcome a selective barrier within the NPC1. Whilst the structure and shape of the cytoplasmic ring of the NPC are relatively well characterized2-5, the selective barrier is situated deep within the central channel of the NPC and depends critically on unstructured nuclear pore proteins5,6, and is therefore not well understood. Here, we show that stiffness topography7 with sharp atomic force microscopy tips can generate nanoscale cross sections of the NPC. The cross sections reveal two distinct structures, a cytoplasmic ring and a central plug structure, which are consistent with the three-dimensional NPC structure derived from electron microscopy2-5. The central plug persists after reactivation of the transport cycle and resultant cargo release, indicating that the plug is an intrinsic part of the NPC barrier. Added nuclear transport receptors accumulate on the intact transport barrier and lead to a homogenization of the barrier stiffness. The observed nanomechanical properties in the NPC indicate the presence of a cohesive barrier to transport, and are quantitatively consistent with the presence of a central condensate of nuclear pore proteins in the NPC channel. PMID:25420031

  9. RISKIND: A computer program for calculating radiological consequences and health risks from transportation of spent nuclear fuel

    SciTech Connect

    Yuan, Y.C.; Chen, S.Y.; LePoire, D.J.; Rothman, R.

    1993-02-01

    This report presents the technical details of RISIUND, a computer code designed to estimate potential radiological consequences and health risks to individuals and the collective population from exposures associated with the transportation of spent nuclear fuel. RISKIND is a user-friendly, semiinteractive program that can be run on an IBM or equivalent personal computer. The program language is FORTRAN-77. Several models are included in RISKIND that have been tailored to calculate the exposure to individuals under various incident-free and accident conditions. The incidentfree models assess exposures from both gamma and neutron radiation and can account for different cask designs. The accident models include accidental release, atmospheric transport, and the environmental pathways of radionuclides from spent fuels; these models also assess health risks to individuals and the collective population. The models are supported by databases that are specific to spent nuclear fuels and include a radionudide inventory and dose conversion factors.

  10. Penetration Factor for Nuclear Fusion Reaction in Nonthermal Astrophysical Plasmas

    NASA Astrophysics Data System (ADS)

    Ki, Dai-Han; Jung, Young-Dae

    2011-02-01

    The nonthermal effects on the nuclear fusion reaction process are investigated in Lorentzian astrophysical plasmas. The closed expression of the classical turning point in Lorentzian plasmas is obtained by the Lambert W-function. Using the WKB analysis with the effective screening length, the closed expressions of the fusion penetration factor and the cross section for the nuclear fusion reaction in Lorentzian plasmas are obtained as functions of the spectral index, relative kinetic energy, and plasma parameters. It is shown that the nonthermal character of the Lorentzian plasma enhances the fusion penetration factor. In addition, the nonthermal effect on the penetration factor is found to be more significant in plasmas with higher densities. It would be expected that the fusion reaction rates of the p-p chain and the CNO cycle in nonthermal plasmas are always greater than those in thermal Maxwellian plasmas.

  11. The mechanism of inhibition of Ran-dependent nuclear transport by cellular ATP depletion

    PubMed Central

    Schwoebel, Eric D.; Ho, Thai H.; Moore, Mary Shannon

    2002-01-01

    Rran-dependent nuclear transport requires a nuclear pool of RanGTP both for the assembly of export complexes and the disassembly of import complexes. Accordingly, in order for these processes to proceed, Ran-dependent nuclear import and export assays in vitro require the addition of GTP to produce RanGTP. Notably, no ATP requirement can be detected for these transport processes in vitro. But in vivo, when cells are depleted of ATP by the addition of sodium azide and 2-deoxyglucose to block ATP production by oxidative phosphorylation and glycolysis, respectively, Ran-dependent nuclear import and export are rapidly inhibited. This raised the question of whether there is an ATP requirement for these nuclear transport pathways in an intact cell that has remained undetected in vitro. Here we report that the free (but not total) GTP concentration rapidly drops to an undetectable level upon ATP depletion as does the availability of RanGTP. Our conclusion is that the inhibition of Ran-dependent nuclear transport observed upon ATP depletion in vivo results from a shortage of RanGTP rather than the inhibition of some ATP-dependent process. PMID:12058015

  12. Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport

    PubMed Central

    Snow, Chelsi J.; Dar, Ashraf; Dutta, Anindya; Kehlenbach, Ralph H.

    2013-01-01

    The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)–containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria. PMID:23649804

  13. Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport.

    PubMed

    Snow, Chelsi J; Dar, Ashraf; Dutta, Anindya; Kehlenbach, Ralph H; Paschal, Bryce M

    2013-05-13

    The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)-containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria.

  14. An overview of a nuclear reprocessing plant Human Factors programme.

    PubMed

    Kirwan, Barry

    2003-09-01

    This paper presents a case study of a large Human Factors programme applied in the nuclear fuel reprocessing industry (1987-1991). The paper outlines the key Human Factors issues addressed, as well as the impacts achieved, and gives an indication of the resources utilised (approximately 15 person-years of effort). It also considers the starting point of the programme, in terms of the factors that led to the need for such an extensive programme. Some general lessons learned are given at the end of the paper.

  15. CTCN: Colloid transport code -- nuclear; A user`s manual

    SciTech Connect

    Jain, R.

    1993-09-01

    This report describes the CTCN computer code, designed to solve the equations of transient colloidal transport of radionuclides in porous and fractured media. This Fortran 77 package solves systems of coupled nonlinear differential-algebraic equations with a wide range of boundary conditions. The package uses the Method of Lines technique with a special section which forms finite-difference discretizations in up to four spatial dimensions to automatically convert the system into a set of ordinary differential equations. The CTCN code then solves these equations using a robust, efficient ODE solver. Thus CTCN can be used to solve population balance equations along with the usual transport equations to model colloid transport processes or as a general problem solver to treat up to four-dimensional differential-algebraic systems.

  16. Colloid transport code-nuclear user`s manual

    SciTech Connect

    Jain, R.

    1992-04-03

    This report describes the CTCN computer code, designed to solve the equations of transient colloidal transport of radionuclides in porous and fractured media. This Fortran 77 package solves systems of coupled nonlinear differential equations with a wide range of boundary conditions. The package uses the Method of Lines technique with a special section which forms finite-difference discretizations in up to four spatial dimensions to automatically convert the system into a set of ordinary differential equations. The CTCN code then solves these equations using a robust, efficient ODE solver. Thus CTCN can be used to solve population balance equations along with the usual transport equations to model colloid transport processes or as a general problem solver to treat up to four-dimensional differential systems.

  17. Storage, transportation and disposal system for used nuclear fuel assemblies

    DOEpatents

    Scaglione, John M.; Wagner, John C.

    2017-07-11

    An integrated storage, transportation and disposal system for used fuel assemblies is provided. The system includes a plurality of sealed canisters and a cask sized to receive the sealed canisters in side by side relationship. The plurality of sealed canisters include an internal basket structure to receive a plurality of used fuel assemblies. The internal basket structure includes a plurality of radiation-absorbing panels and a plurality of hemispherical ribs generally perpendicular to the canister sidewall. The sealed canisters are received within the cask for storage and transportation and are removed from the cask for disposal at a designated repository. The system of the present invention allows the handling of sealed canisters separately or collectively, while allowing storage and transportation of high burnup fuel and damaged fuel to the designated repository.

  18. Storage, transportation and disposal system for used nuclear fuel assemblies

    DOEpatents

    Scaglione, John M.; Wagner, John C.

    2017-01-10

    An integrated storage, transportation and disposal system for used fuel assemblies is provided. The system includes a plurality of sealed canisters and a cask sized to receive the sealed canisters in side by side relationship. The plurality of sealed canisters include an internal basket structure to receive a plurality of used fuel assemblies. The internal basket structure includes a plurality of radiation-absorbing panels and a plurality of hemispherical ribs generally perpendicular to the canister sidewall. The sealed canisters are received within the cask for storage and transportation and are removed from the cask for disposal at a designated repository. The system of the present invention allows the handling of sealed canisters separately or collectively, while allowing storage and transportation of high burnup fuel and damaged fuel to the designated repository.

  19. Kpna7 interacts with egg-specific nuclear factors in the rainbow trout (Oncorhynchus mykiss).

    PubMed

    Wang, Lei; Ma, Hao; Fu, Liyuan; Yao, Jianbo

    2014-12-01

    Nuclear proteins are required for the initiation of transcription in early embryos before embryonic genome activation. The regulated transport of nuclear proteins is mediated by factors known as importins (karyopherins). Kpna7, a newly discovered member of the importin α family, is critical for early development in mammals. In this study, we characterize rainbow trout Kpna7. The cDNA for rainbow trout Kpna7 encodes a 519 amino acid protein that contains a conserved importin β binding (IBB) domain and seven armadillo/beta-catenin-like repeat (ARM) motifs. Reverse-transcriptase PCR and Western blot analyses revealed that Kpna7 is specifically expressed in eggs/ovary. Real-time PCR analysis demonstrated that expression of Kpna7 mRNA is high in unfertilized eggs, gradually decreases in early-stage embryos until 3 days post-fertilization, and declines sharply thereafter, reaching a level that is barely detectable in 4-day-old embryos. Using a yeast two-hybrid screening system, we identified two Kpna7-interacting proteins from a rainbow trout egg cDNA library: Stl3 (rhamnose-binding lectin 3) and an uncharacterized protein. Both genes appear to be expressed specifically in eggs/testis. Co-immunoprecipitation assays confirmed the interaction between Kpna7 and Stl3, and co-transfection experiments using EGFP-tagged Stl3 showed that Kpna7 facilitates the nuclear transport of Stl3 through an interaction with the predicted nuclear-localization signal cluster at the carboxy-terminus of Stl3. Our data suggest that Kpna7 may function in early embryonic development as a unique nuclear transporter for egg-specific proteins.

  20. A Historical Review of the Safe Transport of Spent Nuclear Fuel, Rev. 1

    SciTech Connect

    Connolly, Kevin J.; Pope, Ronald

    2016-09-01

    This report is a revision to M3 milestone M3FT-16OR090402028 for the former Nuclear Fuels Storage and Transportation Planning Project (NFST), “Safety Record of SNF Shipments.” The US Department of Energy (DOE) has since established the Office of Integrated Waste Management (IWM), which builds on the work begun by NFST, to develop an integrated waste management system for spent nuclear fuel (SNF), including the developm

  1. Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis.

    PubMed

    Kinoshita, Yoshimi; Ito, Hidefumi; Hirano, Asao; Fujita, Kengo; Wate, Reika; Nakamura, Masataka; Kaneko, Satoshi; Nakano, Satoshi; Kusaka, Hirofumi

    2009-11-01

    The nucleocytoplasmic transport system is essential for maintaining cell viability; transport of proteins and nucleic acids between the nucleus and the cytoplasm occurs through nuclear pore complexes (NPCs). In this study, we examined the immunohistochemical distribution of the major protein components of NPCs, Nup62, Nup88, and Nup153, in spinal cords from controls and patients with sporadic or familial amyotrophic lateral sclerosis (SALS or FALS) and its mouse model. In control subjects, immunolabeling on the nuclear envelopes of anterior horn cells (AHCs) was invariably smooth and continuous, whereas in SALS and FALS patients, the AHCs predominantly showed irregular nuclear contours. Double immunofluorescence staining demonstrated that in SALS patients, importin-beta immunoreactivity was absent in the nuclei in a subset of AHCs; in these cells, Nup62 immunolabeling of nuclear membrane was invariably irregular, suggesting that there was dysfunctional nucleocytoplasmic transport in those AHCs. In the mouse model, Nup62-immunolabeled AHCs with irregular nuclear contours were predominant as early as the presymptomatic stage and the contours became progressively discontinuous along with disease development. Together, these observations suggest that dysfunctional nucleocytoplasmic transport may underlie the pathogenesis of ALS.

  2. Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ

    SciTech Connect

    Andrews, Joel F.; Sykora, Landon J.; Barik Letostak, Tiasha; Menezes, Mitchell E.; Mitra, Aparna; Barik, Sailen; Shevde, Lalita A.; Samant, Rajeev S.

    2012-06-10

    HSP40 family member MRJ (DNAJB6) has been in the spot light for its relevance to Huntington's, Parkinson's diseases, limb-girdle muscular dystrophy, placental development, neural stem cells, cell cycle and malignancies such as breast cancer and melanoma. This gene has two spliced variants coding for 2 distinct proteins with significant homology. However, MRJ(L) (large variant) is predominantly localized to the nucleus whereas MRJ(S) (small variant) is predominantly cytoplasmic. Interestingly MRJ(S) translocates to the nucleus in response to heat shock. The classical heat shock proteins respond to crises (stress) by increasing the number of molecules, usually by transcriptional up-regulation. Our studies imply that a quick increase in the molar concentration of MRJ in the nuclear compartment is a novel method by which MRJ responds to stress. We found that MRJ(S) shows NLS (nuclear localization signal) independent nuclear localization in response to heat shock and hypoxia. The specificity of this response is realized due to lack of such response by MRJ(S) when challenged by other stressors, such as some cytokines or UV light. Deletion analysis has allowed us to narrow down on a 20 amino acid stretch at the C-terminal region of MRJ(S) as a potential stress sensing region. Functional studies indicated that constitutive nuclear localization of MRJ(S) promoted attributes of malignancy such as proliferation and invasiveness overall indicating distinct phenotypic characteristics of nuclear MRJ(S).

  3. Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ

    PubMed Central

    Andrews, Joel F.; Sykora, Landon J.; Barik-Letostak, Tiasha; Menezes, Mitchell E.; Mitra, Aparna; Barik, Sailen; Shevde, Lalita A.; Samant, Rajeev S.

    2012-01-01

    HSP40 family member MRJ (DNAJB6) has been in the spot light for its relevance to Huntington’s, Parkinson’s diseases, limb-girdle muscular dystrophy, placental development, neural stem cells, cell cycle and malignancies such as breast cancer and melanoma. This gene has two spliced variants coding for 2 distinct proteins with significant homology. However, MRJ(L) (large variant) is predominantly localized to the nucleus whereas MRJ(S) (small variant) is predominantly cytoplasmic. Interestingly MRJ(S) translocates to the nucleus in response to heat shock. The classical heat shock proteins respond to crises (stress) by increasing the number of molecules, usually by transcriptional up-regulation. Our studies imply that a quick increase in the molar concentration of MRJ in the nuclear compartment is a novel method by which MRJ responds to stress. We found that MRJ(S) shows NLS (nuclear localization signal) independent nuclear localization in response to heat shock and hypoxia. The specificity of this response is realized due to lack of such response by MRJ(S) when challenged by other stressors, such as some cytokines or UV light. Deletion analysis has allowed us to narrow down on a 20 amino acid stretch at the C-terminal region of MRJ(S) as a potential stress sensing region. Functional studies indicated that constitutive nuclear localization of MRJ(S) promoted attributes of malignancy such as proliferation and invasiveness overall indicating distinct phenotypic characteristics of nuclear MRJ(S). PMID:22504047

  4. ALARA assessment of spent fuel and nuclear waste transportation systems

    SciTech Connect

    Sutherland, S. H.

    1980-01-01

    The effects of ALARA (as low as reasonably achievable) on transportation system costs were evaluated for LWR spent fuel, high-level commercial and defense wastes, and remotely handled TRU waste. Three dose rate specifications were used: 10 mrem/h at 2m, 5 mrem/h, and 2 mrem/h. The evaluation was done for wastes and LWR spent fuel 1, 3, 5, and 10 years old. Gamma shield materials were depleted uranium, lead, and steel; the neutron shield material was water. Results for a 7-element PWR cask show that uranium shielding is the lightest, and that the increased weight of the low dose rate casks results in 1 to 2 million dollars increase in lifetime transportation costs. 6 figures, 3 tables. (DLC)

  5. Nuclear powered Mars cargo transport mission utilizing advanced ion propulsion

    SciTech Connect

    Galecki, D.L.; Patterson, M.J.

    1987-01-01

    Nuclear-powered ion propulsion technology was combined with detailed trajectory analysis to determine propulsion system and trajectory options for an unmanned cargo mission to Mars in support of manned Mars missions. A total of 96 mission scenarios were identified by combining two power levels, two propellants, four values of specific impulse per propellant, three starting altitudes, and two starting velocities. Sixty of these scenarios were selected for a detailed trajectory analysis; a complete propulsion system study was then conducted for 20 of these trajectories. Trip times ranged from 344 days for a xenon propulsion system operating at 300 kW total power and starting from lunar orbit with escape velocity, to 770 days for an argon propulsion system operating at 300 kW total power and starting from nuclear start orbit with circular velocity. Trip times for the 3 MW cases studied ranged from 356 to 413 days. Payload masses ranged from 5700 to 12,300 kg for the 300 kW power level, and from 72,200 to 81,500 kg for the 3 MW power level.

  6. Unified description of equation of state and transport properties of nuclear matter

    SciTech Connect

    Benhar, Omar; Farina, Nicola; Valli, Marco; Fiorilla, Salvatore

    2008-10-13

    Correlated basis function perturbation theory and the formalism of cluster expansions have been recently employed to obtain an effective interaction from a state-of-the-art nucleon nucleon potential model. The approach based on the effective interaction allows for a consistent description of the nuclear matter ground state and nucleon-nucleon scattering in the nuclear medium. This paper reports the the results of numerical calculations of different properties of nuclear and neutron matter, including the equation of state and the shear viscosity and thermal conductivity transport coefficients, carried out using the effective interaction.

  7. Study of minimum-weight highway transporters for spent nuclear fuel casks: Technical report

    SciTech Connect

    Hoess, J.A.; Drago, V.J.

    1989-05-01

    There are federal and state limits on the maximum tractor-trailer- payload combination and individual axle loads permissible on US highways. These can generally be considered as two sets, i.e., legal-weight and overweight limits. The number of individual shipments required will decrease as the capacity of the spent nuclear fuel cask increases. Thus, there is an incentive for identifying readily available minimum-weight tractors and trailers capable of safely and reliably transporting as large a cask as possible without exceeding the legal gross combination weight (GCW) of 80,000 lb or selected overweight GCW limit of 110,000 lb. This study identifies options for commercially available heavy-duty on-highway tractors and trailers for transporting proposed future loaded spent nuclear fuel casks. Loaded cask weights of 56,000 and 80,000 lb were selected as reference design points for the legal-weight and overweight transporters, respectively. The technical data on tractor and trailer characteristics obtained indicate that it is possible to develop a tractor-trailer combination, tailored for spent nuclear fuel transportation service, utilizing existing technology and commercially available components, capable of safely and reliably transporting 56,000 and 80,000-lb spent nuclear fuel casks without exceeding GCWs of 80,000 and 10,000 lb, respectively. 4 figs., 14 tabs.

  8. Heat resistant materials and their feasibility issues for a space nuclear transportation system

    SciTech Connect

    Olsen, C.S.

    1991-01-01

    A number of nuclear propulsion concepts based on solid-core nuclear propulsion are being evaluated for a nuclear propulsion transportation system to support the Space Exploration Initiative (SEI) involving the reestablishment of a manned lunar base and the subsequent exploration of Mars. These systems will require high-temperature materials to meet the operating conditions with appropriate reliability and safety built into these systems through the selection and testing of appropriate materials. The application of materials for nuclear thermal propulsion (NTP) and nuclear electric propulsion (NEP) systems and the feasibility issues identified for their use will be discussed. Some mechanical property measurements have been obtained, and compatibility tests were conducted to help identify feasibility issues. 3 refs., 1 fig., 4 tabs.

  9. A Transportation Risk Assessment Tool for Analyzing the Transport of Spent Nuclear Fuel and High-Level Radioactive Waste to the Proposed Yucca Mountain Repository

    SciTech Connect

    Ralph Best; T. Winnard; S. Ross; R. Best

    2001-08-17

    The Yucca Mountain Transportation Database was developed as a data management tool for assembling and integrating data from multiple sources to compile the potential transportation impacts presented in the Draft Environmental Impact Statement for a Geologic Repository for the Disposal of Spent Nuclear Fuel and High-Level Radioactive Waste at Yucca Mountain, Nye County, Nevada (DEIS). The database uses the results from existing models and codes such as RADTRAN, RISKIND, INTERLINE, and HIGHWAY to estimate transportation-related impacts of transporting spent nuclear fuel and high-level radioactive waste from commercial reactors and U. S. Department of Energy (DOE) facilities to Yucca Mountain. The source tables in the database are compendiums of information from many diverse sources including: radionuclide quantities for each waste type; route and route characteristics for rail, legal-weight truck, heavy haul. truck, and barge transport options; state-specific accident and fatality rates for routes selected for analysis; packaging and shipment data by waste type; unit risk factors; the complex behavior of the packaged waste forms in severe transport accidents; and the effects of exposure to radiation or the isotopic specific effects of radionclides should they be released in severe transportation accidents. The database works together with the codes RADTRAN (Neuhauser, et al, 1994) and RISKlND (Yuan, et al, 1995) to calculate incident-free dose and accident risk. For the incident-free transportation scenario, the database uses RADTRAN and RISKIND-generated data to calculate doses to offlink populations, onlink populations, people at stops, crews, inspectors, workers at intermodal transfer stations, guards at overnight stops, and escorts, as well as non-radioactive pollution health effects. For accident scenarios, the database uses RADTRAN-generated data to calculate dose risks based on ingestion, inhalation, resuspension, immersion (cloudshine), and groundshine as

  10. Key Response Planning Factors for the Aftermath of Nuclear Terrorism

    SciTech Connect

    Buddemeier, B R; Dillon, M B

    2009-01-21

    Despite hundreds of above-ground nuclear tests and data gathered from Hiroshima and Nagasaki, the effects of a ground-level, low-yield nuclear detonation in a modern urban environment are still the subject of considerable scientific debate. Extensive review of nuclear weapon effects studies and discussions with nuclear weapon effects experts from various federal agencies, national laboratories, and technical organizations have identified key issues and bounded some of the unknowns required to support response planning for a low-yield, ground-level nuclear detonation in a modern U.S. city. This study, which is focused primarily upon the hazards posed by radioactive fallout, used detailed fallout predictions from the advanced suite of three-dimensional (3-D) meteorology and plume/fallout models developed at Lawrence Livermore National Laboratory (LLNL), including extensive global Key Response Planning Factors for the Aftermath of Nuclear Terrorism geographical and real-time meteorological databases to support model calculations. This 3-D modeling system provides detailed simulations that account for complex meteorology and terrain effects. The results of initial modeling and analysis were presented to federal, state, and local working groups to obtain critical, broad-based review and feedback on strategy and messaging. This effort involved a diverse set of communities, including New York City, National Capitol Regions, Charlotte, Houston, Portland, and Los Angeles. The largest potential for reducing casualties during the post-detonation response phase comes from reducing exposure to fallout radiation. This can be accomplished through early, adequate sheltering followed by informed, delayed evacuation.B The response challenges to a nuclear detonation must be solved through multiple approaches of public education, planning, and rapid response actions. Because the successful response will require extensive coordination of a large number of organizations, supplemented by

  11. Nuclear Control of Respiratory Chain Expression by Nuclear Respiratory Factors and PGC-1-Related Coactivator

    PubMed Central

    Scarpulla, Richard C.

    2010-01-01

    Expression of the respiratory apparatus depends on both nuclear and mitochondrial genes. Although these genes are sequestered in distinct cellular organelles, their transcription relies on nucleus-encoded factors. Certain of these factors are directed to the mitochondria, where they sponsor the bi-directional transcription of mitochondrial DNA. Others act on nuclear genes that encode the majority of the respiratory subunits and many other gene products required for the assembly and function of the respiratory chain. The nuclear respiratory factors, NRF-1 and NRF-2, contribute to the expression of respiratory subunits and mitochondrial transcription factors and thus have been implicated in nucleo-mitochondrial interactions. In addition, coactivators of the PGC-1 family serve as mediators between the environment and the transcriptional machinery governing mitochondrial biogenesis. One family member, peroxisome proliferator-activated receptor γ coactivator PGC-1-related coactivator (PRC), is an immediate early gene product that is rapidly induced by mitogenic signals in the absence of de novo protein synthesis. Like other PGC-1 family members, PRC binds NRF-1 and activates NRF-1 target genes. In addition, PRC complexes with NRF-2 and HCF-1 (host cell factor-1) in the activation of NRF-2-dependent promoters. HCF-1 functions in cell-cycle progression and has been identified as an NRF-2 coactivator. The association of these factors with PRC is suggestive of a role for the complex in cell growth. Finally, shRNA-mediated knock down of PRC expression results in a complex phenotype that includes the inhibition of respiratory growth on galactose and the loss of respiratory complexes. Thus, PRC may help integrate the expression of the respiratory apparatus with the cell proliferative program. PMID:19076454

  12. C-14 release and transport from a nuclear waste repository in an unsaturated medium

    SciTech Connect

    Light, W.B.; Zwahlen, E.D.; Pigford, T.H.; Chambre, P.L.; Lee, W.W.L.

    1990-06-01

    The release of {sup 14}C as {sup 14}CO{sub 2} from partly failed spent fuel containers has been analyzed by the flow of gases into and out of the containers. This flow of gases is driven by pressure differences, which are in turn caused by heating by the spent fuel. In this analysis, the timing and size of holes in the containers are assumed to be given. A better means of predicting the time distribution and sizes of penetrations in nuclear waste containers is needed. For the purposes of far-field transport calculations, we have adopted release rates that are shown to be bonding for the large range of hole sizes studied. The transport of released {sup 14}CO{sub 2} has been analyzed by transport in equivalent porous medium. The peak {sup 14}CO{sub 2} concentration in pore gas at 350 m above the repository does not depend on the time of hole occurrence, although the time of penetration obviously affects the arrival and duration of exposure to {sup 14}C. Nor does water saturation have much effect on peak concentration. In this analysis we have used a constant gas Darcy velocity. We performed limited sensitivity analysis on gas Darcy velocity by using values one order of magnitude above and below the published value. This probably gives us bounds on the likely gas Darcy velocity. Our calculations show that essentially all the released {sup 14}C will reach the ground surface in less than one half-life of {sup 14}C. However, the quantities of {sup 14}C reaching the ground surface are so small that even if all containers fail at emplacement and conservative dose factors are used, the resultant inhalation dose to the maximally exposed individual is about 0.1% of natural background radiation. 14 refs., 18 figs., 3 tabs.

  13. cAMP Response Element-binding Protein (CREB) and Nuclear Factor κB Mediate the Tamoxifen-induced Up-regulation of Glutamate Transporter 1 (GLT-1) in Rat Astrocytes*

    PubMed Central

    Karki, Pratap; Webb, Anton; Smith, Keisha; Lee, Kyuwon; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2013-01-01

    Tamoxifen (TX), a selective estrogen receptor modulator, exerts antagonistic effects on breast tissue and is used to treat breast cancer. Recent evidence also suggests that it may act as an agonist in brain tissue. We reported previously that TX enhanced the expression and function of glutamate transporter 1 (GLT-1) in rat astrocytes, an effect that was mediated by TGF-α. To gain further insight into the mechanisms that mediate TX-induced up-regulation of GLT-1 (EAAT2 in humans), we investigated its effect on GLT-1 at the transcriptional level. TX phosphorylated the cAMP response element-binding protein (CREB) and recruited CREB to the GLT-1 promoter consensus site. The effect of TX on astrocytic GLT-1 was attenuated by the inhibition of PKA, the upstream activator of the CREB pathway. In addition, the effect of TX on GLT-1 promoter activity was abolished by the inhibition of the NF-κB pathway. Furthermore, TX recruited the NF-κB subunits p65 and p50 to the NF-κB binding domain of the GLT-1 promoter. Mutation of NF-κB (triple, −583/-282/-251) or CRE (-308) sites on the GLT-1 promoter led to significant repression of the promoter activity, but neither mutant completely abolished the TX-induced GLT-1 promoter activity. Mutation of both the NF-κB (-583/-282/-251) and CRE (-308) sites led to a complete abrogation of the effect of TX on GLT-1 promoter activity. Taken together, our findings establish that TX regulates GLT-1 via the CREB and NF-κB pathways. PMID:23955341

  14. Functional domains in nuclear import factor p97 for binding the nuclear localization sequence receptor and the nuclear pore.

    PubMed Central

    Chi, N C; Adam, S A

    1997-01-01

    The interaction of the nuclear protein import factor p97 with the nuclear localization sequence (NLS) receptor, the nuclear pore complex, and Ran/TC4 is important for coordinating the events of protein import to the nucleus. We have mapped the binding domains on p97 for the NLS receptor and the nuclear pore. The NLS receptor-binding domain of p97 maps to the C-terminal 60% of the protein between residues 356 and 876. The pore complex-binding domain of p97 maps to residues 152-352. The pore complex-binding domain overlaps the Ran-GTP- and Ran-GDP-binding domains on p97, but only Ran-GTP competes for docking in permeabilized cells. The N-ethylmaleimide sensitivity of the p97 for docking was investigated and found to be due to inhibition of p97 binding to the pore complex and to the NLS receptor. Site-directed mutagenesis of conserved cysteine residues in the pore- and receptor-binding domains identified two cysteines, C223 and C228, that were required for p97 to bind the nuclear pore. Inhibition studies on docking and accumulation of a NLS protein provided additional evidence that the domains identified biochemically are the functional domains involved in protein import. Together, these results suggest that Ran-GTP dissociates the receptor complex and prevents p97 binding to the pore by inducing a conformational change in the structure of p97 rather than simple competition for binding sites. Images PMID:9201707

  15. Integrated Radiation Transport and Nuclear Fuel Performance for Assembly-Level Simulations

    SciTech Connect

    Clarno, Kevin T; Hamilton, Steven P; Philip, Bobby; Berrill, Mark A; Sampath, Rahul S; Allu, Srikanth; Pugmire, Dave; Dilts, Gary; Banfield, James E

    2012-02-01

    The Advanced Multi-Physics (AMP) Nuclear Fuel Performance code (AMPFuel) is focused on predicting the temperature and strain within a nuclear fuel assembly to evaluate the performance and safety of existing and advanced nuclear fuel bundles within existing and advanced nuclear reactors. AMPFuel was extended to include an integrated nuclear fuel assembly capability for (one-way) coupled radiation transport and nuclear fuel assembly thermo-mechanics. This capability is the initial step toward incorporating an improved predictive nuclear fuel assembly modeling capability to accurately account for source-terms and boundary conditions of traditional (single-pin) nuclear fuel performance simulation, such as the neutron flux distribution, coolant conditions, and assembly mechanical stresses. A novel scheme is introduced for transferring the power distribution from the Scale/Denovo (Denovo) radiation transport code (structured, Cartesian mesh with smeared materials within each cell) to AMPFuel (unstructured, hexagonal mesh with a single material within each cell), allowing the use of a relatively coarse spatial mesh (10 million elements) for the radiation transport and a fine spatial mesh (3.3 billion elements) for thermo-mechanics with very little loss of accuracy. In addition, a new nuclear fuel-specific preconditioner was developed to account for the high aspect ratio of each fuel pin (12 feet axially, but 1 4 inches in diameter) with many individual fuel regions (pellets). With this novel capability, AMPFuel was used to model an entire 17 17 pressurized water reactor fuel assembly with many of the features resolved in three dimensions (for thermo-mechanics and/or neutronics), including the fuel, gap, and cladding of each of the 264 fuel pins; the 25 guide tubes; the top and bottom structural regions; and the upper and lower (neutron) reflector regions. The final, full assembly calculation was executed on Jaguar using 40,000 cores in under 10 hours to model over 162

  16. High-speed civil transport study: Special factors

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Studies relating to environmental factors associated with high speed civil transports were conducted. Projected total engine emissions for year 2015 fleets of several subsonic/supersonic transport fleet scenarios, discussion of sonic boom reduction methods, discussion of community noise level requirements, fuels considerations, and air traffic control impact are presented.

  17. Calmodulin-dependent nuclear import of HMG-box family nuclear factors: importance of the role of SRY in sex reversal

    PubMed Central

    Kaur, Gurpreet; Delluc-Clavieres, Aurelie; Poon, Ivan K. H.; Forwood, Jade K.; Glover, Dominic J.; Jans, David A.

    2010-01-01

    The HMG (high-mobility group)-box-containing chromatin-remodelling factor SRY (sex-determining region on the Y chromosome) plays a key role in sex determination. Its role in the nucleus is critically dependent on two NLSs (nuclear localization signals) that flank its HMG domain: the C-terminally located ‘β-NLS’ that mediates nuclear transport through Impβ1 (importin β1) and the N-terminally located ‘CaM-NLS’ which is known to recognize the calcium-binding protein CaM (calmodulin). In the present study, we examined a number of missense mutations in the SRY CaM-NLS from human XY sex-reversed females for the first time, showing that they result in significantly reduced nuclear localization of GFP (green fluorescent protein)–SRY fusion proteins in transfected cells compared with wild-type. The CaM antagonist CDZ (calmidazolium chloride) was found to significantly reduce wild-type SRY nuclear accumulation, indicating dependence of SRY nuclear import on CaM. Intriguingly, the CaM-NLS mutants were all resistant to CDZ's effects, implying a loss of interaction with CaM, which was confirmed by direct binding experiments. CaM-binding/resultant nuclear accumulation was the only property of SRY found to be impaired by two of the CaM-NLS mutations, implying that inhibition of CaM-dependent nuclear import is the basis of sex reversal in these cases. Importantly, the CaM-NLS is conserved in other HMG-box-domain-containing proteins such as SOX-2, -9, -10 and HMGN1, all of which were found for the first time to rely on CaM for optimal nuclear localization. CaM-dependent nuclear translocation is thus a common mechanism for this family of important transcription factors. PMID:20528776

  18. Pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors as emerging players in cancer precision medicine.

    PubMed

    De Mattia, Elena; Cecchin, Erika; Roncato, Rossana; Toffoli, Giuseppe

    2016-09-01

    Great research effort has been focused on elucidating the contribution of host genetic variability on pharmacological outcomes in cancer. Nuclear receptors have emerged as mediators between environmental stimuli and drug pharmacokinetics and pharmacodynamics. The pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors have been reported to regulate transcription of genes that encode drug metabolizing enzymes and transporters. Altered nuclear receptor expression has been shown to affect the metabolism and pharmacological profile of traditional chemotherapeutics and targeted agents. Accordingly, polymorphic variants in these genes have been studied as pharmacogenetic markers of outcome variability. This review summarizes the state of knowledge about the roles played by pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factor expression and genetics as predictive markers of anticancer drug toxicity and efficacy, which can improve cancer precision medicine.

  19. Human Factors Engineering Review Model for advanced nuclear power reactors

    SciTech Connect

    O'Hara, J.; Higgins, J. ); Goodman, C.; Galletti, G.: Eckenrode, R. )

    1993-01-01

    One of the major issues to emerge from the initial design reviews under the certification process was that detailed human-systems interface (HSI) design information was not available for staff review. To address the lack of design detail issue. The Nuclear Regulatory Commission (NRC) is performing the design certification reviews based on a design process plan which describes the human factors engineering (HFE) program elements that are necessary and sufficient to develop an acceptable detailed design specification. Since the review of a design process is unprecedented in the nuclear industry. The criteria for review are not addressed by current regulations or guidance documents and. therefore, had to be developed. Thus, an HFE Program Review Model was developed. This paper will describe the model's rationale, scope, objectives, development, general characteristics. and application.

  20. Human Factors Engineering Review Model for advanced nuclear power reactors

    SciTech Connect

    O`Hara, J.; Higgins, J.; Goodman, C.; Galletti, G.: Eckenrode, R.

    1993-05-01

    One of the major issues to emerge from the initial design reviews under the certification process was that detailed human-systems interface (HSI) design information was not available for staff review. To address the lack of design detail issue. The Nuclear Regulatory Commission (NRC) is performing the design certification reviews based on a design process plan which describes the human factors engineering (HFE) program elements that are necessary and sufficient to develop an acceptable detailed design specification. Since the review of a design process is unprecedented in the nuclear industry. The criteria for review are not addressed by current regulations or guidance documents and. therefore, had to be developed. Thus, an HFE Program Review Model was developed. This paper will describe the model`s rationale, scope, objectives, development, general characteristics. and application.

  1. Approximate penetration factors for nuclear reactions of astrophysical interest

    NASA Technical Reports Server (NTRS)

    Humblet, J.; Fowler, W. A.; Zimmerman, B. A.

    1987-01-01

    The ranges of validity of approximations of P(l), the penetration factor which appears in the parameterization of nuclear-reaction cross sections at low energies and is employed in the extrapolation of laboratory data to even lower energies of astrophysical interest, are investigated analytically. Consideration is given to the WKB approximation, P(l) at the energy of the total barrier, approximations derived from the asymptotic expansion of G(l) for large eta, approximations for small values of the parameter x, applications of P(l) to nuclear reactions, and the dependence of P(l) on channel radius. Numerical results are presented in tables and graphs, and parameter ranges where the danger of serious errors is high are identified.

  2. Methamphetamine oxidative stress, neurotoxicity, and functional deficits are modulated by nuclear factor-E2-related factor 2.

    PubMed

    Ramkissoon, Annmarie; Wells, Peter G

    2015-12-01

    Activation of redox-sensitive transcription factors like nuclear factor-E2-related factor 2 (Nrf2) can enhance the transcription of cytoprotective genes during oxidative stress. We investigated whether Nrf2 is activated by methamphetamine (METH) thereby altering neurotoxicity in Nrf2 +/+ and -/- adult mouse brain. A single dose of METH can induce the mRNA levels of Nrf2-regulated antioxidant and cytoprotective proteins in mouse brain. Multiple-day dosing with METH enhanced DNA oxidation and decreased tyrosine hydroxylase and dopamine transporter staining in the striatum, indicating dopaminergic nerve terminal toxicity, which was more severe in -/- mice, as were deficits in motor coordination and olfactory discrimination. These Nrf2-dependent effects were independent of changes in METH metabolism or the induction of hyperthermia. Similarly, METH increased striatal glial fibrillary acidic protein, indicating neurotoxicity. METH neurotoxicity was also observed in the glial cells and in the GABAergic system of the olfactory bulbs and was enhanced in -/- mice, whereas dopaminergic parameters were unaffected. With one-day dosing of METH, there were no differences between +/+ and -/- mice in either basal or METH-enhanced DNA oxidation and neurotoxicity markers. Nrf2-mediated pathways accordingly may protect against the neurodegenerative effects and functional deficits initiated by METH and perhaps other reactive oxygen species-enhancing neurotoxicants, when there is time for transcriptional activation and protein induction. In human users of METH, this mechanism may be essential when differences in drug abuse patterns may alter the induction and duration of Nrf2 activation thereby modulating susceptibility to the neurotoxic effects of METH.

  3. KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells

    PubMed Central

    Stelma, Tamara; Leaner, Virna D.

    2017-01-01

    Karyopherin β1 is a nuclear import protein involved in the transport of proteins containing a nuclear localisation sequence. Elevated Karyopherin β1 expression has been reported in cancer and transformed cells and is essential for cancer cell proliferation and survival. Transcription factors such as NFĸB and AP-1 contain a nuclear localisation sequence and initiate the expression of multiple factors associated with inflammation and cancer cell biology. Our study investigated the effect of inhibiting nuclear import via Karyopherin β1 on cancer cell motility and inflammatory signaling using siRNA and the novel small molecule, Inhibitor of Nuclear Import-43, INI-43. Inhibition of Karyopherin β1 led to reduced migration and invasion of cervical cancer cells. Karyopherin β1 is essential for the translocation of NFĸB into the nucleus as nuclear import inhibition caused its cytoplasmic retention and decreased transcriptional activity. A similar decrease was seen in AP-1 transcriptional activity upon Karyopherin β1 inhibition. Consequently reduced interleukin-6, interleukin-1 beta, tumour necrosis factor alpha and granulocyte macrophage colony stimulating factor expression, target genes of NFkB and AP-1, was observed. Migration studies inhibiting individual transcription factors suggested that INI-43 may affect a combination of signaling events. Our study provides further evidence that inhibiting KPNB1 has anti-cancer effects and shows promise as a chemotherapeutic target. PMID:28427184

  4. Electrodriven selective transport of Cs+ using chlorinated cobalt dicarbollide in polymer inclusion membrane: a novel approach for cesium removal from simulated nuclear waste solution.

    PubMed

    Chaudhury, Sanhita; Bhattacharyya, Arunasis; Goswami, Asok

    2014-11-04

    The work describes a novel and cleaner approach of electrodriven selective transport of Cs from simulated nuclear waste solutions through cellulose tri acetate (CTA)/poly vinyl chloride (PVC) based polymer inclusion membrane. The electrodriven cation transport together with the use of highly Cs+ selective hexachlorinated derivative of cobalt bis dicarbollide, allows to achieve selective separation of Cs+ from high concentration of Na+ and other fission products in nuclear waste solutions. The transport selectivity has been studied using radiotracer technique as well as atomic emission spectroscopic technique. Transport studies using CTA based membrane have been carried out from neutral solution as well as 0.4 M HNO3, while that with PVC based membrane has been carried out from 3 M HNO3. High decontamination factor for Cs+ over Na+ has been obtained in all the cases. Experiment with simulated high level waste solution shows selective transport of Cs+ from most of other fission products also. Significantly fast Cs+ transport rate along with high selectivity is an interesting feature observed in this membrane. The current efficiency for Cs+ transport has been found to be ∼100%. The promising results show the possibility of using this kind of electrodriven membrane transport methods for nuclear waste treatment.

  5. Distinct functions of the Drosophila Nup153 and Nup214 FG domains in nuclear protein transport.

    PubMed

    Sabri, Nafiseh; Roth, Peggy; Xylourgidis, Nikos; Sadeghifar, Fatemeh; Adler, Jeremy; Samakovlis, Christos

    2007-08-13

    The phenylanine-glycine (FG)-rich regions of several nucleoporins both bind to nuclear transport receptors and collectively provide a diffusion barrier to the nuclear pores. However, the in vivo roles of FG nucleoporins in transport remain unclear. We have inactivated 30 putative nucleoporins in cultured Drosophila melanogaster S2 cells by RNA interference and analyzed the phenotypes on importin alpha/beta-mediated import and CRM1-dependent protein export. The fly homologues of FG nucleoporins Nup358, Nup153, and Nup54 are selectively required for import. The FG repeats of Nup153 are necessary for its function in transport, whereas the remainder of the protein maintains pore integrity. Inactivation of the CRM1 cofactor RanBP3 decreased the nuclear accumulation of CRM1 and protein export. We report a surprisingly antagonistic relationship between RanBP3 and the Nup214 FG region in determining CRM1 localization and its function in protein export. Our data suggest that peripheral metazoan FG nucleoporins have distinct functions in nuclear protein transport events.

  6. Evaluation of SAES COMBOGETTER(r) for Use in Nuclear Material Transportation Packages

    SciTech Connect

    George M. Buffleben; Timothy J. Shepodd; Paul J. Nigrey

    2001-01-01

    This report summarizes the testing of SAES COMBOGETTER{reg_sign} and evaluates its potential use as a hydrogen getter in nuclear material transportation packages. We measured the getters hydrogen uptake capacity, and uptake rates under different conditions including temperature, gas composition, and poisons. We also compared this getter to another commercially available hydrogen getter.

  7. Nuclear reactor heat transport system component low friction support system

    DOEpatents

    Wade, Elman E.

    1980-01-01

    A support column for a heavy component of a liquid metal fast breeder reactor heat transport system which will deflect when the pipes leading coolant to and from the heavy component expand or contract due to temperature changes includes a vertically disposed pipe, the pipe being connected to the heavy component by two longitudinally spaced cycloidal dovetail joints wherein the distal end of each of the dovetails constitutes a part of the surface of a large diameter cylinder and the centerlines of these large diameter cylinders intersect at right angles and the pipe being supported through two longitudinally spaced cycloidal dovetail joints wherein the distal end of each of the dovetails constitutes a part of the surface of a large diameter cylinder and the centerlines of these large diameter cylinders intersect at right angles, each of the cylindrical surfaces bearing on a flat and horizontal surface.

  8. Integrated Radiation Transport and Nuclear Fuel Performance for Assembly-Level Simulations

    SciTech Connect

    Hamilton, Steven P; Clarno, Kevin T; Philip, Bobby; Berrill, Mark A; Sampath, Rahul S; Allu, Srikanth

    2012-01-01

    The Advanced Multi-Physics (AMP) Nuclear Fuel Performance code (AMPFuel) is focused on predicting the temperature and strain within a nuclear fuel assembly to evaluate the performance and safety of existing and advanced nuclear fuel bundles within existing and advanced nuclear reactors. AMPFuel was extended to include an integrated nuclear fuel assembly capability for (one-way) coupled radiation transport and nuclear fuel assembly thermo-mechanics. This capability is the initial step toward incorporating an improved predictive nuclear fuel assembly modeling capability to accurately account for source-terms, such as neutron flux distribution, coolant conditions and assembly mechanical stresses, of traditional (single-pin) nuclear fuel performance simulation. A novel scheme is introduced for transferring the power distribution from the Scale/Denovo (Denovo) radiation transport code (structured, Cartesian mesh with smeared materials within each cell) to AMPFuel (unstructured, hexagonal mesh with a single material within each cell), allowing the use of a relatively coarse spatial mesh (10 million elements) for the radiation transport and a fine spatial mesh (3.3 billion elements) for thermo-mechanics with very little loss of accuracy. With this novel capability, AMPFuel was used to model an entire 1717 pressurized water reactor fuel assembly with many of the features resolved in three dimensions (for thermo-mechanics and/or neutronics). A full assembly calculation was executed on Jaguar using 40,000 cores in under 10 hours to model over 160 billion degrees of freedom for 10 loading steps. The single radiation transport calculation required about 50% of the time required to solve the thermo-mechanics with a single loading step, which demonstrates that it is feasible to incorporate, in a single code, a high-fidelity radiation transport capability with a high-fidelity nuclear fuel thermo-mechanics capability and anticipate acceptable computational requirements. The

  9. Transport of radioactive droplet moisture from a source in a nuclear power plant spray pond

    SciTech Connect

    Elokhin, A.P.

    1995-11-01

    In addition to a change in the microclimate in the region surrounding a nuclear power plant resulting from the emission of vapor form a cooling tower, evaporation of water from the water surface of a cooling pond or a spray pond, in the latter case direct radioactive contamination of the underlying surface around the nuclear power plant can also occur due to discharge of process water (radioactive) into the pond and its transport in the air over a certain distance in the form of droplet moisture. A typical example may be the situation at the Zaporozhe nuclear power plant in 1986 when accidental discharge of process water into the cooling pond occurred. Below we present a solution for the problem of transport of droplet moisture taking into account its evaporation, which may be used to estimate the scale of radioactive contamination of the locality.

  10. Atmospheric radionuclides transported to Fukuoka, Japan remote from the Fukushima Dai-ichi nuclear power complex following the nuclear accident.

    PubMed

    Momoshima, N; Sugihara, S; Ichikawa, R; Yokoyama, H

    2012-09-01

    Radionuclides were detected from the Fukushima nuclear accident at Fukuoka, Japan, 1000 km west of the Fukushima Dai-ichi nuclear power complex. Iodine-131 was first detected 3 d after the accident, indicating that it was probably transported dispersively because of local meteorological conditions, and not global air circulation. The maximum concentrations, 5.07 mBq m(-3) for (131)I, 4.04 mBq m(-3) for (134)Cs, and 4.12 mBq m(-3) for (137)Cs, were recorded in particles collected on April 6, 2011. However, these concentration levels decreased below the detection limit by April 26, 2011. Gaseous (131)I accounted for 30%-67% of the total (131)I content. The increase in dose by inhalation was negligible at Fukuoka. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Cofactor requirements for nuclear export of Rev response element (RRE)- and constitutive transport element (CTE)-containing retroviral RNAs. An unexpected role for actin.

    PubMed

    Hofmann, W; Reichart, B; Ewald, A; Müller, E; Schmitt, I; Stauber, R H; Lottspeich, F; Jockusch, B M; Scheer, U; Hauber, J; Dabauvalle, M C

    2001-03-05

    Nuclear export of proteins containing leucine-rich nuclear export signals (NESs) is mediated by the export receptor CRM1/exportin1. However, additional protein factors interacting with leucine-rich NESs have been described. Here, we investigate human immunodeficiency virus type 1 (HIV-1) Rev-mediated nuclear export and Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE)-mediated nuclear export in microinjected Xenopus laevis oocytes. We show that eukaryotic initiation factor 5A (eIF-5A) is essential for Rev and Rev-mediated viral RNA export, but not for nuclear export of CTE RNA. In vitro binding studies demonstrate that eIF-5A is required for efficient interaction of Rev-NES with CRM1/exportin1 and that eIF-5A interacts with the nucleoporins CAN/nup214, nup153, nup98, and nup62. Quite unexpectedly, nuclear actin was also identified as an eIF-5A binding protein. We show that actin is associated with the nucleoplasmic filaments of nuclear pore complexes and is critically involved in export processes. Finally, actin- and energy-dependent nuclear export of HIV-1 Rev is reconstituted by using a novel in vitro egg extract system. In summary, our data provide evidence that actin plays an important functional role in nuclear export not only of retroviral RNAs but also of host proteins such as protein kinase inhibitor (PKI).

  12. 25 CFR 170.900 - What is the purpose of the provisions relating to transportation of hazardous and nuclear waste?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... transportation of hazardous and nuclear waste? 170.900 Section 170.900 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Miscellaneous Provisions Hazardous and Nuclear Waste Transportation § 170.900 What is the purpose of the provisions relating...

  13. 25 CFR 170.900 - What is the purpose of the provisions relating to transportation of hazardous and nuclear waste?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... transportation of hazardous and nuclear waste? 170.900 Section 170.900 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Miscellaneous Provisions Hazardous and Nuclear Waste Transportation § 170.900 What is the purpose of the provisions relating...

  14. 25 CFR 170.900 - What is the purpose of the provisions relating to transportation of hazardous and nuclear waste?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... transportation of hazardous and nuclear waste? 170.900 Section 170.900 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Miscellaneous Provisions Hazardous and Nuclear Waste Transportation § 170.900 What is the purpose of the provisions relating...

  15. 25 CFR 170.900 - What is the purpose of the provisions relating to transportation of hazardous and nuclear waste?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... transportation of hazardous and nuclear waste? 170.900 Section 170.900 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Miscellaneous Provisions Hazardous and Nuclear Waste Transportation § 170.900 What is the purpose of the provisions relating...

  16. Analysis of nuclear transport signals in the human apurinic/apyrimidinic endonuclease (APE1/Ref1)

    PubMed Central

    Jackson, Elias B.; Theriot, Corey A.; Chattopadhyay, Ranajoy; Mitra, Sankar; Izumi, Tadahide

    2005-01-01

    The mammalian abasic-endonuclease1/redox-factor1 (APE1/Ref1) is an essential protein whose subcellular distribution depends on the cellular physiological status. However, its nuclear localization signals have not been studied in detail. We examined nuclear translocation of APE1, by monitoring enhanced green fluorescent protein (EGFP) fused to APE1. APE1's nuclear localization was significantly decreased by deleting 20 amino acid residues from its N-terminus. Fusion of APE1's N-terminal 20 residues directed nuclear localization of EGFP. An APE1 mutant lacking the seven N-terminal residues (ND7 APE1) showed nearly normal nuclear localization, which was drastically reduced when the deletion was combined with the E12A/D13A double mutation. On the other hand, nearly normal nuclear localization of the full-length E12A/D13A mutant suggests that the first 7 residues and residues 8–13 can independently promote nuclear import. Both far-western analyses and immuno-pull-down assays indicate interaction of APE1 with karyopherin alpha 1 and 2, which requires the 20 N-terminal residues and implicates nuclear importins in APE1's nuclear translocation. Nuclear accumulation of the ND7 APE1(E12A/D13A) mutant after treatment with the nuclear export inhibitor leptomycin B suggests the presence of a previously unidentified nuclear export signal, and the subcellular distribution of APE1 may be regulated by both nuclear import and export. PMID:15942031

  17. Leak-Path Factor Analysis for the Nuclear Materials Storage Facility

    SciTech Connect

    Shaffer, C.; Leonard, M.

    1999-06-13

    Leak-path factors (LPFs) were calculated for the Nuclear Materials Storage Facility (NMSF) located in the Plutonium Facility, Building 41 at the Los Alamos National Laboratory Technical Area 55. In the unlikely event of an accidental fire powerful enough to fail a container holding actinides, the subsequent release of oxides, modeled as PuO{sub 2} aerosols, from the facility and into the surrounding environment was predicted. A 1-h nondestructive assay (NDA) laboratory fire accident was simulated with the MELCOR severe accident analysis code. Fire-driven air movement along with wind-driven air infiltration transported a portion of these actinides from the building. This fraction is referred to as the leak-path factor. The potential effect of smoke aerosol on the transport of the actinides was investigated to verify the validity of neglecting the smoke as conservative. The input model for the NMSF consisted of a system of control volumes, flow pathways, and surfaces sufficient to model the thermal-hydraulic conditions within the facility and the aerosol transport data necessary to simulate the transport of PuO{sub 2} particles. The thermal-hydraulic, heat-transfer, and aerosol-transport models are solved simultaneously with data being exchanged between models. A MELCOR input model was designed such that it would reproduce the salient features of the fire per the corresponding CFAST calculation. Air infiltration into and out of the facility would be affected strongly by wind-driven differential pressures across the building. Therefore, differential pressures were applied to each side of the building according to guidance found in the ASHRAE handbook using a standard-velocity head equation with a leading multiplier to account for the orientation of the wind with the building. The model for the transport of aerosols considered all applicable transport processes, but the deposition within the building clearly was dominated by gravitational settling.

  18. Regulation of NF-κB Oscillation by Nuclear Transport: Mechanisms Determining the Persistency and Frequency of Oscillation.

    PubMed

    Ohshima, Daisuke; Ichikawa, Kazuhisa

    2015-01-01

    The activated transcription factor NF-κB shuttles between the cytoplasm and the nucleus resulting in the oscillation of nuclear NF-κB (NF-κBn). The oscillation pattern of NF-κBn is implicated in the regulation of gene expression profiles. Using computational models, we previously reported that spatial parameters, such as the diffusion coefficient, nuclear to cytoplasmic volume ratio, transport through the nuclear envelope, and the loci of translation of IκB protein, modified the oscillation pattern of NF-κBn. In a subsequent report, we elucidated the importance of the "reset" of NF-κBn (returning of NF-κB to the original level) and of a "reservoir" of IκB in the cytoplasm. When the diffusion coefficient of IκB was large, IκB stored at a distant location from the nucleus diffused back to the nucleus and "reset" NF-κBn. Herein, we report mechanisms that regulate the persistency and frequency of NF-κBn oscillation by nuclear transport. Among the four parameters of nuclear transport tested in our spatio-temporal computational model, the export of IκB mRNA from the nucleus regulated the persistency of oscillation. The import of IκB to the nucleus regulated the frequency of oscillation. The remaining two parameters, import and export of NF-κB to and from the nucleus, had virtually no effect on the persistency or frequency. Our analyses revealed that lesser export of IκB mRNA allowed NF-κBn to transcript greater amounts of IκB mRNA, which was retained in the nucleus, and was subsequently exported to the cytoplasm, where large amounts of IκB were synthesized to "reset" NF-κBn and drove the persistent oscillation. On the other hand, import of greater amounts of IκB led to an increase in the influx and the efflux of NF-κB to and from the nucleus, resulting in an increase in the oscillation frequency. Our study revealed the importance of nuclear transport in regulating the oscillation pattern of NF-κBn.

  19. A genetically encoded indicator for assaying bioactive chemicals that induce nuclear transport of glucocorticoid receptor.

    PubMed

    Kim, Sung Bae; Ozawa, Takeaki; Umezawa, Yoshio

    2005-12-15

    Glucocorticoids, the adrenal steroid hormones secreted during stress, are essential to homeostasis and metabolism in the human body. An impaired glucocorticoid signaling due to dysfunction of the glucocorticoid receptor (GR) by synthetic chemicals can cause diseases and disruptions of the homeostasis and metabolism. Here we demonstrate the development of a method for screening endocrine-disrupting chemicals and potent risk factors of human diseases based on the nuclear trafficking of the GR. We constructed a new assay using a pair of genetic indicators with the full length of the GR, split Renilla luciferase (RLuc), and split DnaE (a protein splicing element). The GR-containing fusion protein with C-terminal halves of DnaE and RLuc is localized in cytosol due to the cytosolic character of the GR, whereas the fusion protein with N-terminal halves of DnaE and RLuc stays in the nucleus due to the cofused nucleus localization signal. On being stimulated with a ligand, the GR is translocated into the cellular nucleus. Thus, a protein splicing occurs in the nucleus by an interaction between the splicing junctions of each DnaE fragment. The enzymatic activities from the reconstituted RLuc allow the ligand-dependent luminescence intensities. The feasibility of the method was evaluated by quantifying the hormonal activities of 20 different kinds of steroids and synthetic chemicals using the NIH 3T3 cells carrying the pair of indicators. The hormonal activities of tested ligands are discussed based on the chemical structure-activity relationship. We found that androgens, testosterone, and 19-nortestosterone weakly induce the nuclear transport of the GR. The current assay allows high-throughput screening of risk chemicals and drug candidates influential to a signal transduction pathway of the GR.

  20. Structural mechanism of nuclear transport mediated by importin β and flexible amphiphilic proteins.

    PubMed

    Yoshimura, Shige H; Kumeta, Masahiro; Takeyasu, Kunio

    2014-12-02

    Karyopherin β family proteins mediate the nuclear/cytoplasmic transport of various proteins through the nuclear pore complex (NPC), although they are substantially larger than the size limit of the NPC.To elucidate the molecular mechanism underlying this paradoxical function, we focused on the unique structures called HEAT repeats, which consist of repetitive amphiphilic α helices. An in vitro transport assay and FRAP analyses demonstrated that not only karyopherin β family proteins but also other proteins with HEAT repeats could pass through the NPC by themselves, and serve as transport mediators for their binding partners. Biochemical and spectroscopic analyses and molecular dynamics simulations of purified HEAT-rich proteins revealed that they interact with hydrophobic groups, including phenyl and alkyl groups, and undergo reversible conformational changes in tertiary structures, but not in secondary structures. These results show that conformational changes in the flexible amphiphilic motifs play a critical role in translocation through the NPC.

  1. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies.

    PubMed

    Gambhir, Sahil; Vyas, Dinesh; Hollis, Michael; Aekka, Apporva; Vyas, Arpita

    2015-03-21

    Nuclear factor kappa B (NF-κB) has an established role in the regulation of innate immunity and inflammation. NF-κB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-κB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-κB's function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-κB's role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy.

  2. Importin {beta}-type nuclear transport receptors have distinct binding affinities for Ran-GTP

    SciTech Connect

    Hahn, Silvia; Schlenstedt, Gabriel

    2011-03-18

    Highlights: {yields} Determination of binding properties of nuclear transport receptor/Ran-GTP complexes. {yields} Biosensor measurements provide constants for dissociation, on-rates, and off-rates. {yields} The affinity of receptors for Ran-GTP is widely divergent. {yields} Dissociation constants differ for three orders of magnitude. {yields} The cellular concentration of yeast Ran is not limiting. -- Abstract: Cargos destined to enter or leave the cell nucleus are typically transported by receptors of the importin {beta} family to pass the nuclear pore complex. The yeast Saccharomyces cerevisiae comprises 14 members of this protein family, which can be divided in importins and exportins. The Ran GTPase regulates the association and dissociation of receptors and cargos as well as the transport direction through the nuclear pore. All receptors bind to Ran exclusively in its GTP-bound state and this event is restricted to the nuclear compartment. We determined the Ran-GTP binding properties of all yeast transport receptors by biosensor measurements and observed that the affinity of importins for Ran-GTP differs significantly. The dissociation constants range from 230 pM to 270 nM, which is mostly based on a variability of the off-rate constants. The divergent affinity of importins for Ran-GTP suggests the existence of a novel mode of nucleocytoplasmic transport regulation. Furthermore, the cellular concentration of {beta}-receptors and of other Ran-binding proteins was determined. We found that the number of {beta}-receptors altogether about equals the amounts of yeast Ran, but Ran-GTP is not limiting in the nucleus. The implications of our results for nucleocytoplasmic transport mechanisms are discussed.

  3. Hepatocyte nuclear factor 4α regulation of bile acid and drug metabolism

    PubMed Central

    Chiang, John YL

    2013-01-01

    The hepatocyte nuclear factor 4α (HNF4α) is a liver-enriched nuclear receptor that plays a critical role in early morphogenesis, fetal liver development, liver differentiation and metabolism. Human HNF4α gene mutations cause maturity on-set diabetes of the young type 1, an autosomal dominant non-insulin-dependent diabetes mellitus. HNF4α is an orphan nuclear receptor because of which the endogenous ligand has not been firmly identified. The trans-activating activity of HNF4α is enhanced by interacting with co-activators and inhibited by corepressors. Recent studies have revealed that HNF4α plays a central role in regulation of bile acid metabolism in the liver. Bile acids are required for biliary excretion of cholesterol and metabolites, and intestinal absorption of fat, nutrients, drug and xenobiotics for transport and distribution to liver and other tissues. Bile acids are signaling molecules that activate nuclear receptors to control lipids and drug metabolism in the liver and intestine. Therefore, HNF4α plays a central role in coordinated regulation of bile acid and xenobiotics metabolism. Drugs that specifically activate HNF4α could be developed for treating metabolic diseases such as diabetes, dyslipidemia and cholestasis, as well as drug metabolism and detoxification. PMID:19239393

  4. Human Factors Considerations in New Nuclear Power Plants: Detailed Analysis.

    SciTech Connect

    OHara,J.; Higgins, J.; Brown, W.; Fink, R.

    2008-02-14

    This Nuclear Regulatory Commission (NRC) sponsored study has identified human-performance issues in new and advanced nuclear power plants. To identify the issues, current industry developments and trends were evaluated in the areas of reactor technology, instrumentation and control technology, human-system integration technology, and human factors engineering (HFE) methods and tools. The issues were organized into seven high-level HFE topic areas: Role of Personnel and Automation, Staffing and Training, Normal Operations Management, Disturbance and Emergency Management, Maintenance and Change Management, Plant Design and Construction, and HFE Methods and Tools. The issues where then prioritized into four categories using a 'Phenomena Identification and Ranking Table' methodology based on evaluations provided by 14 independent subject matter experts. The subject matter experts were knowledgeable in a variety of disciplines. Vendors, utilities, research organizations and regulators all participated. Twenty issues were categorized into the top priority category. This Brookhaven National Laboratory (BNL) technical report provides the detailed methodology, issue analysis, and results. A summary of the results of this study can be found in NUREG/CR-6947. The research performed for this project has identified a large number of human-performance issues for new control stations and new nuclear power plant designs. The information gathered in this project can serve as input to the development of a long-term strategy and plan for addressing human performance in these areas through regulatory research. Addressing human-performance issues will provide the technical basis from which regulatory review guidance can be developed to meet these challenges. The availability of this review guidance will help set clear expectations for how the NRC staff will evaluate new designs, reduce regulatory uncertainty, and provide a well-defined path to new nuclear power plant licensing.

  5. The transcription factor regulatory factor X1 increases the expression of neuronal glutamate transporter type 3.

    PubMed

    Ma, Kaiwen; Zheng, Shuqiu; Zuo, Zhiyi

    2006-07-28

    Glutamate transporters (excitatory amino acid transporters, EAAT) play an important role in maintaining extracellular glutamate homeostasis and regulating glutamate neurotransmission. However, very few studies have investigated the regulation of EAAT expression. A binding sequence for the regulatory factor X1 (RFX1) exists in the promoter region of the gene encoding for EAAT3, a neuronal EAAT, but not in the promoter regions of the genes encoding for EAAT1 and EAAT2, two glial EAATs. RFX proteins are transcription factors binding to X-boxes of DNA sequences. Although RFX proteins are necessary for the normal function of sensory neurons in Caenorhabditis elegans, their roles in the mammalian brain are not known. We showed that RFX1 increased EAAT3 expression and activity in C6 glioma cells. RFX1 binding complexes were found in the nuclear extracts of C6 cells. The activity of EAAT3 promoter as measured by luciferase reporter activity was increased by RFX1 in C6 cells and the neuron-like SH-SY5Y cells. However, RFX1 did not change the expression of EAAT2 proteins in the NRK52E cells. RFX1 proteins were expressed in the neurons of rat brain. A high expression level of RFX1 proteins was found in the neurons of cerebral cortex and Purkinje cells. Knockdown of the RFX1 expression by RFX1 antisense oligonucleotides decreased EAAT3 expression in rat cortical neurons in culture. These results suggest that RFX1 enhances the activity of EAAT3 promoter to increase the expression of EAAT3 proteins. This study provides initial evidence for the regulation of gene expression in the nervous cells by RFX1.

  6. Criticality Calculations of Fresh LEU and MOX Assemblies for Transport and Storage at the Balakovo Nuclear Power Plant

    SciTech Connect

    Goluoglu, S.

    2001-01-11

    Transportation of low-enriched uranium (LEU) and mixed-oxide (MOX) assemblies to and within the VVER-1000-type Balakovo Nuclear Power Plant is investigated. Effective multiplication factors for fresh fuel assemblies on the railroad platform, fresh fuel assemblies in the fuel transportation vehicle, and fresh fuel assemblies in the spent fuel storage pool are calculated. If there is no absorber between the units, the configurations with all MOX assemblies result in higher effective multiplication factors than the configurations with all LEU assemblies when the system is dry. When the system is flooded, the configurations with all LEU assemblies result in higher effective multiplication factors. For normal operating conditions, effective multiplication factors for all configurations are below the presumed upper subcritical limit of 0.95. For an accident condition of a fully loaded fuel transportation vehicle that is flooded with low-density water (possibly from a fire suppression system), the presumed upper subcritical limit is exceeded by configurations containing LEU assemblies.

  7. Factors controlling large-wood transport in a mountain river

    NASA Astrophysics Data System (ADS)

    Ruiz-Villanueva, Virginia; Wyżga, Bartłomiej; Zawiejska, Joanna; Hajdukiewicz, Maciej; Stoffel, Markus

    2016-11-01

    As with bedload transport, wood transport in rivers is governed by several factors such as flow regime, geomorphic configuration of the channel and floodplain, or wood size and shape. Because large-wood tends to be transported during floods, safety and logistical constraints make field measurements difficult. As a result, direct observation and measurements of the conditions of wood transport are scarce. This lack of direct observations and the complexity of the processes involved in wood transport may result in an incomplete understanding of wood transport processes. Numerical modelling provides an alternative approach to addressing some of the unknowns in the dynamics of large-wood in rivers. The aim of this study is to improve the understanding of controls governing wood transport in mountain rivers, combining numerical modelling and direct field observations. By defining different scenarios, we illustrate relationships between the rate of wood transport and discharge, wood size, and river morphology. We test these relationships for a wide, multithread reach and a narrower, partially channelized single-thread reach of the Czarny Dunajec River in the Polish Carpathians. Results indicate that a wide range of quantitative information about wood transport can be obtained from a combination of numerical modelling and field observations and from document contrasting patterns of wood transport in single- and multithread river reaches. On the one hand, log diameter seems to have a greater importance for wood transport in the multithread channel because of shallower flow, lower flow velocity, and lower stream power. Hydrodynamic conditions in the single-thread channel allow transport of large-wood pieces, whereas in the multithread reach, logs with diameters similar to water depth are not being moved. On the other hand, log length also exerts strong control on wood transport, more so in the single-thread than in the multithread reach. In any case, wood transport strongly

  8. Distinct, but not completely separate spatial transport routes in the nuclear pore complex

    PubMed Central

    2013-01-01

    The nuclear pore complex (NPC), which provides the permeable and selective transport path between the nucleus and cytoplasm of eukaryotic cells, allows both the passive diffusion of small molecules in a signal-independent manner and the transport receptor-facilitated translocation of cargo molecules in a signal-dependent manner. However, the spatial and functional relationships between these two transport pathways, which represent critical information for unraveling the fundamental nucleocytoplasmic transport mechanism, remain in dispute. The direct experimental examination of passive and facilitated transport with a high spatiotemporal resolution under real-time trafficking conditions in native NPCs is still difficult. To address this issue and further define these transport mechanisms, we recently developed single-point edge-excitation sub-diffraction (SPEED) microscopy and a deconvolution algorithm to directly map both passive and facilitated transport routes in three dimensions (3D) in native NPCs. Our findings revealed that passive and facilitated transport occur through spatially distinct transport routes. Signal-independent small molecules exhibit a high probability of passively diffusing through an axial central viscous channel, while transport receptors and their cargo complexes preferentially travel through the periphery, around this central channel, after interacting with phenylalanine-glycine (FG) filaments. Strikingly, these two distinct transport zones are not completely separate either spatially or functionally. Instead, their conformations are closely correlated and simultaneously regulated. In this review, we will specifically highlight a detailed procedure for 3D mapping of passive and facilitated transport routes, demonstrate the correlation between these two distinct pathways, and finally, speculate regarding the regulation of the transport pathways driven by the conformational changes of FG filaments in NPCs. PMID:23669120

  9. Assessment and Requirements of Nuclear Reaction Databases for GCR Transport in the Atmosphere and Structures

    NASA Technical Reports Server (NTRS)

    Cucinotta, F. A.; Wilson, J. W.; Shinn, J. L.; Tripathi, R. K.

    1998-01-01

    The transport properties of galactic cosmic rays (GCR) in the atmosphere, material structures, and human body (self-shielding) am of interest in risk assessment for supersonic and subsonic aircraft and for space travel in low-Earth orbit and on interplanetary missions. Nuclear reactions, such as knockout and fragmentation, present large modifications of particle type and energies of the galactic cosmic rays in penetrating materials. We make an assessment of the current nuclear reaction models and improvements in these model for developing required transport code data bases. A new fragmentation data base (QMSFRG) based on microscopic models is compared to the NUCFRG2 model and implications for shield assessment made using the HZETRN radiation transport code. For deep penetration problems, the build-up of light particles, such as nucleons, light clusters and mesons from nuclear reactions in conjunction with the absorption of the heavy ions, leads to the dominance of the charge Z = 0, 1, and 2 hadrons in the exposures at large penetration depths. Light particles are produced through nuclear or cluster knockout and in evaporation events with characteristically distinct spectra which play unique roles in the build-up of secondary radiation's in shielding. We describe models of light particle production in nucleon and heavy ion induced reactions and make an assessment of the importance of light particle multiplicity and spectral parameters in these exposures.

  10. Arenavirus Nucleoproteins Prevent Activation of Nuclear Factor Kappa B

    PubMed Central

    Rodrigo, W. W. Shanaka I.; Ortiz-Riaño, Emilio; Pythoud, Christelle; Kunz, Stefan

    2012-01-01

    Arenaviruses include several causative agents of hemorrhagic fever (HF) disease in humans that are associated with high morbidity and significant mortality. Morbidity and lethality associated with HF arenaviruses are believed to involve the dysregulation of the host innate immune and inflammatory responses that leads to impaired development of protective and efficient immunity. The molecular mechanisms underlying this dysregulation are not completely understood, but it is suggested that viral infection leads to disruption of early host defenses and contributes to arenavirus pathogenesis in humans. We demonstrate in the accompanying paper that the prototype member in the family, lymphocytic choriomeningitis virus (LCMV), disables the host innate defense by interfering with type I interferon (IFN-I) production through inhibition of the interferon regulatory factor 3 (IRF3) activation pathway and that the viral nucleoprotein (NP) alone is responsible for this inhibitory effect (C. Pythoud, W. W. Rodrigo, G. Pasqual, S. Rothenberger, L. Martínez-Sobrido, J. C. de la Torre, and S. Kunz, J. Virol. 86:7728–7738, 2012). In this report, we show that LCMV-NP, as well as NPs encoded by representative members of both Old World (OW) and New World (NW) arenaviruses, also inhibits the nuclear translocation and transcriptional activity of the nuclear factor kappa B (NF-κB). Similar to the situation previously reported for IRF3, Tacaribe virus NP (TCRV-NP) does not inhibit NF-κB nuclear translocation and transcriptional activity to levels comparable to those seen with other members in the family. Altogether, our findings demonstrate that arenavirus infection inhibits NF-κB-dependent innate immune and inflammatory responses, possibly playing a key role in the pathogenesis and virulence of arenavirus. PMID:22623788

  11. Arenavirus nucleoproteins prevent activation of nuclear factor kappa B.

    PubMed

    Rodrigo, W W Shanaka I; Ortiz-Riaño, Emilio; Pythoud, Christelle; Kunz, Stefan; de la Torre, Juan C; Martínez-Sobrido, Luis

    2012-08-01

    Arenaviruses include several causative agents of hemorrhagic fever (HF) disease in humans that are associated with high morbidity and significant mortality. Morbidity and lethality associated with HF arenaviruses are believed to involve the dysregulation of the host innate immune and inflammatory responses that leads to impaired development of protective and efficient immunity. The molecular mechanisms underlying this dysregulation are not completely understood, but it is suggested that viral infection leads to disruption of early host defenses and contributes to arenavirus pathogenesis in humans. We demonstrate in the accompanying paper that the prototype member in the family, lymphocytic choriomeningitis virus (LCMV), disables the host innate defense by interfering with type I interferon (IFN-I) production through inhibition of the interferon regulatory factor 3 (IRF3) activation pathway and that the viral nucleoprotein (NP) alone is responsible for this inhibitory effect (C. Pythoud, W. W. Rodrigo, G. Pasqual, S. Rothenberger, L. Martínez-Sobrido, J. C. de la Torre, and S. Kunz, J. Virol. 86:7728-7738, 2012). In this report, we show that LCMV-NP, as well as NPs encoded by representative members of both Old World (OW) and New World (NW) arenaviruses, also inhibits the nuclear translocation and transcriptional activity of the nuclear factor kappa B (NF-κB). Similar to the situation previously reported for IRF3, Tacaribe virus NP (TCRV-NP) does not inhibit NF-κB nuclear translocation and transcriptional activity to levels comparable to those seen with other members in the family. Altogether, our findings demonstrate that arenavirus infection inhibits NF-κB-dependent innate immune and inflammatory responses, possibly playing a key role in the pathogenesis and virulence of arenavirus.

  12. Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression.

    PubMed

    Ning, Bei-Fang; Ding, Jin; Liu, Jiao; Yin, Chuan; Xu, Wen-Ping; Cong, Wen-Ming; Zhang, Qing; Chen, Fei; Han, Tao; Deng, Xing; Wang, Pei-Qin; Jiang, Cai-Feng; Zhang, Jun-Ping; Zhang, Xin; Wang, Hong-Yang; Xie, Wei-Fen

    2014-11-01

    Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4α expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-κB activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4α on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4α, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-κB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4α levels through down-regulating HNF4α-3'UTR activity. Collectively, an HNF4α-NF-κB feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis. These findings broaden the knowledge of hepatic inflammation and cancer initiation/progression, and also provide novel prognostic biomarkers and therapeutic targets for HCC. © 2014 by the American Association for the Study of Liver Diseases.

  13. The Exposure Rate Conversion Factor for Nuclear Fallout

    SciTech Connect

    Spriggs, G D

    2009-02-11

    Nuclear fallout is comprised of approximately 2000 radionuclides. About 1000 of these radionuclides are either primary fission products or activated fission products that are created during the burn process. The exposure rate one meter above the surface produced by this complex mixture of radionuclides varies rapidly with time since many of the radionuclides are short-lived and decay numerous times before reaching a stable isotope. As a result, the mixture of radionuclides changes rapidly with time. Using a new code developed at the Lawrence Livermore National Laboratory, the mixture of radionuclides at any given point in time can be calculated. The code also calculates the exposure rate conversion factor (ECF) for all 3864 individual isotopes contained in its database based on the total gamma energy released per decay. Based on the combination of isotope mixture and individual ECFs, the time-dependent variation of the composite exposure rate conversion factor for nuclear fallout can be easily calculated. As example of this new capability, a simple test case corresponding to a 10 kt, uranium-plutonium fuel has been calculated. The results for the time-dependent, composite ECF for this test case are shown in Figure 1. For comparison, we also calculated the composite exposure rate conversion factor using the conversion factors found in Federal Guidance Report No.12 (FGR-12) published by ORNL, which contains the conversion factors for approximately 1000 isotopes. As can be noted from Figure 1, the two functions agree reasonably well at times greater than about 30 minutes. However, they do not agree at early times since FGR-12 does not include all of the short-lived isotopes that are produced in nuclear fallout. It should also be noted that the composite ECF at one hour is 19.7 R/hr per Ci/m{sup 2}. This corresponds to 3148 R/hr per 1 kt per square mile, which agrees reasonably well with the value of 3000 R/hr per 1 kt per square mile as quoted by Glasstone. We have

  14. The role of nuclear factor kappa B in human labour.

    PubMed

    Lindström, Tamsin M; Bennett, Phillip R

    2005-11-01

    Preterm birth remains the leading cause of perinatal mortality and morbidity, largely as a result of a poor understanding of the precise mechanisms controlling labour onset in humans. Inflammation has long been recognised as a key feature of both preterm and term labour, with an influx of inflammatory cells into the uterus and elevated levels of pro-inflammatory cytokines observed during parturition. Nuclear factor kappa B (NF-kappaB) is a transcription factor family classically associated with inflammation. Accumulating evidence points to a role for NF-kappaB in the physiology and pathophysiology of labour. NF-kappaB activity increases with labour onset and is central to multiple prolabour pathways. Premature or aberrant activation of NF-kappaB may thus contribute to preterm labour. The current understanding of NF-kappaB in the context of human labour is discussed here.

  15. The nuclear transport capacity of a human-pancreatic ribonuclease variant is critical for its cytotoxicity.

    PubMed

    Tubert, Pere; Rodríguez, Montserrat; Ribó, Marc; Benito, Antoni; Vilanova, Maria

    2011-10-01

    We have previously described a human pancreatic-ribonuclease variant, named PE5, which carries a non-contiguous extended bipartite nuclear localization signal. This signal comprises residues from at least three regions of the protein. We postulated that the introduction of this signal in the ribonuclease provides it with cytotoxic activity because although the variant poorly evades the ribonuclease inhibitor in vitro, it is routed to the nucleus, which is devoid of the inhibitor. In this work, we have investigated the relationship between the cytotoxicity produced by PE5 and its ability to reach the nucleus. First, we show that this enzyme, when incubated with HeLa cells, specifically cleaves nuclear RNA while it leaves cytoplasmic RNA unaffected. On the other hand, we have created new variants in which the residues of the nuclear localization signal that are important for the nuclear transport have been replaced. As expected, the individual changes produce a significant decrease in the cytotoxicity of the resulting variants. We conclude that the nuclear transport of PE5 is critical for its cytotoxicity. Therefore, routing a ribonuclease to the nucleus is an alternative strategy to endow it with cytotoxic activity.

  16. FK506-Binding Protein 51 Regulates Nuclear Transport of the Glucocorticoid Receptor β and Glucocorticoid Responsiveness

    PubMed Central

    Zhang, Xinyu; Clark, Abbot F.; Yorio, Thomas

    2008-01-01

    PURPOSE A spliced variant of the human glucocorticoid receptor GRβ has been implicated in glucocorticoid responsiveness in glaucoma. Over-expression of the FK506-binding immunophilin FKBP51 also causes a generalized state of glucocorticoid resistance. In the present study, the roles of FKBP51 in the nuclear transport of GRβ and glucocorticoid responsiveness were investigated. METHODS Human trabecular meshwork cells (GTM3 and TM5) and HeLa cells were treated with dexamethasone (DEX) and FK506 and transfected with GRβ and FKBP51 expression vectors. Coimmunoprecipitation and Western blot analyses were performed to study interactions of FKBP51 and FKBP52 with GRα, GRβ, Hsp90, or dynein. The cells were transfected with a GRE-luciferase reporter to evaluate the effects of DEX and FK506 and the overexpression of GRβ and FKBP51 on glucocorticoid-mediated gene expression. RESULTS FKBP51 was involved in constitutive nuclear transport of both GRα and -β in the absence of ligands. FKBP52 appeared to be solely responsible for the nuclear transport of ligand-activated GRα. DEX stimulated the translocation of GRα but not GRβ. Overexpression of either GRβ or FKBP51 stimulated GRβ translocation and reduced DEX-induced luciferase in HeLa cells. FK506 did not alter DEX-induced translocation of GRα. However, FK506 increased the association of FKBP51 with GRβ and stimulated DEX-induced translocation of GRβ in normal TM cells, but not in glaucoma TM cells. Increased nuclear GRβ significantly inhibited glucocorticoid responsiveness in TM cells. CONCLUSIONS Nuclear transport of GRβ represents a novel mechanism through which FKBP51 alters GC sensitivity. GRβ and FKBP51 may be responsible for increased responsiveness in steroid-induced ocular hypertensive individuals as well as in patients with glaucoma. PMID:18326728

  17. FK506-binding protein 51 regulates nuclear transport of the glucocorticoid receptor beta and glucocorticoid responsiveness.

    PubMed

    Zhang, Xinyu; Clark, Abbot F; Yorio, Thomas

    2008-03-01

    A spliced variant of the human glucocorticoid receptor GRbeta has been implicated in glucocorticoid responsiveness in glaucoma. Over-expression of the FK506-binding immunophilin FKBP51 also causes a generalized state of glucocorticoid resistance. In the present study, the roles of FKBP51 in the nuclear transport of GRbeta and glucocorticoid responsiveness were investigated. Human trabecular meshwork cells (GTM3 and TM5) and HeLa cells were treated with dexamethasone (DEX) and FK506 and transfected with GRbeta and FKBP51 expression vectors. Coimmunoprecipitation and Western blot analyses were performed to study interactions of FKBP51 and FKBP52 with GRalpha, GRbeta, Hsp90, or dynein. The cells were transfected with a GRE-luciferase reporter to evaluate the effects of DEX and FK506 and the overexpression of GRbeta and FKBP51 on glucocorticoid-mediated gene expression. FKBP51 was involved in constitutive nuclear transport of both GRalpha and -beta in the absence of ligands. FKBP52 appeared to be solely responsible for the nuclear transport of ligand-activated GRalpha. DEX stimulated the translocation of GRalpha but not GRbeta. Overexpression of either GRbeta or FKBP51 stimulated GRbeta translocation and reduced DEX-induced luciferase in HeLa cells. FK506 did not alter DEX-induced translocation of GRalpha. However, FK506 increased the association of FKBP51 with GRbeta and stimulated DEX-induced translocation of GRbeta in normal TM cells, but not in glaucoma TM cells. Increased nuclear GRbeta significantly inhibited glucocorticoid responsiveness in TM cells. Nuclear transport of GRbeta represents a novel mechanism through which FKBP51 alters GC sensitivity. GRbeta and FKBP51 may be responsible for increased responsiveness in steroid-induced ocular hypertensive individuals as well as in patients with glaucoma.

  18. Development of a test system for verification and validation of nuclear transport simulations

    SciTech Connect

    White, Morgan C; Triplett, Brian S; Anghaie, Samim

    2008-01-01

    Verification and validation of nuclear data is critical to the accuracy of both stochastic and deterministic particle transport codes. In order to effectively test a set of nuclear data, the data must be applied to a wide variety of transport problems. Performing this task in a timely, efficient manner is tedious. The nuclear data team at Los Alamos National laboratory in collaboration with the University of Florida has developed a methodology to automate the process of nuclear data verification and validation (V and V). This automated V and V process can efficiently test a number of data libraries using well defined benchmark experiments, such as those in the International Criticality Safety Benchmark Experiment Project (ICSBEP). The process is implemented through an integrated set of Pyton scripts. Material and geometry data are read from an existing medium or given directly by the user to generate a benchmark experiment template file. The user specifies the choice of benchmark templates, codes, and libraries to form a V and V project. The Python scripts generate input decks for multiple transport codes from the templates, run and monitor individual jobs, and parse the relevant output automatically. The output can then be used to generate reports directly or can be stored into a database for later analysis. This methodology eases the burden on the user by reducing the amount of time and effort required for obtaining and compiling calculation results. The resource savings by using this automated methodology could potentially be an enabling technology for more sophisticated data studies, such as nuclear data uncertainty quantification. Once deployed, this tool will allow the nuclear data community to more thoroughly test data libraries leading to higher fidelity data in the future.

  19. The rationale/benefits of nuclear thermal rocket propulsion for NASA's lunar space transportation system

    NASA Technical Reports Server (NTRS)

    Borowski, Stanley K.

    1991-01-01

    Two nuclear thermal rocket (NTR) technology options are examined - one derived from the graphite-moderated reactor concept developed by NASA and the AEC under the Rover/NERVA (Nuclear Engine for Rocket Vehicle Application) programs, and a second concept, the Particle Bed Reactor. The paper also summarizes NASA's lunar outpost scenario, compares relative performance provided by different lunar space transportation system concepts, and discusses important operational issues (e.g., reusability, engine 'end-of-life' disposal, etc.) associated with using this important propulsion technology.

  20. Recombinant modular transporters on the basis of epidermal growth factor for targeted intracellular delivery of photosensitizers

    NASA Astrophysics Data System (ADS)

    Gilyazova, Dinara G.; Rosenkranz, Andrey A.; Gulak, Pavel V.; Lunin, Vladimir G.; Sergienko, Olga V.; Grin, Mikhail A.; Mironov, Andrey F.; Rubin, Andrey B.; Sobolev, Alexander S.

    2005-08-01

    The search for new pharmaceuticals has raised interest in locally-acting drugs which act over short distances within the cell, and for which different cell compartments have different sensitivities. Thus, photosensitizers used in anti-cancer therapy should be transported to the most sensitive subcellular compartments where their action is most pronounced. Earlier, we described the effects of bacterially expressed modular recombinant transporters for photosensitizers comprising a-melanocyte-stimulating hormone as an internalizable, cell-specific ligand, an optimized nuclear localization sequence, an Escherichia coli hemoglobin-like protein as a carrier, and an endosomolytic amphipathic polypeptide. These transporters delivered photosensitizers into the murine melanoma cells nuclei to result in cytotoxic effects 2 orders of magnitude greater than those of nonmodified photosensitizers. Here we describe new transporters possessing the same modules except for a ligand that is replaced with epidermal growth factor specific for other cancer cell types. The new transporter modules retained their functional activities within the chimera, this transporter delivered photosensitizers into the human carcinoma cells nuclei to result in photocytotoxic effects almost 3 orders of magnitude greater than those of nonmodified photosensitizers. The obtained results show that ligand modules of such transporters are interchangeable, meaning that they can be tailored for particular applications.

  1. Factors controlling radionuclide transport behavior in a generic geological radioactive waste repository

    NASA Astrophysics Data System (ADS)

    Bianchi, M.; Liu, H.; Birkholzer, J. T.

    2013-12-01

    One of the main challenges in designing a geological repository for high-level nuclear waste is the assessment of postclosure safety, which involves the long-term ability of the engineered system and the geological host formation to contain and delay the leakage of radionuclides toward the biosphere. A correct assessment requires detailed knowledge of the factors controlling radionuclide transport in the different components of the geological disposal system. For instance, molecular diffusion, which is considered the dominant transport mechanism in low-permeable geological formations, may be influenced by the heterogeneity of the diffusive parameters and by electrochemical processes. Likewise, the prevalence of advective transport in the near-field excavation damaged zone (EDZ) may be controlled by the hydrogeological conditions in the host formation, as well as by hydrogeological and geometrical properties. In this study, we performed two-dimensional numerical simulations of groundwater flow and radionuclide transport to study the influence of several factors on the prevailing transport mechanism (i.e., advection or molecular diffusion) in the different components of a geological nuclear waste repository system. Particular attention was given to the excavation damaged zone (EDZ) around the repository tunnels and access shaft, which was modeled as a single effective continuum as well as with the dual-porosity approach. We considered different hydrogeological and geometrical factors, including the ambient hydraulic gradient, the presence of groundwater pressure anomalies, and the thickness of the EDZ and its hydraulic properties. By comparing simulation results, we show that transport behavior and the role of the EDZ as a preferential flow path for radionuclide transport is most sensitive to the hydrogeological conditions in the host rock. When the hydraulic gradient in the host rock is reduced by a factor of 5 from the unit value, we observe a significant reduction

  2. Training on Transport Security of Nuclear/Radioactive Materials for Key Audiences

    SciTech Connect

    Pope, Ronald; Liu, Yung; Shuler, J.M.

    2016-01-01

    Beginning in 2013, the U.S. Department of Energy (DOE) Packaging Certification Program (PCP), Office of Packaging and Transportation, Office of Environmental Management has sponsored a series of three training courses on Security of Nuclear and Other Radioactive Materials during Transport. These courses were developed and hosted by Argonne National Laboratory staff with guest lecturers from both the U.S. and international organizations and agencies including the U.S. Nuclear Regulatory Commission (NRC), Federal Bureau of Investigation (FBI), the U.S. Department of Energy (DOE), National Nuclear Security Administration (NNSA), DOE national laboratories, the International Atomic Energy Agency (IAEA), the World Nuclear Transport Institute (WNTI), and the World Institute for Nuclear Security (WINS). Each of the three courses held to date were one-week in length. The courses delved in detail into the regulatory requirements for transport security, focusing on international and U.S.-domestic requirements and guidance documents. Lectures, in-class discussions and small group exercises, including tabletop (TTX) and field exercises were designed to enhance the learning objectives for the participants. For example, the field exercise used the ARG-US radio frequency identification (RFID) remote surveillance system developed by Argonne for DOE/PCP to track and monitor packages in a mock shipment, following in-class exercises of developing a transport security plan (TSP) for the mock shipment, performing a readiness review and identifying needed corrective actions. Participants were able to follow the mock shipment on the webpage in real time in the ARG-US Command Center at Argonne including “staged” incidents that were designed to illustrate the importance of control, command, communication and coordination in ensuring transport security. Great lessons were learned based on feedback from the participant’s course evaluations with the series of the courses. Since the

  3. BRIEF REPORT: Pair production from nuclear collisions and cosmic ray transport

    NASA Astrophysics Data System (ADS)

    Norbury, John W.

    2006-09-01

    Modern cosmic ray transport codes, that are capable of use for a variety of applications, need to include all significant atomic, nuclear and particle reactions at a variety of energies. Lepton pair production from nucleus nucleus collisions has not been included in transport codes to date. Using the methods of Baur, Bertulani and Baron, the present report provides estimates of electron positron pair production cross sections for nuclei and energies relevant to cosmic ray transport. It is shown that the cross sections are large compared to other typical processes such as single neutron removal due to strong or electromagnetic interactions. Therefore, lepton pair production may need to be included in some transport code applications involving MeV electrons.

  4. A TRANSPORTATION RISK ASSESSMENT TOOL FOR ANALYZING THE TRANSPORT OF SPENT NUCLEAR FUEL AND HIGH-LEVEL RADIOACTIVE WASTE TO THE PROPOSED YUCCA MOUNTAIN REPOSITORY

    SciTech Connect

    NA

    2001-02-15

    The Yucca Mountain Draft Environmental Impact Statement (DEIS) analysis addressed the potential for transporting spent nuclear fuel and high-level radioactive waste from 77 origins for 34 types of spent fuel and high-level radioactive waste, 49,914 legal weight truck shipments, and 10,911 rail shipments. The analysis evaluated transportation over 59,250 unique shipment links for travel outside Nevada (shipment segments in urban, suburban or rural zones by state), and 22,611 links in Nevada. In addition, the analysis modeled the behavior of 41 isotopes, 1091 source terms, and used 8850 food transfer factors (distinct factors by isotope for each state). The analysis also used mode-specific accident rates for legal weight truck, rail, and heavy haul truck by state, and barge by waterway. This complex mix of data and information required an innovative approach to assess the transportation impacts. The approach employed a Microsoft{reg_sign} Access database tool that incorporated data from many sources, including unit risk factors calculated using the RADTRAN IV transportation risk assessment computer program. Using Microsoft{reg_sign} Access, the analysts organized data (such as state-specific accident and fatality rates) into tables and developed queries to obtain the overall transportation impacts. Queries are instructions to the database describing how to use data contained in the database tables. While a query might be applied to thousands of table entries, there is only one sequence of queries that is used to calculate a particular transportation impact. For example, the incident-free dose to off-link populations in a state is calculated by a query that uses route segment lengths for each route in a state that could be used by shipments, populations for each segment, number of shipments on each segment, and an incident-free unit risk factor calculated using RADTRAN IV. In addition to providing a method for using large volumes of data in the calculations, the

  5. Roles of hepatocyte nuclear factors in hepatitis B virus infection

    PubMed Central

    Kim, Doo Hyun; Kang, Hong Seok; Kim, Kyun-Hwan

    2016-01-01

    Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB. PMID:27610013

  6. Hepatic nuclear factor 3 and nuclear factor 1 regulate 5-aminolevulinate synthase gene expression and are involved in insulin repression.

    PubMed

    Scassa, María E; Guberman, Alejandra S; Ceruti, Julieta M; Cánepa, Eduardo T

    2004-07-02

    Although the negative regulation of gene expression by insulin has been widely studied, the transcription factors responsible for the insulin effect are still unknown. The purpose of this work was to explore the molecular mechanisms involved in the insulin repression of the 5-aminolevulinate synthase (ALAS) gene. Deletion analysis of the 5'-regulatory region allowed us to identify an insulin-responsive region located at -459 to -354 bp. This fragment contains a highly homologous insulin-responsive (IRE) sequence. By transient transfection assays, we determined that hepatic nuclear factor 3 (HNF3) and nuclear factor 1 (NF1) are necessary for an appropriate expression of the ALAS gene. Insulin overrides the HNF3beta or HNF3beta plus NF1-mediated stimulation of ALAS transcriptional activity. Electrophoretic mobility shift assay and Southwestern blotting indicate that HNF3 binds to the ALAS promoter. Mutational analysis of this region revealed that IRE disruption abrogates insulin action, whereas mutation of the HNF3 element maintains hormone responsiveness. This dissociation between HNF3 binding and insulin action suggests that HNF3beta is not the sole physiologic mediator of insulin-induced transcriptional repression. Furthermore, Southwestern blotting assay shows that at least two polypeptides other than HNF3beta can bind to ALAS promoter and that this binding is dependent on the integrity of the IRE. We propose a model in which insulin exerts its negative effect through the disturbance of HNF3beta binding or transactivation potential, probably due to specific phosphorylation of this transcription factor by Akt. In this regard, results obtained from transfection experiments using kinase inhibitors support this hypothesis. Due to this event, NF1 would lose accessibility to the promoter. The posttranslational modification of HNF3 would allow the binding of a protein complex that recognizes the core IRE. These results provide a potential mechanism for the insulin

  7. Floppy but not sloppy: Interaction mechanism of FG-nucleoporins and nuclear transport receptors.

    PubMed

    Aramburu, Iker Valle; Lemke, Edward A

    2017-08-01

    The nuclear pore complex (NPC) forms a permeability barrier between the nucleus and the cytoplasm. Molecules that are able to cross this permeability barrier encounter different disordered phenylalanine glycine rich nucleoporins (FG-Nups) that act as a molecular filter and regulate the selective NPC crossing of biomolecules. In this review, we provide a current overview regarding the interaction mechanism between FG-Nups and the carrier molecules that recognize and enable the transport of cargoes through the NPC aiming to understand the general molecular mechanisms that facilitate the nucleocytoplasmic transport. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Expression of nuclear receptors (AhR, PXR, CAR) and transcription factor (Nrf2) in human parotid gland.

    PubMed

    Droździk, Agnieszka; Kowalczyk, Robert; Urasińska, Elzbieta; Kurzawski, Mateusz

    2013-01-01

    Nuclear receptors and transcription factors coordinate expression of many genes, and regulation of their expression determines cellular response to various endo- and exogenous factors. There is paucity of data regarding expression of nuclear receptors and factors in salivary glands. In the present study, a focus was placed on human parotid gland expression of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (CAR, NR1I3) and nuclear factor E2-related factor 2 (Nrf2). Parotid salivary tissue was obtained from patients undergoing the gland dissection. Quantitative real-time PCR aimmunohistochemical staining were used for expression studies. The highest mRNA expression was documented for NFE2L2 coding for Nrf2. Lower expression was seen in the case of AHR gene coding for AhR. PXR was constitutively present at very low level and CAR expression was below the limit of quantification. Immunohistochemical evaluation of the parotid gland specimens revealed cytoplasmic Nrf2 expression in striated duct cells as well as within myoepithelial cells. Acinar cells were mostly negative for Nrf2. Expression of AhR was found within the cytoplasm in striated duct cells. Acinar and myoepithelial cells were negative for AhR. Having in mind their role in regulating function of many enzymes and transmembrane transporters, expression of these factors seem play a role in salivary gland physiology, pathology as well as drug transport and metabolism.

  9. Spent Nuclear Fuel Transportation: An Examination of Potential Lessons Learned From Prior Shipping Campaigns

    SciTech Connect

    Marsha Keister; Kathryn McBride

    2006-08-01

    The Nuclear Waste Policy Act of 1982 (NWPA), as amended, assigned the Department of Energy (DOE) responsibility for developing and managing a Federal system for the disposal of spent nuclear fuel (SNF) and high-level radioactive waste (HLW). The Office of Civilian Radioactive Waste Management (OCRWM) is responsible for accepting, transporting, and disposing of SNF and HLW at the Yucca Mountain repository in a manner that protects public health, safety, and the environment; enhances national and energy security; and merits public confidence. OCRWM faces a near-term challenge—to develop and demonstrate a transportation system that will sustain safe and efficient shipments of SNF and HLW to a repository. To better inform and improve its current planning, OCRWM has extensively reviewed plans and other documents related to past high-visibility shipping campaigns of SNF and other radioactive materials within the United States. This report summarizes the results of this review and, where appropriate, lessons learned.

  10. Ultrathin nucleoporin phenylalanine–glycine repeat films and their interaction with nuclear transport receptors

    PubMed Central

    Eisele, Nico B; Frey, Steffen; Piehler, Jacob; Görlich, Dirk; Richter, Ralf P

    2010-01-01

    Nuclear pore complexes (NPCs) are highly selective gates that mediate the exchange of all proteins and nucleic acids between the cytoplasm and the nucleus. Their selectivity relies on a supramolecular assembly of natively unfolded nucleoporin domains containing phenylalanine–glycine (FG)-rich repeats (FG repeat domains), in a way that is at present poorly understood. We have developed ultrathin FG domain films that reproduce the mode of attachment and the density of FG repeats in NPCs, and that exhibit a thickness that corresponds to the nanoscopic dimensions of the native permeability barrier. By using a combination of biophysical characterization techniques, we quantified the binding of nuclear transport receptors (NTRs) to such FG domain films and analysed how this binding affects the swelling behaviour and mechanical properties of the films. The results extend our understanding of the interaction of FG domain assemblies with NTRs and contribute important information to refine the model of transport across the permeability barrier. PMID:20379223

  11. Nucleocytoplasmic transport in cells with progerin-induced defective nuclear lamina.

    PubMed

    Ferri, Gianmarco; Storti, Barbara; Bizzarri, Ranieri

    2017-10-01

    Recent data indicate that nuclear lamina (NL) plays a relevant role in many fundamental cellular functions. The peculiar role of NL in cells is dramatically demonstrated by the Hutchinson-Gilford progeria syndrome (HGPS), an inherited laminopathy that causes premature, rapid aging shortly after birth. In HGPS, a mutant form of Lamin A (progeria) leads to a dysmorphic NL structure, but how this perturbation is transduced into cellular changes is still largely unknown. Owing to the close structural relationship between NL and the Nuclear Pore Complex (NPC), in this work we test whether HGPS affects passive and active nucleo-cytoplasmic shuttling of cargoes by means of an established model based of fluorescence recovery after photobleaching. Our findings clearly demonstrate that dysmorphic NL is decoupled from the dynamic characteristics of passive and active transport towards and from the nucleus, as well as from the binding affinity of transport protein mediators. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies.

    PubMed

    Zahn, Raphael; Osmanović, Dino; Ehret, Severin; Araya Callis, Carolina; Frey, Steffen; Stewart, Murray; You, Changjiang; Görlich, Dirk; Hoogenboom, Bart W; Richter, Ralf P

    2016-04-08

    The permeability barrier of nuclear pore complexes (NPCs) controls bulk nucleocytoplasmic exchange. It consists of nucleoporin domains rich in phenylalanine-glycine motifs (FG domains). As a bottom-up nanoscale model for the permeability barrier, we have used planar films produced with three different end-grafted FG domains, and quantitatively analyzed the binding of two different nuclear transport receptors (NTRs), NTF2 and Importin β, together with the concomitant film thickness changes. NTR binding caused only moderate changes in film thickness; the binding isotherms showed negative cooperativity and could all be mapped onto a single master curve. This universal NTR binding behavior - a key element for the transport selectivity of the NPC - was quantitatively reproduced by a physical model that treats FG domains as regular, flexible polymers, and NTRs as spherical colloids with a homogeneous surface, ignoring the detailed arrangement of interaction sites along FG domains and on the NTR surface.

  13. Anomalous solute transport in saturated porous media: Relating transport model parameters to electrical and nuclear magnetic resonance properties

    NASA Astrophysics Data System (ADS)

    Swanson, Ryan D.; Binley, Andrew; Keating, Kristina; France, Samantha; Osterman, Gordon; Day-Lewis, Frederick D.; Singha, Kamini

    2015-02-01

    The advection-dispersion equation (ADE) fails to describe commonly observed non-Fickian solute transport in saturated porous media, necessitating the use of other models such as the dual-domain mass-transfer (DDMT) model. DDMT model parameters are commonly calibrated via curve fitting, providing little insight into the relation between effective parameters and physical properties of the medium. There is a clear need for material characterization techniques that can provide insight into the geometry and connectedness of pore spaces related to transport model parameters. Here, we consider proton nuclear magnetic resonance (NMR), direct-current (DC) resistivity, and complex conductivity (CC) measurements for this purpose, and assess these methods using glass beads as a control and two different samples of the zeolite clinoptilolite, a material that demonstrates non-Fickian transport due to intragranular porosity. We estimate DDMT parameters via calibration of a transport model to column-scale solute tracer tests, and compare NMR, DC resistivity, CC results, which reveal that grain size alone does not control transport properties and measured geophysical parameters; rather, volume and arrangement of the pore space play important roles. NMR cannot provide estimates of more-mobile and less-mobile pore volumes in the absence of tracer tests because these estimates depend critically on the selection of a material-dependent and flow-dependent cutoff time. Increased electrical connectedness from DC resistivity measurements are associated with greater mobile pore space determined from transport model calibration. CC was hypothesized to be related to length scales of mass transfer, but the CC response is unrelated to DDMT.

  14. Nuclear waste transportation: case studies of identifying stakeholder risk information needs.

    PubMed Central

    Drew, Christina H; Grace, Deirdre A; Silbernagel, Susan M; Hemmings, Erin S; Smith, Alan; Griffith, William C; Takaro, Timothy K; Faustman, Elaine M

    2003-01-01

    The U.S. Department of Energy (DOE) is responsible for the cleanup of our nation's nuclear legacy, involving complex decisions about how and where to dispose of nuclear waste and how to transport it to its ultimate disposal site. It is widely recognized that a broad range of stakeholders and tribes should be involved in this kind of decision. All too frequently, however, stakeholders and tribes are only invited to participate by commenting on processes and activities that are near completion; they are not included in the problem formulation stages. Moreover, it is often assumed that high levels of complexity and uncertainty prevent meaningful participation by these groups. Considering the types of information that stakeholders and tribes need to be able to participate in the full life cycle of decision making is critical for improving participation and transparency of decision making. Toward this objective, the Consortium for Risk Evaluation with Stakeholder Participation (CRESP) participated in three public processes relating to nuclear waste transportation and disposal in 1997-1998. First, CRESP organized focus groups to identify concerns about nuclear waste transportation. Second, CRESP conducted exit surveys at regional public workshops held by DOE to get input from stakeholders on intersite waste transfer issues. Third, CRESP developed visual tools to synthesize technical information and allow stakeholders and tribes with varying levels of knowledge about nuclear waste to participate in meaningful discussion. In this article we share the results of the CRESP findings, discuss common themes arising from these interactions, and comment on special considerations needed to facilitate stakeholder and tribal participation in similar decision-making processes. PMID:12611653

  15. Nuclear waste transportation: case studies of identifying stakeholder risk information needs.

    PubMed

    Drew, Christina H; Grace, Deirdre A; Silbernagel, Susan M; Hemmings, Erin S; Smith, Alan; Griffith, William C; Takaro, Timothy K; Faustman, Elaine M

    2003-03-01

    The U.S. Department of Energy (DOE) is responsible for the cleanup of our nation's nuclear legacy, involving complex decisions about how and where to dispose of nuclear waste and how to transport it to its ultimate disposal site. It is widely recognized that a broad range of stakeholders and tribes should be involved in this kind of decision. All too frequently, however, stakeholders and tribes are only invited to participate by commenting on processes and activities that are near completion; they are not included in the problem formulation stages. Moreover, it is often assumed that high levels of complexity and uncertainty prevent meaningful participation by these groups. Considering the types of information that stakeholders and tribes need to be able to participate in the full life cycle of decision making is critical for improving participation and transparency of decision making. Toward this objective, the Consortium for Risk Evaluation with Stakeholder Participation (CRESP) participated in three public processes relating to nuclear waste transportation and disposal in 1997-1998. First, CRESP organized focus groups to identify concerns about nuclear waste transportation. Second, CRESP conducted exit surveys at regional public workshops held by DOE to get input from stakeholders on intersite waste transfer issues. Third, CRESP developed visual tools to synthesize technical information and allow stakeholders and tribes with varying levels of knowledge about nuclear waste to participate in meaningful discussion. In this article we share the results of the CRESP findings, discuss common themes arising from these interactions, and comment on special considerations needed to facilitate stakeholder and tribal participation in similar decision-making processes.

  16. Constraining nuclear data via cosmological observations: Neutrino energy transport and big bang nucleosynthesis

    NASA Astrophysics Data System (ADS)

    Paris, Mark; Fuller, George; Grohs, Evan; Kishimoto, Chad; Vlasenko, Alexey

    2017-09-01

    We introduce a new computational capability that moves toward a self-consistent calculation of neutrino transport and nuclear reactions for big bang nucleosynthesis (BBN). Such a self-consistent approach is needed to be able to extract detailed information about nuclear reactions and physics beyond the standard model from precision cosmological observations of primordial nuclides and the cosmic microwave background radiation. We calculate the evolution of the early universe through the epochs of weak decoupling, weak freeze-out and big bang nucleosynthesis (BBN) by simultaneously coupling a full strong, electromagnetic, and weak nuclear reaction network with a multi-energy group Boltzmann neutrino energy transport scheme. The modular structure of our approach allows the dissection of the relative contributions of each process responsible for evolving the dynamics of the early universe. Such an approach allows a detailed account of the evolution of the active neutrino energy distribution functions alongside and self-consistently with the nuclear reactions and entropy/heat generation and 'ow between the neutrino and photon/electron/positron/baryon plasma components. Our calculations reveal nonlinear feedback in the time evolution of neutrino distribution functions and plasma thermodynamic conditions. We discuss the time development of neutrino spectral distortions and concomitant entropy production and extraction from the plasma. These e↑ects result in changes in the computed values of the BBN deuterium and helium-4 yields that are on the order of a half-percent relative to a baseline standard BBN calculation with no neutrino transport. This is an order of magnitude larger e↑ect than in previous estimates. For particular implementations of quantum corrections in plasma thermodynamics, our calculations show a 0.4% increase in deuterium and a 0.6% decrease in 4He over our baseline. The magnitude of these changes are on the order of uncertainties in the nuclear

  17. 10 CFR Appendix E to Part 73 - Levels of Physical Protection To Be Applied in International Transport of Nuclear Material 1

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... International Transport of Nuclear Material 1 E Appendix E to Part 73 Energy NUCLEAR REGULATORY COMMISSION... Physical Protection To Be Applied in International Transport of Nuclear Material 1 1 See appendix C to part 110 of this chapter from the physical description of the categories of nuclear material as set forth...

  18. 10 CFR Appendix E to Part 73 - Levels of Physical Protection To Be Applied in International Transport of Nuclear Material 1

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... International Transport of Nuclear Material 1 E Appendix E to Part 73 Energy NUCLEAR REGULATORY COMMISSION... Physical Protection To Be Applied in International Transport of Nuclear Material 1 1 See appendix C to part 110 of this chapter from the physical description of the categories of nuclear material as set forth...

  19. 10 CFR Appendix E to Part 73 - Levels of Physical Protection To Be Applied in International Transport of Nuclear Material 1

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... International Transport of Nuclear Material 1 E Appendix E to Part 73 Energy NUCLEAR REGULATORY COMMISSION... Physical Protection To Be Applied in International Transport of Nuclear Material 1 1 See appendix C to part 110 of this chapter from the physical description of the categories of nuclear material as set forth...

  20. Subsurface mass transport affects the radioxenon signatures that are used to identify clandestine nuclear tests

    NASA Astrophysics Data System (ADS)

    Lowrey, J. D.; Biegalski, S. R.; Osborne, A. G.; Deinert, M. R.

    2013-01-01

    The ratios of noble gas radioisotopes can provide critical information with which to verify that a belowground nuclear test has taken place. The relative abundance of anthropogenic isotopes is typically assumed to rely solely on their fission yield and decay rate. The xenon signature of a nuclear test is then bounded by the signal from directly produced fission xenon, and by the signal that would come from the addition of xenon from iodine precursors. Here we show that this signal range is too narrowly defined. Transport simulations were done to span the range of geological conditions within the Nevada Test Site. The simulations assume a 1 kt test and the barometric history following the nuclear test at Pahute Mesa in March 1992. Predicted xenon ratios fall outside of the typically assumed range 20% of the time and situations can arise where the ground level signal comes entirely from the decay of iodine precursors.

  1. Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine

    PubMed Central

    Weerachayaphorn, Jittima; Mennone, Albert; Soroka, Carol J.; Harry, Kathy; Hagey, Lee R.; Kensler, Thomas W.

    2012-01-01

    The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2−/− mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2−/− compared with wild-type control mice. The mRNA expression of the bile acid transporters bile salt export pump (Bsep) and organic solute transporter (Ostα) were increased in the face of impaired expression of the multidrug resistance-associated proteins Mrp3 and Mrp4. Deletion of Nrf2 also decreased ileal apical sodium-dependent bile acid transporter (Asbt) expression, leading to reduced bile acid reabsorption and increased loss of bile acid in feces. Finally, when cholestasis is induced by BDL, liver injury was not different from that in wild-type BDL mice. These Nrf2−/− mice also had increased pregnane X receptor (Pxr) and Cyp3a11 mRNA expression in association with enhanced hepatic bile acid hydroxylation. In conclusion, this study finds that Nrf2 plays a major role in the regulation of bile acid homeostasis in the liver and intestine. Deletion of Nrf2 results in a cholestatic phenotype but does not augment liver injury following BDL. PMID:22345550

  2. RISKIND: A computer program for calculating radiological consequences and health risks from transportation of spent nuclear fuel

    SciTech Connect

    Yuan, Y.C.; Chen, S.Y.; Biwer, B.M.; LePoire, D.J.

    1995-11-01

    This report presents the technical details of RISKIND, a computer code designed to estimate potential radiological consequences and health risks to individuals and the collective population from exposures associated with the transportation of spent nuclear fuel. RISKIND is a user-friendly, interactive program that can be run on an IBM or equivalent personal computer under the Windows{trademark} environment. Several models are included in RISKIND that have been tailored to calculate the exposure to individuals under various incident-free and accident conditions. The incident-free models assess exposures from both gamma and neutron radiation and can account for different cask designs. The accident models include accidental release, atmospheric transport, and the environmental pathways of radionuclides from spent fuels; these models also assess health risks to individuals and the collective population. The models are supported by databases that are specific to spent nuclear fuels and include a radionuclide inventory and dose conversion factors. In addition, the flexibility of the models allows them to be used for assessing any accidental release involving radioactive materials. The RISKIND code allows for user-specified accident scenarios as well as receptor locations under various exposure conditions, thereby facilitating the estimation of radiological consequences and health risks for individuals. Median (50% probability) and typical worst-case (less than 5% probability of being exceeded) doses and health consequences from potential accidental releases can be calculated by constructing a cumulative dose/probability distribution curve for a complete matrix of site joint-wind-frequency data. These consequence results, together with the estimated probability of the entire spectrum of potential accidents, form a comprehensive, probabilistic risk assessment of a spent nuclear fuel transportation accident.

  3. Full-Scale Accident Testing in Support of Used Nuclear Fuel Transportation.

    SciTech Connect

    Durbin, Samuel G.; Lindgren, Eric R.; Rechard, Rob P.; Sorenson, Ken B.

    2014-09-01

    The safe transport of spent nuclear fuel and high-level radioactive waste is an important aspect of the waste management system of the United States. The Nuclear Regulatory Commission (NRC) currently certifies spent nuclear fuel rail cask designs based primarily on numerical modeling of hypothetical accident conditions augmented with some small scale testing. However, NRC initiated a Package Performance Study (PPS) in 2001 to examine the response of full-scale rail casks in extreme transportation accidents. The objectives of PPS were to demonstrate the safety of transportation casks and to provide high-fidelity data for validating the modeling. Although work on the PPS eventually stopped, the Blue Ribbon Commission on America’s Nuclear Future recommended in 2012 that the test plans be re-examined. This recommendation was in recognition of substantial public feedback calling for a full-scale severe accident test of a rail cask to verify evaluations by NRC, which find that risk from the transport of spent fuel in certified casks is extremely low. This report, which serves as the re-assessment, provides a summary of the history of the PPS planning, identifies the objectives and technical issues that drove the scope of the PPS, and presents a possible path for moving forward in planning to conduct a full-scale cask test. Because full-scale testing is expensive, the value of such testing on public perceptions and public acceptance is important. Consequently, the path forward starts with a public perception component followed by two additional components: accident simulation and first responder training. The proposed path forward presents a series of study options with several points where the package performance study could be redirected if warranted.

  4. Thermodynamics of competitive molecular channel transport: application to artificial nuclear pores.

    PubMed

    Bauer, Wolfgang R; Nadler, Walter

    2010-12-13

    In an analytical model channel transport is analyzed as a function of key parameters, determining efficiency and selectivity of particle transport in a competitive molecular environment. These key parameters are the concentration of particles, solvent-channel exchange dynamics, as well as particle-in-channel- and interparticle interaction. These parameters are explicitly related to translocation dynamics and channel occupation probability. Slowing down the exchange dynamics at the channel ends, or elevating the particle concentration reduces the in-channel binding strength necessary to maintain maximum transport. Optimized in-channel interaction may even shift from binding to repulsion. A simple equation gives the interrelation of access dynamics and concentration at this transition point. The model is readily transferred to competitive transport of different species, each of them having their individual in-channel affinity. Combinations of channel affinities are determined which differentially favor selectivity of certain species on the cost of others. Selectivity for a species increases if its in-channel binding enhances the species' translocation probability when compared to that of the other species. Selectivity increases particularly for a wide binding site, long channels, and fast access dynamics. Recent experiments on competitive transport of in-channel binding and inert molecules through artificial nuclear pores serve as a paradigm for our model. It explains qualitatively and quantitatively how binding molecules are favored for transport at the cost of the transport of inert molecules.

  5. Thermodynamics of Competitive Molecular Channel Transport: Application to Artificial Nuclear Pores

    PubMed Central

    Bauer, Wolfgang R.; Nadler, Walter

    2010-01-01

    In an analytical model channel transport is analyzed as a function of key parameters, determining efficiency and selectivity of particle transport in a competitive molecular environment. These key parameters are the concentration of particles, solvent-channel exchange dynamics, as well as particle-in-channel- and interparticle interaction. These parameters are explicitly related to translocation dynamics and channel occupation probability. Slowing down the exchange dynamics at the channel ends, or elevating the particle concentration reduces the in-channel binding strength necessary to maintain maximum transport. Optimized in-channel interaction may even shift from binding to repulsion. A simple equation gives the interrelation of access dynamics and concentration at this transition point. The model is readily transferred to competitive transport of different species, each of them having their individual in-channel affinity. Combinations of channel affinities are determined which differentially favor selectivity of certain species on the cost of others. Selectivity for a species increases if its in-channel binding enhances the species' translocation probablity when compared to that of the other species. Selectivity increases particularly for a wide binding site, long channels, and fast access dynamics. Recent experiments on competitive transport of in-channel binding and inert molecules through artificial nuclear pores serve as a paradigm for our model. It explains qualitatively and quantitatively how binding molecules are favored for transport at the cost of the transport of inert molecules. PMID:21179205

  6. Evaluation of groundwater flow and transport at the Shoal underground nuclear test: An interim report

    SciTech Connect

    Pohll, G.; Chapman, J.; Hassan, A.; Papelis, C.; Andricevic, R.; Shirley, C.

    1998-07-01

    Since 1962, all United States nuclear tests have been conducted underground. A consequence of this testing has been the deposition of large amounts of radioactive materials in the subsurface, sometimes in direct contact with groundwater. The majority of this testing occurred on the Nevada Test Site, but a limited number of experiments were conducted in other locations. One of these is the subject of this report, the Project Shoal Area (PSA), located about 50 km southeast of Fallon, Nevada. The Shoal test consisted of a 12-kiloton-yield nuclear detonation which occurred on October 26, 1963. Project Shoal was part of studies to enhance seismic detection of underground nuclear tests, in particular, in active earthquake areas. Characterization of groundwater contamination at the Project Shoal Area is being conducted by the US Department of Energy (DOE) under the Federal Facility Agreement and Consent Order (FFACO) with the State of Nevada Department of Environmental Protection and the US Department of Defense (DOD). This order prescribes a Corrective Action Strategy (Appendix VI), which, as applied to underground nuclear tests, involves preparing a Corrective Action Investigation Plan (CAIP), Corrective Action Decision Document (CADD), Corrective Action Plan, and Closure Report. The scope of the CAIP is flow and transport modeling to establish contaminant boundaries that are protective of human health and the environment. This interim report describes the current status of the flow and transport modeling for the PSA.

  7. Advances in nuclear data and all-particle transport for radiation oncology

    SciTech Connect

    White, R.M.; Chadwick, M.B.; Chandler, W.P.; Hartmann Siantar, C.L.; Westbrook, C.K.

    1994-05-01

    Fast neutrons have been used to treat over 15,000 cancer patients worldwide and proton therapy is rapidly emerging as a treatment of choice for tumors around critical anatomical structures. Neutron therapy requires evaluated data to {approximately}70 MeV while proton therapy requires data to {approximately}250 MeV. Collaboration between Lawrence Livermore National Laboratory (LLNL) and the medical physics community has revealed limitations in nuclear cross section evaluations and radiation transport capabilities that have prevented neutron and proton radiation therapy centers from using Monte Carlo calculations to accurately predict dose in patients. These evaluations require energy- and angle-dependent cross sections for secondary neutrons, charged-particles and recoil nuclei. We are expanding the LLNL nuclear databases to higher energies for biologically important elements and have developed a three-dimensional, all-particle Monte Carlo radiation transport code that uses computer-assisted-tomography (CT) images as the input mesh. This code, called PEREGRINE calculates dose distributions in the human body and can be used as a tool to determine the dependence of dose on details of the evaluated nuclear data. In this paper, we will review the status of the nuclear data required for neutron and proton therapy, describe the capabilities of the PEREGRINE package, and show the effects of tissue inhomogeneities on dose distribution.

  8. A Preliminary Evaluation of Using Fill Materials to Stabilize Used Nuclear Fuel During Storage and Transportation

    SciTech Connect

    Maheras, Steven J.; Best, Ralph; Ross, Steven B.; Lahti, Erik A.; Richmond, David J.

    2012-08-01

    This report contains a preliminary evaluation of potential fill materials that could be used to fill void spaces in and around used nuclear fuel contained in dry storage canisters in order to stabilize the geometry and mechanical structure of the used nuclear fuel during extended storage and transportation after extended storage. Previous work is summarized, conceptual descriptions of how canisters might be filled were developed, and requirements for potential fill materials were developed. Elements of the requirements included criticality avoidance, heat transfer or thermodynamic properties, homogeneity and rheological properties, retrievability, material availability and cost, weight and radiation shielding, and operational considerations. Potential fill materials were grouped into 5 categories and their properties, advantages, disadvantages, and requirements for future testing were discussed. The categories were molten materials, which included molten metals and paraffin; particulates and beads; resins; foams; and grout. Based on this analysis, further development of fill materials to stabilize used nuclear fuel during storage and transportation is not recommended unless options such as showing that the fuel remains intact or canning of used nuclear fuel do not prove to be feasible.

  9. Atmospheric transport patterns and possible consequences for the European North after a nuclear accident.

    PubMed

    Baklanov, A; Mahura, A; Jaffe, D; Thaning, L; Bergman, R; Andres, R

    2002-01-01

    The main purpose of this study is to examine possible impacts and consequences of a hypothetical accident at the Kola nuclear plant in north-west Russia on different geographical regions: Scandinavia, central Europe, European FSU and Taymyr. The period studied is 1991-1996. An isentropic trajectory model has been used to calculate forward trajectories that originated over the nuclear accident region. Atmospheric transport patterns were identified using the isentropic trajectories and a cluster analysis technique. From the trajectory model results, a number of cases were chosen for examination in detail using more complete transport models. For this purpose, the models MATHEW/ADPIC, DERMA and a newly developed FOA Random Displacement Model have been used to simulate the radionuclide transport and contamination in the case of a nuclear accident and their results have been compared with those of the trajectory modelling. Estimation of the long-term consequences for populations after an accident has been performed for several specific dates by empirical models and correlation between fallout and doses to humans on the basis of the Chernobyl accident exposures in Scandinavia.

  10. Nuclear transportation of diacylglycerol kinase gamma and its possible function in the nucleus.

    PubMed

    Matsubara, Takehiro; Shirai, Yasuhito; Miyasaka, Kei; Murakami, Takuya; Yamaguchi, Yasuto; Ueyama, Takehiko; Kai, Masahiro; Sakane, Fumio; Kanoh, Hideo; Hashimoto, Toshiaki; Kamada, Shinji; Kikkawa, Ushio; Saito, Naoaki

    2006-03-10

    Diacylglycerol kinases (DGKs) convert diacylglycerol (DG) to phosphatidic acid, and both lipids are known to play important roles in lipid signal transduction. Thereby, DGKs are considered to be a one of the key players in lipid signaling, but its physiological function remains to be solved. In an effort to investigate one of nine subtypes, we found that DGKgamma came to be localized in the nucleus with time in all cell lines tested while seen only in the cytoplasm at the early stage of culture, indicating that DGKgamma is transported from the cytoplasm to the nucleus. The nuclear transportation of DGKgamma didn't necessarily need DGK activity, but its C1 domain was indispensable, suggesting that the C1 domain of DGKgamma acts as a nuclear transport signal. Furthermore, to address the function of DGKgamma in the nucleus, we produced stable cell lines of wild-type DGKgamma and mutants, including kinase negative, and investigated their cell size, growth rate, and cell cycle. The cells expressing the kinase-negative mutant of DGKgamma were larger in size and showed slower growth rate, and the S phase of the cells was extended. These findings implicate that nuclear DGKgamma regulates cell cycle.

  11. Vehicle emission unit risk factors for transportation risk assessments

    SciTech Connect

    Biwer, B.M.; Butler, J.P.

    1999-12-01

    When the transportation risk posed by shipments of hazardous chemical and radioactive materials is being assessed, it is necessary to evaluate the risks associated with both vehicle emissions and cargo-related risks. Diesel exhaust and fugitive dust emissions from vehicles transporting hazardous shipments lead to increased air pollution, which increases the risk of latent fatalities in the affected population along the transport route. The estimated risk from these vehicle-related sources can often by as large or larger than the estimated risk associated with the material being transported. In this paper, data from the US Environmental Protection Agency's Motor Vehicle-Related Air Toxics Study are first used to develop latent cancer fatality estimates per kilometer of travel in rural and urban areas for all diesel truck classes. These unit risk factors are based on studies investigating the carcinogenic nature of diesel exhaust. With the same methodology, the current per=kilometer latent fatality risk factor used in transportation risk assessment for heavy diesel trucks in urban areas is revised and the analysis expanded to provide risk factors for rural areas and all diesel truck classes. These latter fatality estimates may include, but are not limited to, cancer fatalities and are based primarily on the most recent epidemiological data available on mortality rates associated with ambient air PM-10 concentrations.

  12. Vehicle emission unit risk factors for transportation risk assessments.

    PubMed

    Biwer, B M; Butler, J P

    1999-12-01

    When the transportation risk posed by shipments of hazardous chemical and radioactive materials is being assessed, it is necessary to evaluate the risks associated with both vehicle emissions and cargo-related risks. Diesel exhaust and fugitive dust emissions from vehicles transporting hazardous shipments lead to increased air pollution, which increases the risk of latent fatalities in the affected population along the transport route. The estimated risk from these vehicle-related sources can often be as large or larger than the estimated risk associated with the material being transported. In this paper, data from the U.S. Environmental Protection Agency's Motor Vehicle-Related Air Toxics Study are first used to develop latent cancer fatality estimates per kilometer of travel in rural and urban areas for all diesel truck classes. These unit risk factors are based on studies investigating the carcinogenic nature of diesel exhaust. With the same methodology, the current per-kilometer latent fatality risk factor used in transportation risk assessments for heavy diesel trucks in urban areas is revised and the analysis expanded to provide risk factors for rural areas and all diesel truck classes. These latter fatality estimates may include, but are not limited to, cancer fatalities and are based primarily on the most recent epidemiological data available on mortality rates associated with ambient air PM-10 concentrations.

  13. Nuclear fact book

    SciTech Connect

    Hill, O. F.; Platt, A. M.; Robinson, J. V.

    1983-05-01

    This reference provides significant highlights and summary facts in the following areas: general energy; nuclear energy; nuclear fuel cycle; uranium supply and enrichment; nuclear reactors; spent fuel and advanced repacking concepts; reprocessing; high-level waste; gaseous waste; transuranic waste; low-level waste; remedial action; transportation; disposal; radiation information; environment; legislation; socio-political aspects; conversion factors; and a glossary. (GHT)

  14. The Use of Transportable Processing Systems for the Treatment of Radioactive Nuclear Wastes

    SciTech Connect

    Phillips, Ch.; Houghton, D.; Crawford, G.

    2008-07-01

    EnergySolutions has developed two major types of radioactive processing plants based on its experience in the USA and UK, and its exclusive North American access to the intellectual property and know-how developed over 50 years at the Sellafield nuclear site in the UK. Passive Secure Cells are a type of hot cell used in place of the Canyons typically used in US-designed radioactive facilities. They are used in permanent, large scale plants suitable for long term processing of large amounts of radioactive material. The more recently developed Transportable Processing Systems, which are the subject of this paper, are used for nuclear waste processing and clean-up when processing is expected to be complete within shorter timescales and when it is advantageous to be able to move the processing equipment amongst a series of geographically spread-out waste treatment sites. Such transportable systems avoid the construction of a monolithic waste processing plant which itself would require extensive decommissioning and clean-up when its mission is complete. This paper describes a range of transportable radioactive waste processing equipment that EnergySolutions and its partners have developed including: the portable MOSS drum-based waste grouting system, the skid mounted MILWPP large container waste grouting system, the IPAN skid-mounted waste fissile content non-destructive assay system, the Wiped Film Evaporator low liquid hold-up transportable evaporator system, the CCPU transportable solvent extraction cesium separation system, and the SEP mobile shielded cells for emptying radioactive debris from water-filled silos. Maximum use is made of proven, robust, and compact processing equipment such as centrifugal contactors, remote sampling systems, and cement grout feed and metering devices. Flexible, elastomer-based Hose-in-Hose assemblies and container-based transportable pump booster stations are used in conjunction with these transportable waste processing units for

  15. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.

    PubMed

    Arias, J; Alberts, A S; Brindle, P; Claret, F X; Smeal, T; Karin, M; Feramisco, J; Montminy, M

    1994-07-21

    A number of signalling pathways stimulate transcription of target genes through nuclear factors whose activities are primarily regulated by phosphorylation. Cyclic AMP regulates the expression of numerous genes, for example, through the protein kinase-A (PKA)-mediated phosphorylation of transcription factor CREB at Ser 133. Although phosphorylation may stimulate transcriptional activators by modulating their nuclear transport or DNA-binding affinity, CREB belongs to a class of proteins whose phosphorylation appears specifically to enhance their trans-activation potential. Recent work describing a phospho-CREB binding protein (CBP) which interacts specifically with the CREB trans-activation domain prompted us to examine whether CBP is necessary for cAMP regulated transcription. We report here that microinjection of an anti-CBP antiserum into fibroblasts can inhibit transcription from a cAMP responsive promoter. Surprisingly, CBP also cooperates with upstream activators such as c-Jun, which are involved in mitogen responsive transcription. We propose that CBP is recruited to the promoter through interaction with certain phosphorylated factors, and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptor to the transcriptional apparatus.

  16. Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3.

    PubMed

    van Mullem, Alies A; van Gucht, Anja L M; Visser, W Edward; Meima, Marcel E; Peeters, Robin P; Visser, Theo J

    2016-12-05

    Transport of thyroid hormone (TH) across the plasma membrane is necessary for the genomic action of T3 mediated by its nuclear T3 receptor. MCT8 and MCT10 have been identified as important TH transporters. Mutations in MCT8 result in severe psychomotor retardation. In addition to TH transport into the cell, MCT8 and MCT10 also facilitate TH efflux from cells. Therefore, the aim of this study was to examine if MCT8 and MCT10 increase the availability of T3 for its nuclear receptor rather than generate a rapid equilibrium between cellular and serum T3. T3 action was investigated in JEG3 cells co-transfected with TRβ1 and a T3 response element-driven luciferase construct, and T3 metabolism was analyzed in cells transfected with type 3 deiodinase (D3). In addition, cells were transfected with MCT8 or MCT10 and/or the cytoplasmic T3-binding protein mu-crystallin (CRYM). Luciferase signal was markedly stimulated by incubating cells for 24 h with 1 nM T3, but this response was not augmented by MCT8 or MCT10 expression. Limiting the time of T3 exposure to 1-6 h and co-transfection with CRYM allowed for a modest increase in luciferase response to T3. In contrast, T3 metabolism by D3 was potently stimulated by MCT8 or MCT10 expression, but it was not affected by expression of CRYM. These results suggest that MCT8 and MCT10 by virtue of their bidirectional T3 transport have less effect on steady-state nuclear T3 levels than on T3 levels at the cell periphery where D3 is located. CRYM alters the dynamics of cellular TH transport but its exact function in the cellular distribution of TH remains to be determined.

  17. Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA.

    PubMed

    Calado, Angelo; Treichel, Nathalie; Müller, Eva-Christina; Otto, Albrecht; Kutay, Ulrike

    2002-11-15

    Transport of proteins and RNA into and out of the cell nucleus is mediated largely by a family of RanGTP-binding transport receptors. Export receptors (exportins) need to bind RanGTP for efficient loading of their export cargo. We have identified eukaryotic elongation factor 1A (eEF1A) and tRNA as RanGTP-dependent binding partners of exportin-5 (Exp5). Exp5 stimulates nuclear export of eEF1A when microinjected into the nucleus of Xenopus laevis oocytes. Surprisingly, the interaction between eEF1A and Exp5 is dependent on tRNA that can interact directly with Exp5 and, if aminoacylated, recruits eEF1A into the export complex. These data suggested to us that Exp5 might support tRNA export. Indeed, not only the canonical tRNA export receptor, exportin-t, but also Exp5 can drive nuclear export of tRNA. Taken together, we show that there exists an alternative tRNA export pathway which can be exploited to keep eEF1A out of the cell nucleus.

  18. Structural and functional analysis of Hikeshi, a new nuclear transport receptor of Hsp70s.

    PubMed

    Song, Jinsue; Kose, Shingo; Watanabe, Ai; Son, Se Young; Choi, Saehae; Hong, Hyerim; Yamashita, Eiki; Park, Il Yeong; Imamoto, Naoko; Lee, Soo Jae

    2015-03-01

    Hikeshi is a nuclear transport receptor required for cell survival after stress. It mediates heat-shock-induced nuclear import of 70 kDa heat-shock proteins (Hsp70s) through interactions with FG-nucleoporins (FG-Nups), which are proteins in nuclear pore complexes (NPCs). Here, the crystal structure of human Hikeshi is presented at 1.8 Å resolution. Hikeshi forms an asymmetric homodimer that is responsible for the interaction with Hsp70s. The asymmetry of Hikeshi arises from the distinct conformation of the C-terminal domain (CTD) and the flexibility of the linker regions of each monomer. Structure-guided mutational analyses showed that both the flexible linker region and the CTD are important for nuclear import of Hsp70. Pull-down assays revealed that only full-length Hsp70s can interact with Hikeshi. The N-terminal domain (NTD) consists of a jelly-roll/β-sandwich fold structure which contains hydrophobic pockets involved in FG-Nup recognition. A unique extended loop (E-loop) in the NTD is likely to regulate the interactions of Hikeshi with FG-Nups. The crystal structure of Hikeshi explains how Hikeshi participates in the regulation of nuclear import through the recognition of FG-Nups and which part of Hikeshi affects its binding to Hsp70. This study is the first to yield structural insight into this highly unique import receptor.

  19. Costs and impacts of transporting nuclear waste to candidate repository sites

    SciTech Connect

    McSweeney, T.I.; Peterson, R.W.; Gupta, R.

    1983-12-31

    In this paper, a status report on the current estimated costs and impacts of transporting high-level nuclear wastes to candidate disposal sites is given. Impacts in this analysis are measured in terms of risk to public health and safety. Since it is difficult to project the status of the nuclear industry to the time of repository operation - 20 to 50 years in the future - particular emphasis in the paper is placed on the evaluation of uncertainties. The first part of this paper briefly describes the characteristics of the waste that must be transported to a high-level waste disposal site. This discussion is followed by a section describing the characteristics of the waste transport system. Subsequent sections describe the costs and risk assessments of waste transport. Finally, in a concluding section, the effect of the uncertainties in the definition of the waste disposal system on cost and risk levels is evaluated. This last section also provides some perspectives on the magnitude of the cost and risk levels relative to other comparable costs and risks generally encountered. 13 references, 2 figures, 16 tables.

  20. Large cargo transport by nuclear pores: implications for the spatial organization of FG-nucleoporins

    PubMed Central

    Tu, Li-Chun; Fu, Guo; Zilman, Anton; Musser, Siegfried M

    2013-01-01

    Nuclear pore complexes (NPCs) mediate cargo traffic between the nucleus and the cytoplasm of eukaryotic cells. Nuclear transport receptors (NTRs) carry cargos through NPCs by transiently binding to phenylalanine-glycine (FG) repeats on intrinsically disordered polypeptides decorating the NPCs. Major impediments to understand the transport mechanism are the thousands of FG binding sites on each NPC, whose spatial distribution is unknown, and multiple binding sites per NTR, which leads to multivalent interactions. Using single molecule fluorescence microscopy, we show that multiple NTR molecules are required for efficient transport of a large cargo, while a single NTR promotes binding to the NPC but not transport. Particle trajectories and theoretical modelling reveal a crucial role for multivalent NTR interactions with the FG network and indicate a non-uniform FG repeat distribution. A quantitative model is developed wherein the cytoplasmic side of the pore is characterized by a low effective concentration of free FG repeats and a weak FG-NTR affinity, and the centrally located dense permeability barrier is overcome by multivalent interactions, which provide the affinity necessary to permeate the barrier. PMID:24213245

  1. Large cargo transport by nuclear pores: implications for the spatial organization of FG-nucleoporins.

    PubMed

    Tu, Li-Chun; Fu, Guo; Zilman, Anton; Musser, Siegfried M

    2013-12-11

    Nuclear pore complexes (NPCs) mediate cargo traffic between the nucleus and the cytoplasm of eukaryotic cells. Nuclear transport receptors (NTRs) carry cargos through NPCs by transiently binding to phenylalanine-glycine (FG) repeats on intrinsically disordered polypeptides decorating the NPCs. Major impediments to understand the transport mechanism are the thousands of FG binding sites on each NPC, whose spatial distribution is unknown, and multiple binding sites per NTR, which leads to multivalent interactions. Using single molecule fluorescence microscopy, we show that multiple NTR molecules are required for efficient transport of a large cargo, while a single NTR promotes binding to the NPC but not transport. Particle trajectories and theoretical modelling reveal a crucial role for multivalent NTR interactions with the FG network and indicate a non-uniform FG repeat distribution. A quantitative model is developed wherein the cytoplasmic side of the pore is characterized by a low effective concentration of free FG repeats and a weak FG-NTR affinity, and the centrally located dense permeability barrier is overcome by multivalent interactions, which provide the affinity necessary to permeate the barrier.

  2. Multiphase, multicomponent flow and transport models for Nuclear Test-Ban Treaty monitoring and nuclear waste disposal applications

    NASA Astrophysics Data System (ADS)

    Jordan, Amy

    Open challenges remain in using numerical models of subsurface flow and transport systems to make useful predictions related to nuclear waste storage and nonproliferation. The work presented here addresses the sensitivity of model results to unknown parameters, states, and processes, particularly uncertainties related to incorporating previously unrepresented processes (e.g., explosion-induced fracturing, hydrous mineral dehydration) into a subsurface flow and transport numerical simulator. The Finite Element Heat and Mass (FEHM) transfer code is used for all numerical models in this research. An experimental campaign intended to validate the predictive capability of numerical models that include the strongly coupled thermal, hydrological, and chemical processes in bedded salt is also presented. Underground nuclear explosions (UNEs) produce radionuclide gases that may seep to the surface over weeks to months. The estimated timing of gas arrival at the surface may be used to deploy personnel and equipment to the site of a suspected UNE, if allowed under the terms of the Comprehensive Nuclear Test-Ban Treaty. A model was developed using FEHM that considers barometrically pumped gas transport through a simplified fractured medium and was used to quantify the impact of uncertainties in hydrologic parameters (fracture aperture, matrix permeability, porosity, and saturation) and season of detonation on the timing of gas breakthrough. Numerical sensitivity analyses were performed for the case of a 1 kt UNE at a 400 m burial depth. Gas arrival time was found to be most affected by matrix permeability and fracture aperture. Gases having higher diffusivity were more sensitive to uncertainty in the rock properties. The effect of seasonality in the barometric pressure forcing was found to be important, with detonations in March the least likely to be detectable based on barometric data for Rainier Mesa, Nevada. Monte Carlo modeling was also used to predict the window of

  3. Nuclear receptors, nuclear-receptor factors, and nuclear-receptor-like orphans form a large paralog cluster in Homo sapiens.

    PubMed

    Garcia-Vallvé, S; Palau, J

    1998-06-01

    We studied a human protein paralog cluster formed by 38 nonredundant sequences taken from the Swiss-Prot database and its supplement, TrEMBL. These sequences include nuclear receptors, nuclear-receptor factors and nuclear-receptor-like orphans. Working separately with both the central cysteine-rich DNA-binding domain and the carboxy-terminal ligand-binding domain, we performed multialignment analyses that included drawings of paralog trees. Our results show that the cluster is highly multibranched, with considerable differences in the amino acid sequence in the ligand-binding domain (LBD), and 17 proximal subbranches which are identifiable and fully coincident when independent trees from both domains are compared. We identified the six recently proposed subfamilies as groups of neighboring clusters in the LBD paralog tree. We found similarities of 80%-100% for the N-terminal transactivation domain among mammalian ortholog receptors, as well as some paralog resemblances within diverse subbranches. Our studies suggest that during the evolutionary process, the three domains were assembled in a modular fashion with a nonshuffled modular fusion of the LBD. We used the EMBL server PredictProtein to make secondary-structure predictions for all 38 LBD subsequences. Amino acid residues in the multialigned homologous domains--taking the beginning of helix H3 of the human retinoic acid receptor-gamma as the initial point of reference--were substituted with H or E, which identify residues predicted to be helical or extended, respectively. The result was a secondary structure multialignment with the surprising feature that the prediction follows a canonical pattern of alignable alpha-helices with some short extended elements in between, despite the fact that a number of subsequences resemble each other by less than 25% in terms of the similarity index. We also identified the presence of a binary patterning in all of the predicted helices that were conserved throughout the 38

  4. A highly organized structure mediating nuclear localization of a Myb2 transcription factor in the protozoan parasite Trichomonas vaginalis.

    PubMed

    Chu, Chien-Hsin; Chang, Lung-Chun; Hsu, Hong-Ming; Wei, Shu-Yi; Liu, Hsing-Wei; Lee, Yu; Kuo, Chung-Chi; Indra, Dharmu; Chen, Chinpan; Ong, Shiou-Jeng; Tai, Jung-Hsiang

    2011-12-01

    Nuclear proteins usually contain specific peptide sequences, referred to as nuclear localization signals (NLSs), for nuclear import. These signals remain unexplored in the protozoan pathogen, Trichomonas vaginalis. The nuclear import of a Myb2 transcription factor was studied here using immunodetection of a hemagglutinin-tagged Myb2 overexpressed in the parasite. The tagged Myb2 was localized to the nucleus as punctate signals. With mutations of its polybasic sequences, 48KKQK51 and 61KR62, Myb2 was localized to the nucleus, but the signal was diffusive. When fused to a C-terminal non-nuclear protein, the Myb2 sequence spanning amino acid (aa) residues 48 to 143, which is embedded within the R2R3 DNA-binding domain (aa 40 to 156), was essential and sufficient for efficient nuclear import of a bacterial tetracycline repressor (TetR), and yet the transport efficiency was reduced with an additional fusion of a firefly luciferase to TetR, while classical NLSs from the simian virus 40 T-antigen had no function in this assay system. Myb2 nuclear import and DNA-binding activity were substantially perturbed with mutation of a conserved isoleucine (I74) in helix 2 to proline that altered secondary structure and ternary folding of the R2R3 domain. Disruption of DNA-binding activity alone by point mutation of a lysine residue, K51, preceding the structural domain had little effect on Myb2 nuclear localization, suggesting that nuclear translocation of Myb2, which requires an ordered structural domain, is independent of its DNA binding activity. These findings provide useful information for testing whether myriad Mybs in the parasite use a common module to regulate nuclear import.

  5. Method to develop data supporting consequence analyses of transporting nuclear materials in the United States

    SciTech Connect

    Reese, R.T.; Sandoval, R.P.

    1980-01-01

    The Transportation System Safety Evaluation (TSSE) program at Sandia National Laboratories' Transportation Technology Center was initiated to provide the necessary information on source terms for nuclear materials subjected to extreme environments. The techniques for derivation of source terms for the fuel alone has been described as well as the outline for package response. An additional facet of this problem is the development of analytical methods to describe the transport of the released radionuclides from the fuel rods to possible release points. This work is also covered in the TSSE program. Not all the work required will be performed or funded by Sandia; rather existing work will be sought out and ongoing work will be utilized in an attempt to unify the presentation of data and thus increase its usefulness.

  6. Spent nuclear fuel system dynamic stability under normal conditions of transportation

    DOE PAGES

    Jiang, Hao; Wang, Jy-An John

    2016-10-14

    In a horizontal layout of a spent nuclear fuel (SNF) assembly under normal conditions of transportation (NCT), the fuel assembly’s skeleton formed by guide tubes and spacer grids is the primary load bearing structure for carrying and transferring the vibration loads within an SNF assembly. Therefore, the integrity of guide tubes and spacer grids will dictate the vibration amplitude/intensity of the fuel assembly during transport, and must be considered when designing multipurpose purpose canister (MPC) for safe SNF transport. This paper investigates the SNF assembly deformation dynamics during normal vibration mode, as well as the transient shock mode inside themore » cask during NCT. In conclusion, dynamic analyses were performed in the frequency domain to study frequency characteristic of the fuel assembly system and in the time domain to simulate the transient dynamic response of the fuel assembly.« less

  7. Spent nuclear fuel system dynamic stability under normal conditions of transportation

    SciTech Connect

    Jiang, Hao; Wang, Jy-An John

    2016-10-14

    In a horizontal layout of a spent nuclear fuel (SNF) assembly under normal conditions of transportation (NCT), the fuel assembly’s skeleton formed by guide tubes and spacer grids is the primary load bearing structure for carrying and transferring the vibration loads within an SNF assembly. Therefore, the integrity of guide tubes and spacer grids will dictate the vibration amplitude/intensity of the fuel assembly during transport, and must be considered when designing multipurpose purpose canister (MPC) for safe SNF transport. This paper investigates the SNF assembly deformation dynamics during normal vibration mode, as well as the transient shock mode inside the cask during NCT. In conclusion, dynamic analyses were performed in the frequency domain to study frequency characteristic of the fuel assembly system and in the time domain to simulate the transient dynamic response of the fuel assembly.

  8. Nuclear materials transportation workshops: USDOE outreach to local governments. Final report

    SciTech Connect

    Not Available

    1987-09-28

    To provide direct outreach to local governments, the Transportation Management Division of the United States Department of Energy asked the Urban Consortium and its Energy Task Force to assemble representatives for two workshops focusing on the transport of nuclear materials. The first session, for jurisdictions east of the Mississippi River, was held in New Orleans on May 5--6, 1988; the second was conducted on June 6--7, 1988 in Denver for jurisdictions to the west. Twenty local government professionals with management or operational responsibility for hazardous materials transportation within their jurisdictions were selected to attend each workshop. The discussions identified five major areas of concern to local government professionals; coordination; training; information resources; marking and placarding; and responder resources. Integrated federal, state, and local levels of government emerged as a priority coordination issue along with the need for expanded availability of training and training resources for first-reponders.

  9. New approach to creation of geometrical module for nuclear reactor neutron transport computer simulation analysis

    SciTech Connect

    Poveschenko, T.; Poveschenko, O.

    2012-07-01

    This paper presents the new approach to creation of geometrical module for nuclear reactor neutron transport computer simulation analysis so called the differential cross method. It is elaborated for detecting boards between physical zones. It is proposed to use GMSH open source mesh editor extended by some features: a special option and a special kind of mesh (cubic background mesh).This method is aimed into Monte Carlo Method as well as for deterministic neutron transport methods. Special attention is attended for reactor core composed of a set of material zones with complicate geometrical boundaries. The idea of this approach is described. In general case method works for 3-D space. Algorithm of creation of the geometrical module is given. 2-D neutron transport benchmark-test for RBMK reactor cluster cell is described. It demonstrates the ability of this approach to provide flexible definition of geometrical meshing with preservation of curved surface or any level of heterogeneity. (authors)

  10. Sources of inner radiation zone energetic helium ions: cross-field transport versus in-situ nuclear reactions.

    PubMed

    Spjeldvik, W N; Pugacheva, G I; Gusev, A A; Martin, I M; Sobolevsky, N M

    1998-01-01

    Radial transport theory for inner radiation zone MeV He ions has been extended by combining radial diffusive transport, losses due to Coulomb friction and charge exchange reaction with local generation of 3He and 4He ions due to nuclear reactions taking place on the inner edge of the inner radiation zone. From interactions between high energy trapped protons and upper atmospheric constituents we have included a nuclear reaction yield helium flux source that was numerically derived from a nuclear reaction model originally developed at the Institute of Nuclear Researches of Moscow, Russia and implemented in the computer system at the University of Campinas, Brazil. Magnetospheric transport computations have been made covering the L-shell range L=1.0 to 1.6 and the resulting MeV He ion flux distributions show a strong influence of the local nuclear source mechanism on the inner zone energetic He ion content.

  11. Assessment of hydrologic transport of radionuclides from the Rio Blanco underground nuclear test site, Colorado

    SciTech Connect

    Chapman, J.; Earman, S.; Andricevic, R.

    1996-10-01

    DOE is operating an environmental restoration program to characterize, remediate, and close non-Nevada Test Site locations used for nuclear testing. Evaluation of radionuclide transport by groundwater is part of preliminary risk analysis. These evaluations allow prioritization of test areas in terms of risk, provide a basis for discussions with regulators and the public about future work, and provide a framework for assessing site characterization data needs. The Rio Blanco site in Colorado was the location of the simultaneous detonation of three 30-kiloton nuclear devices. The devices were located 1780, 1899, and 2039 below ground surface in the Fort Union and Mesaverde formations. Although all the bedrock formations at the site are thought to contain water, those below the Green River Formation (below 1000 in depth) are also gas-bearing, and have very low permeabilities. The transport scenario evaluated was the migration of radionuclides from the blast-created cavity through the Fort Union Formation. Transport calculations were performed using the solute flux method, with input based on the limited data available for the site. Model results suggest that radionuclides from the test are contained entirely within the area currently administered by DOE. This modeling was performed to investigate how the uncertainty in various physical parameters affect radionuclide transport at the site, and to serve as a starting point for discussion regarding further investigation; it was not intended to be a definitive simulation of migration pathways or radionuclide concentration values. Given the sparse data, the modeling results may differ significantly from reality. Confidence in transport predictions can be increased by obtaining more site data, including the amount of radionuclides which would have been available for transport (i.e., not trapped in melt glass or vented during gas flow testing), and the hydraulic properties of the formation. 38 refs., 6 figs., 1 tab.

  12. Rapid Isolation of Nuclear Transport-Competent Xenopus Nucleoplasmin Produced in Escherichia coli Strain BL21(DE3)

    DTIC Science & Technology

    1994-01-01

    method to produce nuclear transport-competent nucleo-plasmin avoids the lengthy purification procedure used to isolate nucleoplasmin from Xenopus laevis oocytes as well as the cost of purchasing and maintaining a toad colony.

  13. Cell penetrating peptide inhibitors of Nuclear Factor-kappa B

    PubMed Central

    Orange, J. S.; May, M. J.

    2010-01-01

    The nuclear factor kappa B (NF-κB) transcription factors are activated by a range of stimuli including pro-inflammatory cytokines. Active NF-κB regulates the expression of genes involved in inflammation and cell survival and aberrant NF-κB activity plays pathological roles in certain types of cancer and diseases characterized by chronic inflammation. NF-κB signaling is an attractive target for the development of novel anti-inflammatory or anti-cancer drugs and we discuss here how the method of peptide transduction has been used to specifically target NF-κB. Peptide transduction relies on the ability of certain small cell-penetrating peptides (CPPs) to enter cells, and a panel of CPP-linked inhibitors (CPP-Is) has been developed to directly inhibit NF-κB signaling. Remarkably, several of these NF-κB-targeting CPP-Is are effective in vivo and therefore offer exciting potential in the clinical setting. PMID:18668204

  14. Factors involved in the systemic transport of plant RNA viruses: the emerging role of the nucleus.

    PubMed

    Solovyev, Andrey G; Savenkov, Eugene I

    2014-04-01

    Compatible virus-host interactions depend on a suitable milieu in the host cells permitting viral gene expression, replication, and spread. During pathogenesis, viruses hijack the plant cellular machinery to access molecules, subcellular structures, and host transport pathways needed for infection. Vascular trafficking of virus transport forms (VTF) within the phloem is a crucial step in setting-up virus infection within the entire plant. Moreover, vascular trafficking is an essential step for the further transmission of the viruses by their natural vectors as movement of the viruses to the distant parts of the plant from the initial site of infection guarantees accessibility of the virus particle for vector transmission. With the recent advances in the field of plant virology several emerging themes of viral systemic movement occur linking the role of virus-mediated transcriptional reprogramming and nuclear factors in vascular trafficking. Recent studies have uncovered host factors involved in virus vascular trafficking. Surprisingly, it appears that the role of the nucleus and nuclear factors in virus movement is still under-appreciated. This review describes how these new themes started to emerge by using two contrasting modes of virus vascular trafficking. It is argued that the translocation of viral movement proteins into the nuclei is, in many cases, an essential step in promoting virus systemic infection.

  15. Land and Water Use, CO2 Emissions, and Worker Radiological Exposure Factors for the Nuclear Fuel Cycle

    SciTech Connect

    Brett W Carlsen; Brent W Dixon; Urairisa Pathanapirom; Eric Schneider; Bethany L. Smith; Timothy M. AUlt; Allen G. Croff; Steven L. Krahn

    2013-08-01

    The Department of Energy Office of Nuclear Energy’s Fuel Cycle Technologies program is preparing to evaluate several proposed nuclear fuel cycle options to help guide and prioritize Fuel Cycle Technology research and development. Metrics are being developed to assess performance against nine evaluation criteria that will be used to assess relevant impacts resulting from all phases of the fuel cycle. This report focuses on four specific environmental metrics. • land use • water use • CO2 emissions • radiological Dose to workers Impacts associated with the processes in the front-end of the nuclear fuel cycle, mining through enrichment and deconversion of DUF6 are summarized from FCRD-FCO-2012-000124, Revision 1. Impact estimates are developed within this report for the remaining phases of the nuclear fuel cycle. These phases include fuel fabrication, reactor construction and operations, fuel reprocessing, and storage, transport, and disposal of associated used fuel and radioactive wastes. Impact estimates for each of the phases of the nuclear fuel cycle are given as impact factors normalized per unit process throughput or output. These impact factors can then be re-scaled against the appropriate mass flows to provide estimates for a wide range of potential fuel cycles. A companion report, FCRD-FCO-2013-000213, applies the impact factors to estimate and provide a comparative evaluation of 40 fuel cycles under consideration relative to these four environmental metrics.

  16. DOS-HEATING6: A general conduction code with nuclear heat generation derived from DOT-IV transport calculations

    SciTech Connect

    Williams, M.L.; Yuecel, A.; Nadkarny, S.

    1988-05-01

    The HEATING6 heat conduction code is modified to (a) read the multigroup particle fluxes from a two-dimensional DOT-IV neutron- photon transport calculation, (b) interpolate the fluxes from the DOT-IV variable (optional) mesh to the HEATING6 control volume mesh, and (c) fold the interpolated fluxes with kerma factors to obtain a nuclear heating source for the heat conduction equation. The modified HEATING6 is placed as a module in the ORNL discrete ordinates system (DOS), and has been renamed DOS-HEATING6. DOS-HEATING6 provides the capability for determining temperature distributions due to nuclear heating in complex, multi-dimensional systems. All of the original capabilities of HEATING6 are retained for the nuclear heating calculation; e.g., generalized boundary conditions (convective, radiative, finned, fixed temperature or heat flux), temperature and space dependent thermal properties, steady-state or transient analysis, general geometry description, etc. The numerical techniques used in the code are reviewed and the user input instructions and JCL to perform DOS-HEATING6 calculations are presented. Finally a sample problem involving coupled DOT-IV and DOS-HEATING6 calculations of a complex space-reactor configurations described, and the input and output of the calculations are listed. 10 refs., 11 figs., 6 tabs.

  17. [Medical and hygienic aspects of instrumental supervision system over nuclear materials and radioactive substances transport on Russian Federation territory].

    PubMed

    Grabskiĭ, Iu V; Gavrish, N N; Shevchenko, G T; Viaz'min, S O; Pertsev, V S; Kirillov, V F; Tsov'ianov, A G

    2014-01-01

    Hygienic evaluation of radiation situation in operation of mobile and stationery elements within a project of national system for instrumental supervision over nuclear materials and radioactive substances transport, created with a Global initiative against nuclear terrorism. Levels of exposure to ionizing radiation of the screening complexes appeared to match requirements on radiation safety for service personnel and general population.

  18. Categorisation of nuclear explosions from legitimate radioxenon sources with atmospheric transport modelling

    NASA Astrophysics Data System (ADS)

    Schoeppner, M.; Postelt, F.; Kalinowski, M.; Plastino, W.

    2012-04-01

    Radioxenon is produced during nuclear explosions and due to its high fission ratio during the reaction and its noble gas character the isotopes can be detected remote from the location of the explosion. Therefore it is used by the Comprehensive Nuclear-Test-Ban Organization (CTBTO) as an indicator for the nuclear character of an explosion and is monitored with the International Monitoring System (IMS). The concentration of radioxenon in the air is continuously measured by multiple stations worldwide and is in need of an automatic categorization scheme in order to highlight signals of interest and to sort out signals that can be explained by legitimate sources. The dispersion and transport of radioxenon emissions through the atmosphere can be simulated with atmospheric transport modelling. Many legitimate sources of radioxenon exist: Nuclear power plants and isotope production facilities are mainly responsible for the worldwide background. The characterisation of this background is an important prerequisite to discriminate nuclear explosion signals against the background. It has been discovered that the few existing isotope production facilities are the major contributors to the background, each with emission strengths in the order of magnitude or more than all nuclear power plants together. Therefore, especially the characterization of these few, but strong, emitters can improve the quality of the signal prediction. Since the location of such an emitter is usually known the source-receptor sensitivity matrices can be utilized together with measured radioxenon concentrations from IMS stations in order to deduct information about the time dependent emissions from the strong emitter. An automatic method to determine an approximated, time dependent source term of an emitter with known location has been developed and is presented. This is a potentially valid tool for the categorization of radioxenon samples, because it can be used to assess whether the measured

  19. Thermodynamic Paradigm for Solution Demixing Inspired by Nuclear Transport in Living Cells

    NASA Astrophysics Data System (ADS)

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    2017-04-01

    Living cells display a remarkable capacity to compartmentalize their functional biochemistry. A particularly fascinating example is the cell nucleus. Exchange of macromolecules between the nucleus and the surrounding cytoplasm does not involve traversing a lipid bilayer membrane. Instead, large protein channels known as nuclear pores cross the nuclear envelope and regulate the passage of other proteins and RNA molecules. Beyond simply gating diffusion, the system of nuclear pores and associated transport receptors is able to generate substantial concentration gradients, at the energetic expense of guanosine triphosphate hydrolysis. In contrast to conventional approaches to demixing such as reverse osmosis and dialysis, the biological system operates continuously, without application of cyclic changes in pressure or solvent exchange. Abstracting the biological paradigm, we examine this transport system as a thermodynamic machine of solution demixing. Building on the construct of free energy transduction and biochemical kinetics, we find conditions for the stable operation and optimization of the concentration gradients as a function of dissipation in the form of entropy production.

  20. Plasticity of an Ultrafast Interaction between Nucleoporins and Nuclear Transport Receptors

    PubMed Central

    Milles, Sigrid; Mercadante, Davide; Aramburu, Iker Valle; Jensen, Malene Ringkjøbing; Banterle, Niccolò; Koehler, Christine; Tyagi, Swati; Clarke, Jane; Shammas, Sarah L.; Blackledge, Martin; Gräter, Frauke; Lemke, Edward A.

    2015-01-01

    Summary The mechanisms by which intrinsically disordered proteins engage in rapid and highly selective binding is a subject of considerable interest and represents a central paradigm to nuclear pore complex (NPC) function, where nuclear transport receptors (NTRs) move through the NPC by binding disordered phenylalanine-glycine-rich nucleoporins (FG-Nups). Combining single-molecule fluorescence, molecular simulations, and nuclear magnetic resonance, we show that a rapidly fluctuating FG-Nup populates an ensemble of conformations that are prone to bind NTRs with near diffusion-limited on rates, as shown by stopped-flow kinetic measurements. This is achieved using multiple, minimalistic, low-affinity binding motifs that are in rapid exchange when engaging with the NTR, allowing the FG-Nup to maintain an unexpectedly high plasticity in its bound state. We propose that these exceptional physical characteristics enable a rapid and specific transport mechanism in the physiological context, a notion supported by single molecule in-cell assays on intact NPCs. PMID:26456112

  1. A thermodynamic paradigm for solution demixing inspired by nuclear transport in living cells

    PubMed Central

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    2017-01-01

    Living cells display a remarkable capacity to compartmentalize their functional biochemistry. A particularly fascinating example is the cell nucleus. Exchange of macromolecules between the nucleus and the surrounding cytoplasm does not involve traversing a lipid bilayer membrane. Instead, large protein channels known as nuclear pores cross the nuclear envelope and regulate the passage of other proteins and RNA molecules. Beyond simply gating diffusion, the system of nuclear pores and associated transport receptors is able to generate substantial concentration gradients, at the energetic expense of guanosine triphosphate (GTP) hydrolysis. In contrast to conventional approaches to demixing such as reverse osmosis or dialysis, the biological system operates continuously, without application of cyclic changes in pressure or solvent exchange. Abstracting the biological paradigm, we examine this transport system as a thermodynamic machine of solution demixing. Building on the construct of free energy transduction and biochemical kinetics, we find conditions for stable operation and optimization of the concentration gradients as a function of dissipation in the form of entropy production. PMID:28452496

  2. CHARACTERISTICS OF NEXT-GENERATION SPENT NUCLEAR FUEL (SNF) TRANSPORT AND STORAGE CASKS

    SciTech Connect

    Haire, M.J.; Forsberg, C.W.; Matveev, V.Z.; Shapovalov, V.I.

    2004-10-03

    The design of spent nuclear fuel (SNF) casks used in the present SNF disposition systems has evolved from early concepts about the nuclear fuel cycle. The reality today is much different from that envisioned by early nuclear scientists. Most SNF is placed in pool storage, awaiting reprocessing (as in Russia) or disposal at a geologic SNF repository (as in the United States). Very little transport of SNF occurs. This paper examines the requirements for SNF casks from today's perspective and attempts to answer this question: What type of SNF cask would be produced if we were to start over and design SNF casks based on today's requirements? The characteristics for a next-generation SNF cask system are examined and are found to be essentially the same in Russia and the United States. It appears that the new depleted uranium dioxide (DUO2)-steel cermet material will enable these requirements to be met. Depleted uranium (DU) is uranium in which a portion of the 235U isotope has been removed during a uranium enrichment process. The DUO2-steel cermet material is described. The United States and Russia are cooperating toward the development of a next-generation, dual-purpose, storage and transport SNF system.

  3. Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors.

    PubMed

    Milles, Sigrid; Mercadante, Davide; Aramburu, Iker Valle; Jensen, Malene Ringkjøbing; Banterle, Niccolò; Koehler, Christine; Tyagi, Swati; Clarke, Jane; Shammas, Sarah L; Blackledge, Martin; Gräter, Frauke; Lemke, Edward A

    2015-10-22

    The mechanisms by which intrinsically disordered proteins engage in rapid and highly selective binding is a subject of considerable interest and represents a central paradigm to nuclear pore complex (NPC) function, where nuclear transport receptors (NTRs) move through the NPC by binding disordered phenylalanine-glycine-rich nucleoporins (FG-Nups). Combining single-molecule fluorescence, molecular simulations, and nuclear magnetic resonance, we show that a rapidly fluctuating FG-Nup populates an ensemble of conformations that are prone to bind NTRs with near diffusion-limited on rates, as shown by stopped-flow kinetic measurements. This is achieved using multiple, minimalistic, low-affinity binding motifs that are in rapid exchange when engaging with the NTR, allowing the FG-Nup to maintain an unexpectedly high plasticity in its bound state. We propose that these exceptional physical characteristics enable a rapid and specific transport mechanism in the physiological context, a notion supported by single molecule in-cell assays on intact NPCs.

  4. Thermodynamic Paradigm for Solution Demixing Inspired by Nuclear Transport in Living Cells.

    PubMed

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    2017-04-14

    Living cells display a remarkable capacity to compartmentalize their functional biochemistry. A particularly fascinating example is the cell nucleus. Exchange of macromolecules between the nucleus and the surrounding cytoplasm does not involve traversing a lipid bilayer membrane. Instead, large protein channels known as nuclear pores cross the nuclear envelope and regulate the passage of other proteins and RNA molecules. Beyond simply gating diffusion, the system of nuclear pores and associated transport receptors is able to generate substantial concentration gradients, at the energetic expense of guanosine triphosphate hydrolysis. In contrast to conventional approaches to demixing such as reverse osmosis and dialysis, the biological system operates continuously, without application of cyclic changes in pressure or solvent exchange. Abstracting the biological paradigm, we examine this transport system as a thermodynamic machine of solution demixing. Building on the construct of free energy transduction and biochemical kinetics, we find conditions for the stable operation and optimization of the concentration gradients as a function of dissipation in the form of entropy production.

  5. [Influence of work factors on health state in personnel servicing military nuclear technical objects].

    PubMed

    Poluboiarinov, V N; Iusov, I G; Ivanchenko, A V; Turlakov, Iu S

    2014-01-01

    Complex of occupational studies and medical, statistical research helped to reveal climate, geographic and other factors influencing health state of personnel servicing military nuclear technical objects. Considering peculiarities of occupational activities in various specialists, the authors specified measures to improve medical service for nuclear technical military officers directly working with nuclear ammunition. Practical application of the measures helped to gain 1.5-1.7 times improvement in morbidity parameters among nuclear technical military officers.

  6. Bim Nuclear Translocation and Inactivation by Viral Interferon Regulatory Factor

    PubMed Central

    Choi, Young Bong; Nicholas, John

    2010-01-01

    Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8 (HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors (vIRFs 1–4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFβ receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, co-localization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication

  7. Transporter-Mediated Nuclear Entry of Jasmonoyl-Isoleucine Is Essential for Jasmonate Signaling.

    PubMed

    Li, Qingqing; Zheng, Jian; Li, Shuaizhang; Huang, Guanrong; Skilling, Stephen J; Wang, Lijian; Li, Ling; Li, Mengya; Yuan, Lixing; Liu, Pei

    2017-02-05

    To control gene expression by directly responding to hormone concentrations, both animal and plant cells have exploited comparable mechanisms to sense small-molecule hormones in nucleus. Whether nuclear entry of these hormones is actively transported or passively diffused, as conventionally postulated, through the nuclear pore complex, remains enigmatic. Here, we identified and characterized a jasmonate transporter in Arabidopsis thaliana, AtJAT1/AtABCG16, which exhibits an unexpected dual localization at the nuclear envelope and plasma membrane. We show that AtJAT1/AtABCG16 controls the cytoplasmic and nuclear partition of jasmonate phytohormones by mediating both cellular efflux of jasmonic acid (JA) and nuclear influx of jasmonoyl-isoleucine (JA-Ile), and is essential for maintaining a critical nuclear JA-Ile concentration to activate JA signaling. These results illustrate that transporter-mediated nuclear entry of small hormone molecules is a new mechanism to regulate nuclear hormone signaling. Our findings provide an avenue to develop pharmaceutical agents targeting the nuclear entry of small molecules.

  8. The Pseudorabies Virus DNA Polymerase Accessory Subunit UL42 Directs Nuclear Transport of the Holoenzyme

    PubMed Central

    Wang, Yi-Ping; Du, Wen-Juan; Huang, Li-Ping; Wei, Yan-Wu; Wu, Hong-Li; Feng, Li; Liu, Chang-Ming

    2016-01-01

    Pseudorabies virus (PRV) DNA replication occurs in the nuclei of infected cells and requires the viral DNA polymerase. The PRV DNA polymerase comprises a catalytic subunit, UL30, and an accessory subunit, UL42, that confers processivity to the enzyme. Its nuclear localization is a prerequisite for its enzymatic function in the initiation of viral DNA replication. However, the mechanisms by which the PRV DNA polymerase holoenzyme enters the nucleus have not been determined. In this study, we characterized the nuclear import pathways of the PRV DNA polymerase catalytic and accessory subunits. Immunofluorescence analysis showed that UL42 localizes independently in the nucleus, whereas UL30 alone predominantly localizes in the cytoplasm. Intriguingly, the localization of UL30 was completely shifted to the nucleus when it was coexpressed with UL42, demonstrating that nuclear transport of UL30 occurs in an UL42-dependent manner. Deletion analysis and site-directed mutagenesis of the two proteins showed that UL42 contains a functional and transferable bipartite nuclear localization signal (NLS) at amino acids 354–370 and that K354, R355, and K367 are important for the NLS function, whereas UL30 has no NLS. Coimmunoprecipitation assays verified that UL42 interacts with importins α3 and α4 through its NLS. In vitro nuclear import assays demonstrated that nuclear accumulation of UL42 is a temperature- and energy-dependent process and requires both importins α and β, confirming that UL42 utilizes the importin α/β-mediated pathway for nuclear entry. In an UL42 NLS-null mutant, the UL42/UL30 heterodimer was completely confined to the cytoplasm when UL42 was coexpressed with UL30, indicating that UL30 utilizes the NLS function of UL42 for its translocation into the nucleus. Collectively, these findings suggest that UL42 contains an importin α/β-mediated bipartite NLS that transports the viral DNA polymerase holoenzyme into the nucleus in an in vitro expression system

  9. Comprehensive transportation risk assessment system based on unit-consequence factors

    SciTech Connect

    Biwer, B.M.; Monette, F.A.; LePoire, D.J.; Chen, S.Y.

    1994-02-01

    The U.S. Department of Energy (DOE) Environmental Restoration and Waste Management Programmatic Environmental Impact Statement requires a comprehensive transportation risk analysis of radioactive waste shipments for large shipping campaigns. Thousands of unique shipments involving truck and rail transport must be analyzed; a comprehensive risk analysis is impossible with currently available methods. Argonne National Laboratory developed a modular transportation model that can handle the demands imposed by such an analysis. The modular design of the model facilitates the simple addition/updating of transportation routes and waste inventories, as required, and reduces the overhead associated with file maintenance and quality assurance. The model incorporates unit-consequences factors generated with the RADTRAN 4 transportation risk analysis code that are combined with an easy-to-use, menu-driven interface on IBM-compatible computers running under DOS. User selection of multiple origin/destination site pairs for the shipment of multiple radioactive waste inventories is permitted from pop-up lists. Over 800 predefined routes are available among more than 30 DOE sites and waste inventories that include high-level waste, spent nuclear fuel, transuranic waste, low-level waste, low-level mixed waste, and greater-than-Class C waste.

  10. Analysis of the risk of transporting spent nuclear fuel by train

    SciTech Connect

    Elder, H.K.

    1981-09-01

    This report uses risk analyses to analyze the safety of transporting spent nuclear fuel for commercial rail shipping systems. The rail systems analyzed are those expected to be used in the United States when the total electricity-generating capacity by nuclear reactors is 100 GW in the late 1980s. Risk as used in this report is the product of the probability of a release of material to the environment and the consequences resulting from the release. The analysis includes risks in terms of expected fatalities from release of radioactive materials due to transportation accidents involving PWR spent fuel shipped in rail casks. The expected total risk from such shipments is 1.3 x 10/sup -4/ fatalities per year. Risk spectrums are developed for shipments of spent fuel that are 180 days and 4 years out-of-reactor. The risk from transporting spent fuel by train is much less (by 2 to 4 orders of magnitude) than the risk to society from other man-caused events such as dam failure.

  11. SUBSELENE: a nuclear powered melt tunneling concept for high-speed lunar subsurface transportation tunnels

    SciTech Connect

    Neudecker, J.W. Jr.; Blacic, J.D.; Rowley, J.C.

    1986-01-01

    High-speed lunar surface transportation between manned scientific, commercial, or logistical facilities will require subsurface tunnels because humans must be shielded from Galactic Cosmic Ray and Solar Proton Event irradiations. We present a concept called SUBSELENE in which heat from a nuclear reactor is used to melt rock and form a self-supporting, glass-lined tunnel suitable for Maglev or other high-speed transport modes. We argue that SUBSELENE is an optimal approach to forming transportation tunnels on the Moon because: (1) it uses a high-energy-density, high-efficiency, nuclear power supply; (2) it does not require water or other rare volatiles for upon system muck handling or cooling; (3) it can penetrate through a mechanically varied sequence of rock types without complicated configurational changes; (4) it forms its own support structure as it goes; and (5) it is highly amenable to unmanned, automated operation. We outline the R and D needed to develop a SUBSELENE device and give a cost estimate based on experience with small-scale, field-tested, rock-melting penetrators.

  12. Nuclear factor one transcription factors: divergent functions in developmental versus adult stem cell populations

    PubMed Central

    Harris, Lachlan; Genovesi, Laura A.; Gronostajski, Richard M.; Wainwright, Brandon J.; Piper, Michael

    2014-01-01

    Nuclear factor one (NFI) transcription factors are a group of site-specific DNA-binding proteins that are emerging as critical regulators of stem cell biology. During development NFIs promote the production of differentiated progeny at the expense of stem cell fate, with Nfi null mice exhibiting defects such as severely delayed brain and lung maturation, skeletomuscular defects and renal abnormalities, phenotypes that are often consistent with patients with congenital Nfi mutations. Intriguingly, recent research suggests that in adult tissues NFI factors play a qualitatively different role than during development, with NFIs serving to promote the survival and maintenance of slow-cycling adult stem cell populations rather than their differentiation. Here we review the role of NFI factors in development, largely focusing on their role as promoters of stem cell differentiation, and attempt to reconcile this with the emerging role of NFIs in adult stem cell niches. PMID:25156673

  13. A binding site for the transcription factor Grainyhead/Nuclear transcription factor-1 contributes to regulation of the Drosophila proliferating cell nuclear antigen gene promoter.

    PubMed

    Hayashi, Y; Yamagishi, M; Nishimoto, Y; Taguchi, O; Matsukage, A; Yamaguchi, M

    1999-12-03

    The Drosophila proliferating cell nuclear antigen promoter contains multiple transcriptional regulatory elements, including upstream regulatory element (URE), DNA replication-related element, E2F recognition sites, and three common regulatory factor for DNA replication and DNA replication-related element-binding factor genes recognition sites. In nuclear extracts of Drosophila embryos, we detected a protein factor, the URE-binding factor (UREF), that recognizes the nucleotide sequence 5'-AAACCAGTTGGCA located within URE. Analyses in Drosophila Kc cells and transgenic flies revealed that the UREF-binding site plays an important role in promoter activity both in cultured cells and in living flies. A yeast one-hybrid screen using URE as a bait allowed isolation of a cDNA encoding a transcription factor, Grainyhead/nuclear transcription factor-1 (GRH/NTF-1). The nucleotide sequence required for binding to GRH was indistinguishable from that for UREF detected in embryo nuclear extracts. Furthermore, a specific antibody to GRH reacted with UREF in embryo nuclear extracts. From these results we conclude that GRH is identical to UREF. Although GRH has been thought to be involved in regulation of differentiation-related genes, this study demonstrates, for the first time, involvement of a GRH-binding site in regulation of the DNA replication-related proliferating cell nuclear antigen gene.

  14. Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport

    PubMed Central

    Ambrus, Géza; Whitby, Landon R.; Singer, Eric L.; Trott, Oleg; Choi, Euna; Olson, Arthur J.; Boger, Dale L.; Gerace, Larry

    2010-01-01

    Nucleocytoplasmic transport of macromolecules is a fundamental process of eukaryotic cells. Translocation of proteins and many RNAs between the nucleus and cytoplasm is carried out by shuttling receptors of the β-karyopherin family, also called importins and exportins. Leptomycin B, a small molecule inhibitor of the exportin CRM1, has proved to be an invaluable tool for cell biologists, but up to now no small molecule inhibitors of nuclear import have been described. We devised a microtiter plate based permeabilized cell screen for small molecule inhibitors of the importin α/β pathway. By analyzing peptidomimetic libraries, we identified β-turn and α-helix peptidomimetic compounds that selectively inhibit nuclear import by importin α/β but not by transportin. Structure-activity relationship analysis showed that large aromatic residues and/or a histidine side chain are required for effective import inhibition by these compounds. Our validated inhibitors can be useful for in vitro studies of nuclear import, and can also provide a framework for synthesis of higher potency nuclear import inhibitors. PMID:20869252

  15. Characterization of a baculovirus nuclear localization signal domain in the late expression factor 3 protein

    SciTech Connect

    Au, Victoria; Yu Mei; Carstens, Eric B.

    2009-03-01

    The baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) single-stranded DNA binding protein LEF-3 is a multi-functional protein that is required to transport the helicase protein P143 into the nucleus of infected cells where they function to replicate viral DNA. The N-terminal 56 amino acid region of LEF-3 is required for nuclear transport. In this report, we analyzed the effect of site-specific mutagenesis of LEF-3 on its intracellular distribution. Fluorescence microscopy of expression plasmid-transfected cells demonstrated that the residues 28 to 32 formed the core nuclear localization signal, but other adjacent positively-charged residues augmented these sequences. Comparison with other group I Alphabaculoviruses suggested that this core region functionally duplicated residues including 18 and 19. This was demonstrated by the loss of nuclear localization when the equivalent residues (18 to 20) in Choristoneura fumiferana nucleopolyhedrovirus (CfMNPV) LEF-3 were mutated. The AcMNPV LEF-3 nuclear localization domain was also shown to drive nuclear transport in mammalian cells indicating that the protein nuclear import systems in insect and mammalian cells are conserved. We also demonstrated by mutagenesis that two conserved cysteine residues located at 82 and 106 were not essential for nuclear localization or for interaction with P143. However, by using a modified construct of P143 that localized on its own to the nucleus, we demonstrated that a functional nuclear localization domain on LEF-3 was required for interaction between LEF-3 and P143.

  16. A Novel Nuclear Import Pathway for the Transcription Factor TFIIS

    PubMed Central

    Albertini, Markus; Pemberton, Lucy F.; Rosenblum, Jonathan S.; Blobel, Günter

    1998-01-01

    We have identified a novel pathway for protein import into the nucleus. We have shown that the previously identified but uncharacterized yeast protein Nmd5p functions as a karyopherin. It was therefore designated Kap119p (karyopherin with Mr of 119 kD). We localized Kap119p to both the nucleus and the cytoplasm. We identified the transcription elongation factor TFIIS as its major cognate import substrate. The cytoplasmic Kap119p exists as an approximately stoichiometric complex with TFIIS. RanGTP, not RanGDP, dissociated the isolated Kap119p/TFIIS complex and bound to Kap119p. Kap119p also bound directly to a number of peptide repeat containing nucleoporins in overlay assays. In wild-type cells, TFIIS was primarily localized to the nucleus. In a strain where KAP119 has been deleted, TFIIS was mislocalized to the cytoplasm indicating that TFIIS is imported into the nucleus by Kap119p. The transport of various substrates that use other karyopherin-mediated import or export pathways was not affected in a kap119Δ strain. Hence Kap119p is a novel karyopherin that is responsible for the import of the transcription elongation factor TFIIS. PMID:9852143

  17. Modern tools to study nuclear pore complexes and nucleocytoplasmic transport in Caenorhabditis elegans.

    PubMed

    Askjaer, Peter; Galy, Vincent; Meister, Peter

    2014-01-01

    The nematode Caenorhabditis elegans is characterized by many features that make it highly attractive to study nuclear pore complexes (NPCs) and nucleocytoplasmic transport. NPC composition and structure are highly conserved in nematodes and being amenable to a variety of genetic manipulations, key aspects of nuclear envelope dynamics can be observed in great details during breakdown, reassembly, and interphase. In this chapter, we provide an overview of some of the most relevant modern techniques that allow researchers unfamiliar with C. elegans to embark on studies of nucleoporins in an intact organism through its development from zygote to aging adult. We focus on methods relevant to generate loss-of-function phenotypes and their analysis by advanced microscopy. Extensive references to available reagents, such as mutants, transgenic strains, and antibodies are equally useful to scientists with or without prior C. elegans or nucleoporin experience. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Release and transport of gaseous C-14 from a nuclear waste repository in an unsaturated medium

    SciTech Connect

    Light, W.B.; Zwahlen, E.D.; Pigford, T.H.; Chambre, P.L.; Lee, W.W.L.

    1990-11-01

    The potential nuclear waste repository at Yucca Mountain is to be in partially saturated rock. Released radioactive gases such as {sup 14}CO{sub 2} could have a direct pathway to the biosphere. We study the release of {sup 14}C released as {sup 14}CO{sub 2} from partly failed nuclear waste containers by analyzing the flow of gas into and out of a container. We analyze the transport of released {sup 14}CO{sub 2} in an unsaturated, fractured, porous medium with gas-phase advection and dispersion. We calculate the inhalation dose to a maximally exposed individual above ground, based on some conservative assumptions about release from containers. For the assumed parameter values, a simple atmospheric diffusion model gives very small doses when compared to background radiation doses. 12 refs., 4 figs., 1 tab.

  19. Nuclear winter - Three-dimensional simulations including interactive transport, scavenging, and solar heating of smoke

    NASA Technical Reports Server (NTRS)

    Malone, R. C.; Auer, L. H.; Glatzmaier, G. A.; Wood, M. C.; Toon, O. B.

    1986-01-01

    A reexamination is conducted of the 'nuclear winter' hypothesis with a three-dimensional global model modified to allow for localized injection of smoke, its transport by the simulated winds, its absorption of sunlight, and its removal by model-simulated precipitation. Smoke injected into the troposphere is driven upward by solar heating. The tropopause, initially above the smoke, reforms below the heat smoke layer and separates it from precipitation below. Although much smoke is scavenged while the thermal structure is being altered, the residence time of the remaining smoke is greatly increased. Particularly for July conditions, a longer-lasting 'nuclear winter' effect is observed than was found in earlier modeling studies in which normal tropospheric residence times were assumed. In January the smaller solar flux in the northern hemisphere allows faster removal of smoke than in July. Significant cooling of the northern hemisphere continents is predicted; its dependence on season and injected smoke mass is described.

  20. Effects of psychotropic drugs on Nuclear Factor kappa B.

    PubMed

    Troib, A; Azab, A N

    2015-04-01

    Mental disorders affect millions of people worldwide and are associated with a huge suffering and unbearable burden for patients and their care givers. The pathophysiology of mental disorders is not fully understood. In recent years, accumulating data suggest that inflammation may play a role in the pathogenesis of these illnesses and that psychotropic drugs exert some anti-inflammatory effects. Nuclear Factor κB (NF-κB) is a cellular pathway that has a prominent influence on immune and inflammatory responses in humans. Numerous studies examined the effects of psychotropic drugs on different inflammatory mediators (particularly cytokines) both in vitro and in vivo. However, relatively few studies investigated the effects of those drugs on NF-κB. This is quite surprising considering the pivotal role of NF-κB in promoting inflammation. The aim of this article is to review the data over the effects of psychotropic drugs on the NF-κB pathway. Overall, the summarized studies suggest that some psychotropic drugs (such as lithium and imipramine) exert potent inhibitory effects on NF-κB, while the results on other drugs are not conclusive and occasionally contradicting. The discrepancy in the results of different studies seems to derive from the various experimental conditions under which the drugs were tested.

  1. Observation of hysteretic transport due to dynamic nuclear spin polarization in a GaAs lateral double quantum dot.

    PubMed

    Kobayashi, Takashi; Hitachi, Kenichi; Sasaki, Satoshi; Muraki, Koji

    2011-11-18

    We report a new transport feature in a GaAs lateral double quantum dot that emerges for magnetic-field sweeps and shows hysteresis due to dynamic nuclear spin polarization (DNP). This DNP signal appears in the Coulomb blockade regime by virtue of the finite interdot tunnel coupling and originates from the crossing between ground levels of the spin triplet and singlet extensively used for nuclear spin manipulations in pulsed-gate experiments. The magnetic-field dependence of the current level is suggestive of unbalanced DNP between the two dots, which opens up the possibility of controlling electron and nuclear spin states via dc transport.

  2. Nuclear factor Y regulates ancient budgerigar hepadnavirus core promoter activity.

    PubMed

    Shen, Zhongliang; Liu, Yanfeng; Luo, Mengjun; Wang, Wei; Liu, Jing; Liu, Wei; Pan, Shaokun; Xie, Youhua

    2016-09-16

    Endogenous viral elements (EVE) in animal genomes are the fossil records of ancient viruses and provide invaluable information on the origin and evolution of extant viruses. Extant hepadnaviruses include avihepadnaviruses of birds and orthohepadnaviruses of mammals. The core promoter (Cp) of hepadnaviruses is vital for viral gene expression and replication. We previously identified in the budgerigar genome two EVEs that contain the full-length genome of an ancient budgerigar hepadnavirus (eBHBV1 and eBHBV2). Here, we found eBHBV1 Cp and eBHBV2 Cp were active in several human and chicken cell lines. A region from nt -85 to -11 in eBHBV1 Cp was critical for the promoter activity. Bioinformatic analysis revealed a putative binding site of nuclear factor Y (NF-Y), a ubiquitous transcription factor, at nt -64 to -50 in eBHBV1 Cp. The NF-Y core binding site (ATTGG, nt -58 to -54) was essential for eBHBV1 Cp activity. The same results were obtained with eBHBV2 Cp and duck hepatitis B virus Cp. The subunit A of NF-Y (NF-YA) was recruited via the NF-Y core binding site to eBHBV1 Cp and upregulated the promoter activity. Finally, the NF-Y core binding site is conserved in the Cps of all the extant avihepadnaviruses but not of orthohepadnaviruses. Interestingly, a putative and functionally important NF-Y core binding site is located at nt -21 to -17 in the Cp of human hepatitis B virus. In conclusion, our findings have pinpointed an evolutionary conserved and functionally critical NF-Y binding element in the Cps of avihepadnaviruses.

  3. Cadmium in rice: Transport mechanisms, influencing factors, and minimizing measures.

    PubMed

    Li, Hui; Luo, Na; Li, Yan Wen; Cai, Quan Ying; Li, Hui Yuan; Mo, Ce Hui; Wong, Ming Hung

    2017-05-01

    Cadmium (Cd) accumulation in rice and its subsequent transfer to food chain is a major environmental issue worldwide. Understanding of Cd transport processes and its management aiming to reduce Cd uptake and accumulation in rice may help to improve rice growth and grain quality. Moreover, a thorough understanding of the factors influencing Cd accumulation will be helpful to derive efficient strategies to minimize Cd in rice. In this article, we reviewed Cd transport mechanisms in rice, the factors affecting Cd uptake (including physicochemical characters of soil and ecophysiological features of rice) and discussed efficient measures to immobilize Cd in soil and reduce Cd uptake by rice (including agronomic practices, bioremediation and molecular biology techniques). These findings will contribute to ensuring food safety, and reducing Cd risk on human beings.

  4. Anomalous Solute Transport in Saturated Porous Media: Linking Transport Model Parameters to Electrical and Nuclear Magnetic Resonance Properties

    NASA Astrophysics Data System (ADS)

    Swanson, R. D.; Binley, A. M.; Keating, K.; France, S.; Osterman, G. K.; Day-Lewis, F. D.; Singha, K.

    2013-12-01

    The advection-dispersion equation fails to describe non-Fickian solute transport in saturated porous media, necessitating the use of other models. The dual-domain mass transfer (DDMT) model partitions the total porosity into mobile and less-mobile domains with solute exchange between the domains; consequently, the DDMT model can produce a better fit to breakthrough curves (BTCs) in systems defined by more- and less-mobile components. However, direct experimental estimation of DDMT model parameters such as rate of exchange and the mobile and less-mobile porosities remains elusive. Consequently, model parameters are often calculated purely as a model fitting exercise. There is a clear need for material characterization techniques that can offer some insight into the pore space geometrical arrangement, particularly if such techniques can be extended to the field scale. Here, we interpret static direct-current (DC) resistivity, complex resistivity (CR) and nuclear magnetic resonance (NMR) geophysical measurements in the characterization of mass transfer parameters. We use two different samples of the zeolite clinoptilolite, a material shown to demonstrate solute mass transfer due to a significant intragranular porosity, along with glass beads as a control. We explore the relation between geophysical and DDMT parameters in conjunction with supporting material characterization methods. Our results reveal how these geophysical measurements can offer some insight into the pore structures controlling the observed anomalous transport behavior.

  5. The Security of Russia's Nuclear Arsenal: The Human Factor

    SciTech Connect

    Ball, D.Y.

    1999-10-12

    Assertions by the Russian military that all of their nuclear weapons are secure against theft and that nuclear units within the military are somehow insulated from the problems plaguing the Russian military should not be accepted uncritically. Accordingly, we should not give unwarranted credence to the pronouncements of military figures like Cal.-Gen. Igor Valynkin, Chief of the Defense Ministry's 12th Main Directorate, which oversees the country's nuclear arsenal. He contends that ''Russian nuclear weapons are under reliable supervision'' and that ''talk about the unreliability of our control over nuclear weapons has only one pragmatic goal--to convince international society that the country is incapable of maintaining nuclear safety and to introduce international oversight over those weapons, as it is done, for example, in Iraq.'' While the comparison to Iraq is preposterous, many analysts might agree with Valynkin's sanguine appraisal of the security of Russia's nuclear weapons. In contrast, I argue that the numerous difficulties confronting the military as a whole should cause concern in the West over the security of the Russian nuclear arsenal.

  6. Reversible Bending Fatigue Test System for Investigating Vibration Integrity of Spent Nuclear Fuel during Transportation

    SciTech Connect

    Wang, Jy-An John; Wang, Hong; Bevard, Bruce Balkcom; Howard, Rob L; Flanagan, Michelle

    2013-01-01

    Transportation packages for spent nuclear fuel (SNF) must meet safety requirements under normal and accident conditions as specified by federal regulations. During transportation, SNF experiences unique conditions and challenges to cladding integrity due to the vibrational and impact loading during road or rail shipment. Oak Ridge National Laboratory (ORNL) has been developing testing capabilities that can be used to improve the understanding of the impacts on SNF integrity due to vibration loading, especially for high burn-up SNF in normal transportation operation conditions. This information can be used to meet the nuclear industry and U.S. Nuclear Regulatory Commission needs in the area of safety and security of spent nuclear fuel storage and transport operations. The ORNL developed test system can perform reversible-bending fatigue testing to evaluate both the static and dynamic mechanical response of SNF rods under simulated loads. The testing apparatus is also designed to meet the challenges of hot-cell operation, including remote installation and detachment of the SNF test specimen, in-situ test specimen deformation measurement, and implementation of a driving system suitable for use in a hot cell. The system contains a U-frame set-up equipped with uniquely designed grip rigs, to protect SNF rod and to ensure valid test results, and use of 3 specially designed LVDTs to obtain the in-situ curvature measurement. A variety of surrogate test rods have been used to develop and calibrate the test system as well as in performing a series of systematic cyclic fatigue tests. The surrogate rods include stainless steel (SS) cladding, SS cladding with cast epoxy, and SS cladding with alumina pellets inserts simulating fuel pellets. Testing to date has shown that the interface bonding between the SS cladding and the alumina pellets has a significant impact on the bending response of the test rods as well as their fatigue strength. The failure behaviors observed from

  7. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD.

    PubMed

    Boeynaems, Steven; Bogaert, Elke; Michiels, Emiel; Gijselinck, Ilse; Sieben, Anne; Jovičić, Ana; De Baets, Greet; Scheveneels, Wendy; Steyaert, Jolien; Cuijt, Ivy; Verstrepen, Kevin J; Callaerts, Patrick; Rousseau, Frederic; Schymkowitz, Joost; Cruts, Marc; Van Broeckhoven, Christine; Van Damme, Philip; Gitler, Aaron D; Robberecht, Wim; Van Den Bosch, Ludo

    2016-02-12

    Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

  8. Nuclear-polarization correction to the bound-electron g factor in heavy hydrogenlike ions.

    PubMed

    Nefiodov, A V; Plunien, G; Soff, G

    2002-08-19

    The influence of nuclear polarization on the bound-electron g factor in heavy hydrogenlike ions is investigated. Numerical calculations are performed for the K- and L-shell electrons taking into account the dominant virtual nuclear excitations. This determines the ultimate limit for tests of QED utilizing measurements of the bound-electron g factor in highly charged ions.

  9. Additional thyroid dose factor from transportation sources in Russia after the Chernobyl disaster.

    PubMed Central

    Parshkov, E M; Chebotareva, I V; Sokolov, V A; Dallas, C E

    1997-01-01

    Beginning approximately 4 years after the Chernobyl nuclear accident a steady increase in the incidence of thyroid cancer was observed in children and adolescents of the Bryansk Oblast, which received the highest level of radionuclide contaminants in Russia. We examined the spatial relationship between the residence location of patients with identified thyroid cancer (0-18 years old at the time of the accident) and a number of geographic parameters to better account for the etiology of thyroid cancer spatial distribution. Geographic parameters analyzed included spatial distribution of 137Cs and 131I in soil, population demographics, measurements and reconstructions. of absorbed thyroid 131I doses in the population, and maps of major transportation arteries. An interesting finding is the lack of a consistent correlation between the spatial distribution of radionuclides in the soil and thyroid cancer incidence. Instead, most of the thyroid cancer cases were diagnosed in settlements situated on major railways and roads. Correlating population with thyroid cancer cases and transportation arteries reveals a much higher cancer rate on or near major roads and railways than at a distance from them, again independent of radionuclide soil concentration. There are other important factors, of course, that must be considered in future evaluations of this phenomenon. These include the influence of iodine endemic zones, genetic predisposition to thyroid cancer, and duration of residence time in contaminated areas. The feasibility of radionuclide transport on railways and roads is discussed, together with the vectors for transfer of the contaminants to the human population. Developing a model to reconstruct the radiation dose to the thyroid over time in this geographic region is proposed in light of the impact of transportation arteries. Specific studies are outlined to provide the data necessary to develop this model as well as to better characterize the feasibility and

  10. Diffusion in an elastic medium: A model for macromolecule transport across the nuclear pore complex

    NASA Astrophysics Data System (ADS)

    Chakrabarti, Rajarshi; Debnath, Ananya; Sebastian, K. L.

    2014-06-01

    Nuclear pore complexes (NPCs) are very selective filters that sit on the membrane of the nucleus and monitor the transport between the cytoplasm and the nucleoplasm. For the central plug of NPC two models have been suggested in the literature. The first suggests that the plug is a reversible hydrogel while the other suggests that it is a polymer brush. Here we propose a model for the transport of a protein through the plug, which is general enough to cover both the models. The protein stretches the plug and creates a local deformation, which together with the protein, we refer to as the bubble. We start with the free energy for creation of the bubble and consider its motion within the plug. The relevant coordinate is the center of the bubble which executes random walk. We find that for faster relaxation of the gel, the diffusion of the bubble is greater.

  11. Thermally driven advection for radioxenon transport from an underground nuclear explosion

    NASA Astrophysics Data System (ADS)

    Sun, Yunwei; Carrigan, Charles R.

    2016-05-01

    Barometric pumping is a ubiquitous process resulting in migration of gases in the subsurface that has been studied as the primary mechanism for noble gas transport from an underground nuclear explosion (UNE). However, at early times following a UNE, advection driven by explosion residual heat is relevant to noble gas transport. A rigorous measure is needed for demonstrating how, when, and where advection is important. In this paper three physical processes of uncertain magnitude (oscillatory advection, matrix diffusion, and thermally driven advection) are parameterized by using boundary conditions, system properties, and source term strength. Sobol' sensitivity analysis is conducted to evaluate the importance of all physical processes influencing the xenon signals. This study indicates that thermally driven advection plays a more important role in producing xenon signals than oscillatory advection and matrix diffusion at early times following a UNE, and xenon isotopic ratios are observed to have both time and spatial dependence.

  12. Barometric gas transport along geologic faults and its application to nuclear test-ban monitoring

    SciTech Connect

    Carrigan, C.R.; Heinle, R.A.; Hudson, G.B.; Nitao, J.J.

    1996-10-01

    Nuclear explosions produce unique but rapidly decaying radionuclide gases that potentially can be used in the context of a test-ban monitoring program to identify clandestine underground testing activity. To evaluate the upward transport of such gases from an underground explosion, two, non-radioactive gas tracers, spanning a 49-fold difference in species mass, were released in a 400-m-deep, chemical explosive detonation. The more massive tracer was first detected on a fault 50 days following the detonation while the other tracer was detected 375 days after release. Models indicate that both the time scale of arrival and chromatographic behavior of transport are characteristic of barometrically induced flow in a fracture- matrix regime. For a 1-kiloton fission explosion, simulations predict that short-lived isotopes of argon and xenon would be detectable on nearby geologic faults.

  13. Morris Water Maze Training in Mice Elevates Hippocampal Levels of Transcription Factors Nuclear Factor (Erythroid-derived 2)-like 2 and Nuclear Factor Kappa B p65

    PubMed Central

    Snow, Wanda M.; Pahlavan, Payam S.; Djordjevic, Jelena; McAllister, Danielle; Platt, Eric E.; Alashmali, Shoug; Bernstein, Michael J.; Suh, Miyoung; Albensi, Benedict C.

    2015-01-01

    Research has identified several transcription factors that regulate activity-dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-κB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-κB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-κB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-κB, this study simultaneously evaluated protein levels of NF-κB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-κB p50 protein after training relative to controls, whereas NF-κB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-κB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory. PMID:26635523

  14. Nuclear factor-κB signaling contributes to mechanical ventilation-induced diaphragm weakness*.

    PubMed

    Smuder, Ashley J; Hudson, Matthew B; Nelson, W Bradley; Kavazis, Andreas N; Powers, Scott K

    2012-03-01

    Although mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation. Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin). Inhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction. Collectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation

  15. Integrated System for Retrieval, Transportation and Consolidated Storage of Used Nuclear Fuel in the US - 13312

    SciTech Connect

    Bracey, William; Bondre, Jayant; Shelton, Catherine; Edmonds, Robert

    2013-07-01

    The current inventory of used nuclear fuel assemblies (UNFAs) from commercial reactor operations in the United States totals approximately 65,000 metric tons or approximately 232,000 UNFAs primarily stored at the 104 operational reactors in the US and a small number of decommissioned reactors. This inventory is growing at a rate of roughly 2,000 to 2,400 metric tons each year, (Approx. 7,000 UNFAs) as a result of ongoing commercial reactor operations. Assuming an average of 10 metric tons per storage/transportation casks, this inventory of commercial UNFAs represents about 6,500 casks with an additional of about 220 casks every year. In January 2010, the Blue Ribbon Commission (BRC) [1] was directed to conduct a comprehensive review of policies for managing the back end of the nuclear fuel cycle and recommend a new plan. The BRC issued their final recommendations in January 2012. One of the main recommendations is for the United States to proceed promptly to develop one or more consolidated storage facilities (CSF) as part of an integrated, comprehensive plan for safely managing the back end of the nuclear fuel cycle. Based on its extensive experience in storage and transportation cask design, analysis, licensing, fabrication, and operations including transportation logistics, Transnuclear, Inc. (TN), an AREVA Subsidiary within the Logistics Business Unit, is engineering an integrated system that will address the complete process of commercial UNFA management. The system will deal with UNFAs in their current storage mode in various configurations, the preparation including handling and additional packaging where required and transportation of UNFAs to a CSF site, and subsequent storage, operation and maintenance at the CSF with eventual transportation to a future repository or recycling site. It is essential to proceed by steps to ensure that the system will be the most efficient and serve at best its purpose by defining: the problem to be resolved, the criteria to

  16. Transportation infrastructure upgrades in the South: A compilation of state plans for construction near nuclear reactor sites

    SciTech Connect

    Not Available

    1992-03-01

    There are currently 27 nuclear reactor sites located in the southern region. In many instances, the most practicable modes of transportation of spent nuclear fuel from these sites we through the use of highway and rail systems. These two transportation modes have important differences that affect their applicability; chief among these, perhaps, is the fact that while highway systems are publicly owned and maintained rail lines are owned by private entities. For this reason, track condition and maintenance, usage rates and other aspects of rail transport can vary widely. This report reviews southern state, department plans for infrastructure upgrades in the vicinity of nuclear reactor sites. This report includes a summary of planned modifications to bridges, access highways, and rail spurs (where applicable) over the next five years. The information contained herein was gathered from interviews with officials within state departments of transportation. With few exceptions, the contact person was an official within the departmental planning division.

  17. Regulation of nuclear translocation of nuclear factor-kappaB relA: evidence for complex dynamics at the single-cell level.

    PubMed Central

    Schooley, Kenneth; Zhu, Ping; Dower, Steven K; Qwarnström, Eva E

    2003-01-01

    We have analysed activation of nuclear factor-kappaB (NF-kappaB) in response to interleukin-1 (IL-1) in human fibroblasts by tracking intracellular distribution and levels of endogenous relA, NF-kappaB1 and inhibitor of kappaB (I-kappaB) alpha using semi-quantitative confocal microscopy. Nuclear translocation of endogenous relA correlated with I-kappaBalpha degradation during stimulation with IL-1, whereas no effects were seen on levels or localization of NF-kappaB1. During pathway activation, relA was transported up a concentration gradient, resulting in a 3-4-fold increase in nuclear levels, but without any significant decrease in cytoplasmic concentration. IL-1 stimulation caused translocation of only 20% of the relA, but resulted in degradation of up to 70% of the cytoplasmic I-kappaBalpha. RelA nuclear translocation in fibroblasts correlated with DNA-binding activity measured by electrophoretic mobility shift assay (EMSA), both with respect to kinetics and IL-1 concentration-dependence. Clonal populations of cells demonstrated a marked degree of heterogeneity in the response to IL-1. The single-cell assay revealed the presence of responder and non-responder subpopulations, with an enhanced proportion of responder cells, and prolonged responses at higher concentrations of IL-1. Comparing different cell types demonstrated that whereas HepG2 cells, as fibroblasts, showed good correlation between nuclear translocation of relA and activation of DNA binding by relA-containing dimers, EL4 thymoma cells showed no effect on relA localization, even during induction of significant levels NF-kappaB activity, as measured by EMSA. The analysis shows that stimulation by IL-1 results in transient perturbation of the NF-kappaB system, which cycles between the resting and active states with net redistribution of a minor proportion of its DNA-binding component. In addition, it demonstrates significant cell-to-cell variations, as well as cell-type-specific differences in net rel

  18. Up-regulation of nuclear factor E2-related factor 2 upon SVCV infection.

    PubMed

    Yang, Yi; Huang, Jian; Li, Lijuan; Lin, Li; Zhai, Yanhua; Chen, Xiaoxuan; Liu, Xueqin; Wu, Zhixin; Yuan, Junfa

    2014-09-01

    Nuclear factor E2 - related factor 2 (Nrf2) is a crucial transcription factor that regulates the basal and inducible expression of many antioxidant response element (ARE)-dependent genes, including heme oxygenase-1 (HO-1) and superoxide dismutase 1 (SOD1). The Nrf2/ARE pathway has been regarded as a critical switch in the initiation of cellular defence systems for surviving oxidative insults and viral infection. In this study, the Nrf2 gene of EPC cells, which is originally derived from Pimephales promelas, was cloned, and an investigation on the interactions between Nrf2 and spring viraemia of carp virus (SVCV) was performed. These results demonstrated that the virus facilitated the nuclear accumulation of Nrf2 and up-regulated its transcriptional and protein profiles in EPC cells. In addition, exogenous activation of Nrf2 conferred EPC cells with a higher cellular total antioxidant capacity via an increase in the expression of HO-1 and SOD1, but did not suppress the replication of SVCV. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Drug-Metabolizing Enzyme, Transporter and Nuclear Receptor Genetically Modified Mouse Models

    PubMed Central

    Jiang, Xi-Ling; Gonzalez, Frank J.; Yu, Ai-Ming

    2011-01-01

    Determining the in vivo significance of a specific enzyme, transporter or xenobiotic receptor in drug metabolism and pharmacokinetics may be hampered by gene multiplicity and complexity, levels of expression and interaction between various components involved. The development of knockout (loss-of-function) and transgenic (gain-of-function) mouse models opens the door to the improved understanding of gene function in a whole body system. There is also growing interest in the development of humanized mice to overcome species difference in drug metabolism and disposition. This review, therefore, aims to summarize and discuss some successful examples of drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. These genetically modified mouse models have proven as invaluable models for understanding in vivo function of drug-metabolizing enzymes, transporters and xenobiotic receptors in drug metabolism and transport, as well as predicting potential drug-drug interaction and toxicity in humans. Nevertheless, concerns remain about interpretation of data obtained from such genetically modified mouse models in which the expression of related genes is altered significantly. PMID:20854191

  20. Molecular Architecture of the Transport Channel of the Nuclear Pore Complex

    PubMed Central

    Solmaz, Sozanne R.; Chauhan, Radha; Blobel, Günter; Melčák, Ivo

    2012-01-01

    SUMMARY The nuclear pore complex encloses a central channel for nucleocytoplasmic transport, which is thought to consist of three nucleoporins, Nup54, Nup58, and Nup62. However, the structure and composition of the channel are elusive. We determined the crystal structures of the interacting domains between these nucleoporins and pieced together the molecular architecture of the mammalian transport channel. Located in the channel midplane is a flexible Nup54·Nup58 ring that can undergo large rearrangements yielding diameter changes from ~20 to ~40 nm. Nup62·Nup54 triple helices project alternately up and down from either side of the midplane ring and form nucleoplasmic and cytoplasmic entries. The channel consists of as many as 224 copies of the three nucleoporins, amounting to a molar mass of 12.3 MDa and contributing 256 phenylalanine-glycine repeat regions. We propose that the occupancy of these repeat regions with transport receptors modulates ring diameter and transport activity. PMID:22036567

  1. Measurement and modelling of reactive transport in geological barriers for nuclear waste containment.

    PubMed

    Xiong, Qingrong; Joseph, Claudia; Schmeide, Katja; Jivkov, Andrey P

    2015-11-11

    Compacted clays are considered as excellent candidates for barriers to radionuclide transport in future repositories for nuclear waste due to their very low hydraulic permeability. Diffusion is the dominant transport mechanism, controlled by a nano-scale pore system. Assessment of the clays' long-term containment function requires adequate modelling of such pore systems and their evolution. Existing characterisation techniques do not provide complete pore space information for effective modelling, such as pore and throat size distributions and connectivity. Special network models for reactive transport are proposed here using the complimentary character of the pore space and the solid phase. This balances the insufficient characterisation information and provides the means for future mechanical-physical-chemical coupling. The anisotropy and heterogeneity of clays is represented using different length parameters and percentage of pores in different directions. Resulting networks are described as mathematical graphs with efficient discrete calculus formulation of transport. Opalinus Clay (OPA) is chosen as an example. Experimental data for the tritiated water (HTO) and U(vi) diffusion through OPA are presented. Calculated diffusion coefficients of HTO and uranium species are within the ranges of the experimentally determined data in different clay directions. This verifies the proposed pore network model and validates that uranium complexes are diffusing as neutral species in OPA. In the case of U(vi) diffusion the method is extended to account for sorption and convection. Rather than changing pore radii by coarse grained mathematical formula, physical sorption is simulated in each pore, which is more accurate and realistic.

  2. Nuclear pore localization and nucleocytoplasmic transport of eIF-5A: evidence for direct interaction with the export receptor CRM1.

    PubMed

    Rosorius, O; Reichart, B; Krätzer, F; Heger, P; Dabauvalle, M C; Hauber, J

    1999-07-01

    Eukaryotic initiation factor 5A (eIF-5A) is the only cellular protein known to contain the unusual amino acid hypusine. The exact in vivo function of eIF-5A, however, is to date unknown. The finding that eIF-5A is an essential cofactor of the human immunodeficiency virus type 1 (HIV-1) Rev RNA transport factor suggested that eIF-5A is part of a specific nuclear export pathway. In this study we used indirect immunofluorescence and immunogold electron microscopy to demonstrate that eIF-5A accumulates at nuclear pore-associated intranuclear filaments in mammalian cells and Xenopus oocytes. We are able to show that eIF-5A interacts with the general nuclear export receptor, CRM1. Furthermore, microinjection studies in somatic cells revealed that eIF-5A is transported from the nucleus to the cytoplasm, and that this nuclear export is blocked by leptomycin B. Our data demonstrate that eIF-5A is a nucleocytoplasmic shuttle protein.

  3. Cloning animals by somatic cell nuclear transfer – biological factors

    PubMed Central

    Tian, X Cindy; Kubota, Chikara; Enright, Brian; Yang, Xiangzhong

    2003-01-01

    Cloning by nuclear transfer using mammalian somatic cells has enormous potential application. However, somatic cloning has been inefficient in all species in which live clones have been produced. High abortion and fetal mortality rates are commonly observed. These developmental defects have been attributed to incomplete reprogramming of the somatic nuclei by the cloning process. Various strategies have been used to improve the efficiency of nuclear transfer, however, significant breakthroughs are yet to happen. In this review we will discuss studies conducted, in our laboratories and those of others, to gain a better understanding of nuclear reprogramming. Because cattle are a species widely used for nuclear transfer studies, and more laboratories have succeeded in cloning cattle than any other specie, this review will be focused on somatic cell cloning of cattle. PMID:14614770

  4. DUSCOBS - a depleted-uranium silicate backfill for transport, storage, and disposal of spent nuclear fuel

    SciTech Connect

    Forsberg, C.W.; Pope, R.B.; Ashline, R.C.; DeHart, M.D.; Childs, K.W.; Tang, J.S.

    1995-11-30

    A Depleted Uranium Silicate COntainer Backfill System (DUSCOBS) is proposed that would use small, isotopically-depleted uranium silicate glass beads as a backfill material inside storage, transport, and repository waste packages containing spent nuclear fuel (SNF). The uranium silicate glass beads would fill all void space inside the package including the coolant channels inside SNF assemblies. Based on preliminary analysis, the following benefits have been identified. DUSCOBS improves repository waste package performance by three mechanisms. First, it reduces the radionuclide releases from SNF when water enters the waste package by creating a local uranium silicate saturated groundwater environment that suppresses (1) the dissolution and/or transformation of uranium dioxide fuel pellets and, hence, (2) the release of radionuclides incorporated into the SNF pellets. Second, the potential for long-term nuclear criticality is reduced by isotopic exchange of enriched uranium in SNF with the depleted uranium (DU) in the glass. Third, the backfill reduces radiation interactions between SNF and the local environment (package and local geology) and thus reduces generation of hydrogen, acids, and other chemicals that degrade the waste package system. In addition, the DUSCOBS improves the integrity of the package by acting as a packing material and ensures criticality control for the package during SNF storage and transport. Finally, DUSCOBS provides a potential method to dispose of significant quantities of excess DU from uranium enrichment plants at potential economic savings. DUSCOBS is a new concept. Consequently, the concept has not been optimized or demonstrated in laboratory experiments.

  5. Does genetic conflict drive rapid molecular evolution of nuclear transport genes in Drosophila?

    PubMed

    Presgraves, Daven C

    2007-04-01

    The Segregation Distorter (SD) system of Drosophila melanogaster is one the best-characterized meiotic drive complexes known. SD gains an unfair transmission advantage through heterozygous SD/SD(+) males by incapacitating SD(+)-bearing spermatids so that virtually all progeny inherit SD. Segregation distorter (Sd), the primary distorting locus in the SD complex, is a truncated duplication of the RanGAP gene, a major regulator of the small GTPase Ran, which has several functions including the maintenance of the nucleocytoplasmic RanGTP concentration gradient that mediates nuclear transport. The truncated Sd-RanGAP protein is enzymatically active but mislocalizes to the nucleus where it somehow causes distortion. Here I present data consistent with the idea that wild-type RanGAP, and possibly other loci able to influence the RanGTP gradient, has been caught up in an ancient genetic conflict that predates the SD complex. The legacy of this conflict could include the unexpectedly rapid evolution of nuclear transport-related proteins, the accumulation of chromosomal inversions, the recruitment of gene duplications, and the turnover of repetitive sequences in the centric heterochromatin. (c) 2007 Wiley Periodicals, Inc.

  6. The Rationale/Benefits of Nuclear Thermal Rocket Propulsion for NASA's Lunar Space Transportation System

    NASA Technical Reports Server (NTRS)

    Borowski, Stanley K.

    1994-01-01

    The solid core nuclear thermal rocket (NTR) represents the next major evolutionary step in propulsion technology. With its attractive operating characteristics, which include high specific impulse (approximately 850-1000 s) and engine thrust-to-weight (approximately 4-20), the NTR can form the basis for an efficient lunar space transportation system (LTS) capable of supporting both piloted and cargo missions. Studies conducted at the NASA Lewis Research Center indicate that an NTR-based LTS could transport a fully-fueled, cargo-laden, lunar excursion vehicle to the Moon, and return it to low Earth orbit (LEO) after mission completion, for less initial mass in LEO than an aerobraked chemical system of the type studied by NASA during its '90-Day Study.' The all-propulsive NTR-powered LTS would also be 'fully reusable' and would have a 'return payload' mass fraction of approximately 23 percent--twice that of the 'partially reusable' aerobraked chemical system. Two NTR technology options are examined--one derived from the graphite-moderated reactor concept developed by NASA and the AEC under the Rover/NERVA (Nuclear Engine for Rocket Vehicle Application) programs, and a second concept, the Particle Bed Reactor (PBR). The paper also summarizes NASA's lunar outpost scenario, compares relative performance provided by different LTS concepts, and discusses important operational issues (e.g., reusability, engine 'end-of life' disposal, etc.) associated with using this important propulsion technology.

  7. Study of the contaminant transport into granite microfractures using nuclear ion beam techniques.

    PubMed

    Alonso, Ursula; Missana, Tiziana; Patelli, Alessandro; Rigato, Valentino; Rivas, Pedro

    2003-03-01

    Hydrated bentonite is a very plastic material and it is expected to enter in the rock microfractures at the granite/bentonite boundary of a deep geological high-level waste repository. This process is enhanced by the high swelling pressure of the clay. Since bentonite has a very good sorption capability for many radionuclides, the displacement of the clay might lead to a "clay-mediated" contaminant transport into the rock. The aim of this work is to study the contaminant transport into granite microfractures using nuclear ion beam techniques, and to determine to what extent the clay can favour it. To do so, bentonite previously doped with uranium, cesium and europium was put in contact with the surface of granite sheets. Granite sheets contacted with non-doped bentonite and with radionuclide solutions were also prepared as references. This allowed analysing the differences in the diffusion behaviour of the three systems: clay, radionuclides and clay plus radionuclides. A combination of Rutherford backscattering spectrometry (RBS) and other nuclear ion-beam techniques such as particle-induced X-ray emission (PIXE) and microPIXE was used to study the depth and lateral distribution of clay and contaminants inside granite. It was also tried to evaluate not only the diffusion depth and diffusion coefficients but also the different areas of the granite where the diffusants have a preferential access.

  8. Pentagalloylglucose Blocks the Nuclear Transport and the Process of Nucleocapsid Egress to Inhibit HSV-1 Infection.

    PubMed

    Jin, Fujun; Ma, Kaiqi; Chen, Maoyun; Zou, Muping; Wu, Yanting; Li, Feng; Wang, Yifei

    2016-01-01

    Herpes simplex virus type 1 (HSV-1), a widespread virus, causes a variety of human viral diseases worldwide. The serious threat of drug-resistance highlights the extreme urgency to develop novel antiviral drugs with different mechanisms of action. Pentagalloylglucose (PGG) is a natural polyphenolic compound with significant anti-HSV activity; however, the mechanisms underlying its antiviral activity need to be defined by further studies. In this study, we found that PGG treatment delays the nuclear transport process of HSV-1 particles by inhibiting the upregulation of dynein (a cellular major motor protein) induced by HSV-1 infection. Furthermore, PGG treatment affects the nucleocapsid egress of HSV-1 by inhibiting the expression and disrupting the cellular localization of pEGFP-UL31 and pEGFP-UL34, which are indispensable for HSV-1 nucleocapsid egress from the nucleus. However, the over-expression of pEGFP-UL31 and pEGFP-UL34 could decrease the antiviral effect of PGG. In this study, for the first time, the antiviral activity of PGG against acyclovir-resistant virus was demonstrated in vitro, and the possible mechanisms of its anti-HSV activities were identified based on the inhibition of nuclear transport and nucleocapsid egress in HSV-1. It was further confirmed that PGG could be a promising candidate for HSV therapy, especially for drug-resistant strains.

  9. Zero-Mode Waveguide detection of biomolecules transport through artificial nanopores and nuclear pore complexes

    NASA Astrophysics Data System (ADS)

    Auger, Thomas; Auvray, Loic; Montel, Fabien

    We have developed a novel single molecule optical observation method using a custom Zero-Mode Waveguide setup to study the translocation of biopolymers through artificial and biological nanopores. Our work focuses on two aspects. First we monitored the flow driven injection of DNA molecules through solid state nanopores and showed that DNA starts translocating over a flow threshold independent of the pore radius, the DNA concentration and length. We demonstrate that the translocation is controlled by an energy barrier as proposed by the de Gennes - Brochard suction model. The height of the energy barrier can be modulated by functionalizing the nanopores with PEG-Thiols. More recently we adapted our setup to the study of transport through the nuclear pore complex (NPC) using extracted nuclear membranes from Xenopus Laevis oocytes. We aim at probing the conformation of unstructured proteins - the FG-Nucleoporins - crowding the central channel of the NPC by monitoring the free diffusion of small Dextran molecules (3kDa). We have been able to estimate the radius of the central pore of the NPC. We want to study the effects of transporter molecules, which have a high affinity for the FG-Nups, on the central pore size and correlate it to the conformation of FG-Nups.

  10. The rationale/benefits of nuclear thermal rocket propulsion for NASA's lunar space transportation system

    SciTech Connect

    Borowski, S.K.

    1994-09-01

    The solid core nuclear thermal rocket (NTR) represents the next major evolutionary step in propulsion technology. With its attractive operating characteristics, which include high specific impulse (approximately 850-1000 s) and engine thrust-to-weight (approximately 4-20), the NTR can form the basis for an efficient lunar space transportation system (LTS) capable of supporting both piloted and cargo missions. Studies conducted at the NASA Lewis Research Center indicate that an NTR-based LTS could transport a fully-fueled, cargo-laden, lunar excursion vehicle to the Moon, and return it to low Earth orbit (LEO) after mission completion, for less initial mass in LEO than an aerobraked chemical system of the type studied by NASA during its '90-Day Study.' The all-propulsive NTR-powered LTS would also be 'fully reusable' and would have a 'return payload' mass fraction of approximately 23 percent--twice that of the 'partially reusable' aerobraked chemical system. Two NTR technology options are examined--one derived from the graphite-moderated reactor concept developed by NASA and the AEC under the Rover/NERVA (Nuclear Engine for Rocket Vehicle Application) programs, and a second concept, the Particle Bed Reactor (PBR). The paper also summarizes NASA's lunar outpost scenario, compares relative performance provided by different LTS concepts, and discusses important operational issues (e.g., reusability, engine 'end-of life' disposal, etc.) associated with using this important propulsion technology.

  11. Nucleoporin domain topology is linked to the transport status of the nuclear pore complex.

    PubMed

    Paulillo, Sara M; Phillips, Erica M; Köser, Joachim; Sauder, Ursula; Ullman, Katharine S; Powers, Maureen A; Fahrenkrog, Birthe

    2005-08-26

    Nuclear pore complexes (NPCs) facilitate macromolecular exchange between the nucleus and cytoplasm of eukaryotic cells. The vertebrate NPC is composed of approximately 30 different proteins (nucleoporins), of which around one third contain phenylalanine-glycine (FG)-repeat domains that are thought to mediate the main interaction between the NPC and soluble transport receptors. We have recently shown that the FG-repeat domain of Nup153 is flexible within the NPC, although this nucleoporin is anchored to the nuclear side of the NPC. By using domain-specific antibodies, we have now mapped the domain topology of Nup214 in Xenopus oocytes and in human somatic cells by immuno-EM. We have found that whereas Nup214 is anchored to the cytoplasmic side of the NPC via its N-terminal and central domain, its FG-repeat domain appears flexible, residing on both sides of the NPC. Moreover, the spatial distribution of the FG-repeat domains of both Nup153 and Nup214 shifts in a transport-dependent manner, suggesting that the location of FG-repeat domains within the NPC correlates with cargo/receptor interactions and that they concomitantly move with cargo through the central pore of the NPC.

  12. Nuclear microprobe studies of the electronic transport properties of cadmium zinc telluride (CZT) radiation detectors

    NASA Astrophysics Data System (ADS)

    Vizkelethy, Gyorgy; Doyle, Barney L.; Walsh, David S.; James, Ralph B.

    2000-11-01

    Ion Beam Induced Charge Collection (IBICC) is a proven albeit relatively new method to measure the electronic transport properties of room temperature radiation detectors. Using an ion microbeam, the charge collection efficiency of CZT detectors can be mapped with submicron resolution and maps of the electron mobility and lifetime can be calculated. The nuclear microprobe can be used not only for characterizing detectors but also with the use of Time Resolved IBICC (TRIBICC) and lateral IBICC/TRIBICC we can deduce information about the electron and hole mobility and lifetime profiles, and about the variation of electric field along the detectors' axes. The Sandia Nuclear Microprobe has been and is being used routinely to characterize CZT detectors and measure their electronic transport properties. In this paper we will present the results of these measurements for different detectors. Furthermore the damage effects caused by the probing beam will be discussed and a simple model will be presented to explain the characteristic charge collection efficiency pattern observed after high dose irradiation.

  13. A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies

    PubMed Central

    Zahn, Raphael; Osmanović, Dino; Ehret, Severin; Araya Callis, Carolina; Frey, Steffen; Stewart, Murray; You, Changjiang; Görlich, Dirk; Hoogenboom, Bart W; Richter, Ralf P

    2016-01-01

    The permeability barrier of nuclear pore complexes (NPCs) controls bulk nucleocytoplasmic exchange. It consists of nucleoporin domains rich in phenylalanine-glycine motifs (FG domains). As a bottom-up nanoscale model for the permeability barrier, we have used planar films produced with three different end-grafted FG domains, and quantitatively analyzed the binding of two different nuclear transport receptors (NTRs), NTF2 and Importin β, together with the concomitant film thickness changes. NTR binding caused only moderate changes in film thickness; the binding isotherms showed negative cooperativity and could all be mapped onto a single master curve. This universal NTR binding behavior – a key element for the transport selectivity of the NPC – was quantitatively reproduced by a physical model that treats FG domains as regular, flexible polymers, and NTRs as spherical colloids with a homogeneous surface, ignoring the detailed arrangement of interaction sites along FG domains and on the NTR surface. DOI: http://dx.doi.org/10.7554/eLife.14119.001 PMID:27058170

  14. Factors affecting the development of somatic cell nuclear transfer embryos in Cattle.

    PubMed

    Akagi, Satoshi; Matsukawa, Kazutsugu; Takahashi, Seiya

    2014-01-01

    Nuclear transfer is a complex multistep procedure that includes oocyte maturation, cell cycle synchronization of donor cells, enucleation, cell fusion, oocyte activation and embryo culture. Therefore, many factors are believed to contribute to the success of embryo development following nuclear transfer. Numerous attempts to improve cloning efficiency have been conducted since the birth of the first sheep by somatic cell nuclear transfer. However, the efficiency of somatic cell cloning has remained low, and applications have been limited. In this review, we discuss some of the factors that affect the developmental ability of somatic cell nuclear transfer embryos in cattle.

  15. Human factors design guidelines for maintainability of Department of Energy nuclear facilities

    SciTech Connect

    Bongarra, J.P. Jr.; VanCott, H.P.; Pain, R.F.; Peterson, L.R.; Wallace, R.I.

    1985-06-18

    Intent of these guidelines is to provide design and design review teams of DOE nuclear facilities with human factors principles to enhance the design and aid in the inspection of DOE nuclear facilities, systems, and equipment. These guidelines are concerned with design features of DOE nuclear facilities which can potentially affect preventive and corrective maintenance of systems within DOE nuclear facilities. Maintenance includes inspecting, checking, troubleshooting, adjusting, replacing, repairing, and servicing activities. Other factors which influence maintainability such as repair and maintenance suport facilities, maintenance information, and various aspects of the environment are also addressed.

  16. Factors Affecting the Development of Somatic Cell Nuclear Transfer Embryos in Cattle

    PubMed Central

    AKAGI, Satoshi; MATSUKAWA, Kazutsugu; TAKAHASHI, Seiya

    2014-01-01

    Nuclear transfer is a complex multistep procedure that includes oocyte maturation, cell cycle synchronization of donor cells, enucleation, cell fusion, oocyte activation and embryo culture. Therefore, many factors are believed to contribute to the success of embryo development following nuclear transfer. Numerous attempts to improve cloning efficiency have been conducted since the birth of the first sheep by somatic cell nuclear transfer. However, the efficiency of somatic cell cloning has remained low, and applications have been limited. In this review, we discuss some of the factors that affect the developmental ability of somatic cell nuclear transfer embryos in cattle. PMID:25341701

  17. Motor-driven motility of fungal nuclear pores organizes chromosomes and fosters nucleocytoplasmic transport.

    PubMed

    Steinberg, Gero; Schuster, Martin; Theisen, Ulrike; Kilaru, Sreedhar; Forge, Andrew; Martin-Urdiroz, Magdalena

    2012-08-06

    Exchange between the nucleus and the cytoplasm is controlled by nuclear pore complexes (NPCs). In animals, NPCs are anchored by the nuclear lamina, which ensures their even distribution and proper organization of chromosomes. Fungi do not possess a lamina and how they arrange their chromosomes and NPCs is unknown. Here, we show that motor-driven motility of NPCs organizes the fungal nucleus. In Ustilago maydis, Aspergillus nidulans, and Saccharomyces cerevisiae fluorescently labeled NPCs showed ATP-dependent movements at ~1.0 µm/s. In S. cerevisiae and U. maydis, NPC motility prevented NPCs from clustering. In budding yeast, NPC motility required F-actin, whereas in U. maydis, microtubules, kinesin-1, and dynein drove pore movements. In the latter, pore clustering resulted in chromatin organization defects and led to a significant reduction in both import and export of GFP reporter proteins. This suggests that fungi constantly rearrange their NPCs and corresponding chromosomes to ensure efficient nuclear transport and thereby overcome the need for a structural lamina.

  18. Assessment of the announced North Korean nuclear test using long-range atmospheric transport and dispersion modelling.

    PubMed

    De Meutter, Pieter; Camps, Johan; Delcloo, Andy; Termonia, Piet

    2017-08-18

    On 6 January 2016, the Democratic People's Republic of Korea announced to have conducted its fourth nuclear test. Analysis of the corresponding seismic waves from the Punggye-ri nuclear test site showed indeed that an underground man-made explosion took place, although the nuclear origin of the explosion needs confirmation. Seven weeks after the announced nuclear test, radioactive xenon was observed in Japan by a noble gas measurement station of the International Monitoring System. In this paper, atmospheric transport modelling is used to show that the measured radioactive xenon is compatible with a delayed release from the Punggye-ri nuclear test site. An uncertainty quantification on the modelling results is given by using the ensemble method. The latter is important for policy makers and helps advance data fusion, where different nuclear Test-Ban-Treaty monitoring techniques are combined.

  19. Transport properties of isospin asymmetric nuclear matter using the time-dependent Hartree-Fock method

    NASA Astrophysics Data System (ADS)

    Umar, A. S.; Simenel, C.; Ye, W.

    2017-08-01

    Background: The study of deep-inelastic reactions of nuclei provides a vehicle to explore nuclear transport phenomena for a full range of equilibration dynamics. These investigations provide us the ingredients to model such phenomena and help answer important questions about the nuclear equation of state and its evolution as a function of neutron-to-proton (N /Z ) ratio. Purpose: The motivation is to examine the real-time dynamics of nuclear transport phenomena and its dependence on N /Z asymmetry from a microscopic point of view to avoid any pre-conceived assumptions about the involved processes. Method: The time-dependent Hartree-Fock (TDHF) method in full three dimensions is employed to calculate deep-inelastic reactions of 78Kr+208Pb and 92Kr+208Pb systems at 8.5 MeV/nucleon. The impact parameter and energy-loss dependence of relevant observables are calculated. In addition, the density-constrained TDHF method is used to compute excitation energies of the primary fragments. The statistical deexcitation code gemini is utilized to examine the final reaction products. Results: The kinetic energy loss and sticking times as a function of impact parameter are calculated. The final properties of the fragments (charge, mass, scattering angle, and kinetic energy) are computed. Their evolution as a function of energy loss is studied and various intra-relations are investigated. The fragment excitation energy sharing is computed. Conclusions: We find a smooth dependence of the energy loss, Eloss, on the impact parameter for both systems. However, the transfer properties for low Eloss values are very different for the two systems but become similar in the higher Eloss regime. The mean lifetime of the charge equilibration process, obtained from the final (N -Z )/A value of the fragments, is shown to be ˜0.5 zs. This value is slightly larger than (but of the same order as) the value obtained from reactions at Fermi energies.

  20. Atomistic Simulations of Mass and Thermal Transport in Oxide Nuclear Fuels

    SciTech Connect

    Andersson, Anders D.; Uberuaga, Blas P.; Du, Shiyu; Liu, Xiang-Yang; Nerikar, Pankaj; Stanek, Christopher R.; Tonks, Michael; Millet, Paul; Biner, Bulent

    2012-06-04

    In this talk we discuss simulations of the mass and thermal transport in oxide nuclear fuels. Redistribution of fission gases such as Xe is closely coupled to nuclear fuel performance. Most fission gases have low solubility in the fuel matrix, specifically the insolubility is most pronounced for large fission gas atoms such as Xe, and as a result there is a significant driving force for segregation of gas atoms to grain boundaries or dislocations and subsequently for nucleation of gas bubbles at these sinks. The first step of the fission gas redistribution is diffusion of individual gas atoms through the fuel matrix to existing sinks, which is governed by the activation energy for bulk diffusion. Fission gas bubbles are then formed by either separate nucleation events or by filling voids that were nucleated at a prior stage; in both cases their formation and latter growth is coupled to vacancy dynamics and thus linked to the production of vacancies via irradiation or thermal events. In order to better understand bulk Xe behavior (diffusion mechanisms) in UO{sub 2{+-}x} we first calculate the relevant activation energies using density functional theory (DFT) techniques. By analyzing a combination of Xe solution thermodynamics, migration barriers and the interaction of dissolved Xe atoms with U, we demonstrate that Xe diffusion predominantly occurs via a vacancy-mediated mechanism, though other alternatives may exist in high irradiation fields. Since Xe transport is closely related to diffusion of U vacancies, we have also studied the activation energy for this process. In order to explain the low value of 2.4 eV found for U migration from independent damage experiments (not thermal equilibrium) the presence of vacancy clusters must be included in the analysis. Next a continuum transport model for Xe and U is formulated based on the diffusion mechanisms established from DFT. After combining this model with descriptions of the interaction between Xe and grain

  1. Reversal bending fatigue test system for investigating vibration integrity of spent nuclear fuel during transportation

    SciTech Connect

    Wang, Jy -An; Wang, Hong; Bevard, Bruce Balkcom; Howard, Rob L.; Flanagan, Michelle E.

    2014-09-01

    Transportation packages for spent nuclear fuel (SNF) must meet safety requirements under normal and accident conditions as specified by federal regulations. During transportation, SNF experiences unique conditions and challenges to cladding integrity due to the vibrational and impact loading during road or rail shipment. Oak Ridge National Laboratory (ORNL) has been developing testing capabilities that can be used to improve the understanding of the impacts on SNF integrity due to vibration loading, especially for high burn-up SNF in normal transportation operation conditions. This information can be used to meet the nuclear industry and U.S.Nuclear Regulatory Commission needs in the area of safety and security of SNF storage and transportation operations. The ORNL developed test system can perform reversal bending fatigue testing to evaluate both the static and dynamic mechanical response of SNF rods under simulated loads. The testing apparatus is also designed to meet the challenges of hot cell operation, including remote installation and detachment of the SNF test specimen, in situ test specimen deformation measurement, and implementation of a driving system suitable for use in a hot cell. The system contains a U frame set-up equipped with uniquely designed grip rigs to protect the SNF rod sample and to ensure valid test results, and uses three specially designed linear variable differential transformers to obtain the in situ curvature measurement. A variety of surrogate test rods have been used to develop and calibrate the test system as well as in performing a series of systematic cyclic fatigue tests. The surrogate rods include stainless steel (SS) cladding, SS cladding with cast epoxy and SS cladding with alumina pellet inserts simulating fuel pellets. Testing to date has shown that the interface bonding between the SS cladding and the alumina pellets has a significant impact on the bending response of the test rods as well as their fatigue strength. The

  2. Reversal bending fatigue test system for investigating vibration integrity of spent nuclear fuel during transportation

    DOE PAGES

    Wang, Jy -An; Wang, Hong; Bevard, Bruce Balkcom; ...

    2014-09-01

    Transportation packages for spent nuclear fuel (SNF) must meet safety requirements under normal and accident conditions as specified by federal regulations. During transportation, SNF experiences unique conditions and challenges to cladding integrity due to the vibrational and impact loading during road or rail shipment. Oak Ridge National Laboratory (ORNL) has been developing testing capabilities that can be used to improve the understanding of the impacts on SNF integrity due to vibration loading, especially for high burn-up SNF in normal transportation operation conditions. This information can be used to meet the nuclear industry and U.S.Nuclear Regulatory Commission needs in the areamore » of safety and security of SNF storage and transportation operations. The ORNL developed test system can perform reversal bending fatigue testing to evaluate both the static and dynamic mechanical response of SNF rods under simulated loads. The testing apparatus is also designed to meet the challenges of hot cell operation, including remote installation and detachment of the SNF test specimen, in situ test specimen deformation measurement, and implementation of a driving system suitable for use in a hot cell. The system contains a U frame set-up equipped with uniquely designed grip rigs to protect the SNF rod sample and to ensure valid test results, and uses three specially designed linear variable differential transformers to obtain the in situ curvature measurement. A variety of surrogate test rods have been used to develop and calibrate the test system as well as in performing a series of systematic cyclic fatigue tests. The surrogate rods include stainless steel (SS) cladding, SS cladding with cast epoxy and SS cladding with alumina pellet inserts simulating fuel pellets. Testing to date has shown that the interface bonding between the SS cladding and the alumina pellets has a significant impact on the bending response of the test rods as well as their fatigue strength

  3. Hyperin inhibits nuclear factor kappa B and activates nuclear factor E2-related factor-2 signaling pathways in cisplatin-induced acute kidney injury in mice.

    PubMed

    Chao, Chia-Sheng; Tsai, Chien-Sung; Chang, Yee-Phoung; Chen, Jian-Ming; Chin, Hsien-Kuo; Yang, Shyh-Chyun

    2016-11-01

    Hyperin, a flavonoid compound found in Ericaceae, Guttiferae, and Celastraceae, has been reported to have anti-inflammatory effects. In the present study, we investigated the effects of hyperin on cisplatin-induced acute kidney injury (AKI) in mice. The renal tissue damage induced by cisplatin was detected by H&E staining. Blood urea nitrogen (BUN), creatinine, reactive oxygen species (ROS), and malondialdehyde (MDA) were also detected. Further, the effects of hyperin on cisplatin-induced TNF-α, IL-1β and IL-6 were detected by ELISA. In addition, the phosphorylation of nuclear factor kappa B (NF-κB) and the expression of nuclear factor E2-related factor-2 (Nrf2) and HO-1 were detected by western blot analysis. The results showed that hyperin attenuated histological changes of kidney induced by cisplatin. The levels of BUN, creatinine, ROS, MDA, TNF-α, IL-1β and IL-6 induced by cisplatin were also inhibited by hyperin. Cisplatin-induced NF-κB activation was inhibited by hyperin. Additionally, hyperin was found to up regulate the expression of Nrf2 and HO-1. In conclusion, the results suggest that hyperin protects against cisplatin-induced AKI by inhibiting inflammatory and oxidant response.

  4. Nuclear Epidermal Growth Factor Receptor is a Functional Molecular Target in Triple-Negative Breast Cancer

    PubMed Central

    Brand, Toni M.; Iida, Mari; Luthar, Neha; Kostopoulos, Kellie T.; Corrigan, Kelsey L.; Wleklinski, Matthew J.; Yang, David; Wisinski, Kari B.; Salgia, Ravi; Wheeler, Deric L.

    2014-01-01

    Triple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e. estrogen receptor negative, progesterone receptor negative, and HER2 negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBC’s overexpress the epidermal growth factor receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: 1) classical membrane-bound signaling, and 2) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. Based on these findings we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Further, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of TNBC patients. PMID:24634415

  5. Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

    SciTech Connect

    Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald

    2016-04-22

    Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.

  6. Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes.

    PubMed

    Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald

    2016-04-22

    Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle.

  7. Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha.

    PubMed

    Davison, James M; Lickwar, Colin R; Song, Lingyun; Breton, Ghislain; Crawford, Gregory E; Rawls, John F

    2017-04-06

    Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

  8. Osmoprotective Transcription Factor NFAT5/TonEBP Modulates Nuclear Factor-κB Activity

    PubMed Central

    Roth, Isabelle; Leroy, Valérie; Kwon, H. Moo; Martin, Pierre-Yves; Féraille, Eric

    2010-01-01

    Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this “classical” stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-κB (NF-κB) activity. We show that hypertonicity enhances NF-κB stimulation by lipopolysaccharide but not tumor necrosis factor-α, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-α. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IκBα degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-κB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-κB activity is considerably enhanced after binding of NF-κB-TonEBP complexes to κB elements of NF-κB–responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-κB activation on the onset of hypertonic challenge. PMID:20685965

  9. Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity.

    PubMed

    Roth, Isabelle; Leroy, Valérie; Kwon, H Moo; Martin, Pierre-Yves; Féraille, Eric; Hasler, Udo

    2010-10-01

    Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this "classical" stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-κB (NF-κB) activity. We show that hypertonicity enhances NF-κB stimulation by lipopolysaccharide but not tumor necrosis factor-α, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-α. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IκBα degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-κB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-κB activity is considerably enhanced after binding of NF-κB-TonEBP complexes to κB elements of NF-κB-responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-κB activation on the onset of hypertonic challenge.

  10. Changes in the Factors Influencing Public Acceptance of Nuclear Power Generation in Japan Since the 2011 Fukushima Daiichi Nuclear Disaster.

    PubMed

    Tsujikawa, Norifumi; Tsuchida, Shoji; Shiotani, Takamasa

    2016-01-01

    Public support for nuclear power generation has decreased in Japan since the Fukushima Daiichi nuclear accident in March 2011. This study examines how the factors influencing public acceptance of nuclear power changed after this event. The influence factors examined are perceived benefit, perceived risk, trust in the managing bodies, and pro-environmental orientation (i.e., new ecological paradigm). This study is based on cross-sectional data collected from two online nationwide surveys: one conducted in November 2009, before the nuclear accident, and the other in October 2011, after the accident. This study's target respondents were residents of Aomori, Miyagi, and Fukushima prefectures in the Tohoku region of Japan, as these areas were the epicenters of the Great East Japan Earthquake and the locations of nuclear power stations. After the accident, trust in the managing bodies was found to have a stronger influence on perceived risk, and pro-environmental orientation was found to have a stronger influence on trust in the managing bodies; however, perceived benefit had a weaker positive influence on public acceptance. We also discuss the theoretical and practical implications of these findings. © 2015 Society for Risk Analysis.

  11. Hypoxic preconditioning decreases nuclear factor κB activity via Disrupted in Schizophrenia-1.

    PubMed

    Liu, Jia-Ren; Liu, Qian; Khoury, Joseph; Li, Yue-Jin; Han, Xiao-Hui; Li, Jing; Ibla, Juan C

    2016-01-01

    Nuclear factor κB is a key mediator of inflammation during conditions of hypoxia. Here, we used models of hypoxic pre-conditioning as mechanism to decrease nuclear factor κB activity induced by hypoxia. Our initial studies suggested that Disrupted in Schizophrenia-1 may be induced by hypoxic pre-conditioning and possibly involved in the regulation of nuclear factor κB. In this study we used Disrupted in Schizophrenia-1 exogenous over-expression and knock-down to determine its effect on ataxia telangiectasia mutated--nuclear factor κB activation cascade. Our results demonstrated that hypoxic pre-conditioning significantly increased the expression of Disrupted in Schizophrenia-1 at mRNA and protein levels both in vitro and in vivo. Over-expression of Disrupted in Schizophrenia-1 significantly attenuated the hypoxia-mediated ataxia telangiectasia mutated phosphorylation and prevented its cytoplasm translocation where it functions to activate nuclear factor κB. We further determined that Disrupted in Schizophrenia-1 activated the protein phosphatase 2A, preventing the phosphorylation of ataxia telangiectasia mutated serine-1981, the main regulatory site of ataxia telangiectasia mutated activity. Cellular levels of Disrupted in Schizophrenia-1 protein significantly decreased nuclear factor κB activation profiles and pro-inflammatory gene expression. Taken together, these results demonstrate that hypoxic pre-conditioning decreases the activation of nuclear factor κB through the transcriptional induction of Disrupted in Schizophrenia-1.

  12. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations.

    PubMed

    Bellanné-Chantelot, Christine; Chauveau, Dominique; Gautier, Jean-François; Dubois-Laforgue, Danièle; Clauin, Séverine; Beaufils, Sandrine; Wilhelm, Jean-Marie; Boitard, Christian; Noël, Laure-Hélène; Velho, Gilberto; Timsit, José

    2004-04-06

    Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. Multicenter, descriptive study. 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. Maturity-onset diabetes of the young type 5

  13. Importin-beta is a GDP-to-GTP exchange factor of Ran: implications for the mechanism of nuclear import.

    PubMed

    Lonhienne, Thierry G; Forwood, Jade K; Marfori, Mary; Robin, Gautier; Kobe, Bostjan; Carroll, Bernard J

    2009-08-21

    Ran-GTP interacts strongly with importin-beta, and this interaction promotes the release of the importin-alpha-nuclear localization signal cargo from importin-beta. Ran-GDP also interacts with importin-beta, but this interaction is 4 orders of magnitude weaker than the Ran-GTP.importin-beta interaction. Here we use the yeast complement of nuclear import proteins to show that the interaction between Ran-GDP and importin-beta promotes the dissociation of GDP from Ran. The release of GDP from the Ran-GDP-importin-beta complex stabilizes the complex, which cannot be dissociated by importin-alpha. Although Ran has a higher affinity for GDP compared with GTP, Ran in complex with importin-beta has a higher affinity for GTP. This feature is responsible for the generation of Ran-GTP from Ran-GDP by importin-beta. Ran-binding protein-1 (RanBP1) activates this reaction by forming a trimeric complex with Ran-GDP and importin-beta. Importin-alpha inhibits the GDP exchange reaction by sequestering importin-beta, whereas RanBP1 restores the GDP nucleotide exchange by importin-beta by forming a tetrameric complex with importin-beta, Ran, and importin-alpha. The exchange is also inhibited by nuclear-transport factor-2 (NTF2). We suggest a mechanism for nuclear import, additional to the established RCC1 (Ran-guanine exchange factor)-dependent pathway that incorporates these results.

  14. Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

    PubMed Central

    Domingo-Domenech, J; Mellado, B; Ferrer, B; Truan, D; Codony-Servat, J; Sauleda, S; Alcover, J; Campo, E; Gascon, P; Rovira, A; Ross, J S; Fernández, P L; Albanell, J

    2005-01-01

    Nuclear factor (NF)-κB/p65 regulates the transcription of a wide variety of genes involved in cell survival, invasion and metastasis. We characterised by immunohistochemistry the expression of NF-κB/p65 protein in six histologically normal prostate, 13 high-grade prostatic intraepithelial neoplasia (PIN) and 86 prostate adenocarcinoma specimens. Nuclear localisation of p65 was used as a measure of NF-κB active state. Nuclear localisation of NF-κB was only seen in scattered basal cells in normal prostate glands. Prostatic intraepithelial neoplasias exhibited diffuse and strong cytoplasmic staining but no nuclear staining. In prostate adenocarcinomas, cytoplasmic NF-κB was detected in 57 (66.3%) specimens, and nuclear NF-κB (activated) in 47 (54.7%). Nuclear and cytoplasmic NF-κB staining was not correlated (P=0.19). By univariate analysis, nuclear localisation of NF-κB was associated with biochemical relapse (P=0.0009; log-rank test) while cytoplasmic expression did not. On multivariate analysis, serum preoperative prostate specific antigen (P=0.02), Gleason score (P=0.03) and nuclear NF-κB (P=0.002) were independent predictors of biochemical relapse. These results provide novel evidence for NF-κB/p65 nuclear translocation in the transition from PIN to prostate cancer. Our findings also indicate that nuclear localisation of NF-κB is an independent prognostic factor of biochemical relapse in prostate cancer. PMID:16278667

  15. The MacArthur Maze Fire and Roadway Collapse: A "Worst Case Scenario" for Spent Nuclear Fuel Transportation?

    SciTech Connect

    Bajwa, Christopher S.; Easton, Earl P.; Adkins, Harold E.; Cuta, Judith M.; Klymyshyn, Nicholas A.; Suffield, Sarah R.

    2012-07-06

    In 2007, a severe transportation accident occurred near Oakland, California, at the interchange known as the "MacArthur Maze." The accident involved a double tanker truck of gasoline overturning and bursting into flames. The subsequent fire reduced the strength of the supporting steel structure of an overhead interstate roadway causing the collapse of portions of that overpass onto the lower roadway in less than 20 minutes. The US Nuclear Regulatory Commission has analyzed what might have happened had a spent nuclear fuel transportation package been involved in this accident, to determine if there are any potential regulatory implications of this accident to the safe transport of spent nuclear fuel in the United States. This paper provides a summary of this effort, presents preliminary results and conclusions, and discusses future work related to the NRC's analysis of the consequences of this type of severe accident.

  16. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis.

    PubMed Central

    Virbasius, J V; Scarpulla, R C

    1994-01-01

    Mitochondrial transcription factor A (mtTFA), the product of a nuclear gene, stimulates transcription from the two divergent mitochondrial promoters and is likely the principal activator of mitochondrial gene expression in vertebrates. Here we establish that the proximal promoter of the human mtTFA gene is highly dependent upon recognition sites for the nuclear respiratory factors, NRF-1 and NRF-2, for activity. These factors have been previously implicated in the activation of numerous nuclear genes that contribute to mitochondrial respiratory function. The affinity-purified factors from HeLa cells specifically bind to the mtTFA NRF-1 and NRF-2 sites through guanine nucleotide contacts that are characteristic for each site. Mutations in these contacts eliminate NRF-1 and NRF-2 binding and also dramatically reduce promoter activity in transfected cells. Although both factors contribute, NRF-1 binding appears to be the major determinant of promoter function. This dependence on NRF-1 activation is confirmed by in vitro transcription using highly purified recombinant proteins that display the same binding specificities as the HeLa cell factors. The activation of the mtTFA promoter by both NRF-1 and NRF-2 therefore provides a link between the expression of nuclear and mitochondrial genes and suggests a mechanism for their coordinate regulation during organelle biogenesis. Images PMID:8108407

  17. Transport and fate of radionuclides in aquatic environments--the use of ecosystem modelling for exposure assessments of nuclear facilities.

    PubMed

    Kumblad, L; Kautsky, U; Naeslund, B

    2006-01-01

    In safety assessments of nuclear facilities, a wide range of radioactive isotopes and their potential hazard to a large assortment of organisms and ecosystem types over long time scales need to be considered. Models used for these purposes have typically employed approaches based on generic reference organisms, stylised environments and transfer functions for biological uptake exclusively based on bioconcentration factors (BCFs). These models are of non-mechanistic nature and involve no understanding of uptake and transport processes in the environment, which is a severe limitation when assessing real ecosystems. In this paper, ecosystem models are suggested as a method to include site-specific data and to facilitate the modelling of dynamic systems. An aquatic ecosystem model for the environmental transport of radionuclides is presented and discussed. With this model, driven and constrained by site-specific carbon dynamics and three radionuclide specific mechanisms: (i) radionuclide uptake by plants, (ii) excretion by animals, and (iii) adsorption to organic surfaces, it was possible to estimate the radionuclide concentrations in all components of the modelled ecosystem with only two radionuclide specific input parameters (BCF for plants and Kd). The importance of radionuclide specific mechanisms for the exposure to organisms was examined, and probabilistic and sensitivity analyses to assess the uncertainties related to ecosystem input parameters were performed. Verification of the model suggests that this model produces analogous results to empirically derived data for more than 20 different radionuclides.

  18. Nuclear actin activates human transcription factor genes including the OCT4 gene.

    PubMed

    Yamazaki, Shota; Yamamoto, Koji; Tokunaga, Makio; Sakata-Sogawa, Kumiko; Harata, Masahiko

    2015-01-01

    RNA microarray analyses revealed that nuclear actin activated many human transcription factor genes including OCT4, which is required for gene reprogramming. Oct4 is known to be activated by nuclear actin in Xenopus oocytes. Our findings imply that this process of OCT4 activation is conserved in vertebrates and among cell types and could be used for gene reprogramming of human cells.

  19. Experimental wrap-up: p (d) A - particle production and nuclear modification factors

    NASA Astrophysics Data System (ADS)

    Morsch, Andreas

    2014-12-01

    The 6th International Conference on Hard and Electromagnetic Probes in High-Energy Nuclear Collisions was held in November 2013 in Cape Town, South Africa. This contribution is a summary of the results presented on particle production and nuclear modification factors in p-A like collisions.

  20. Bureaucracy and the bomb: the hidden factor behind nuclear madness

    SciTech Connect

    Kaplan, F.

    1983-05-01

    Describing the original of what he considers the most important of the interservice rivalries, that between the Air Force and the Navy, the author blames bureaucratic jealousies for the irrational proliferation of nuclear weapons. Beginning with the 1949 disagreement between the Air Force and the Army and Navy regarding official emphasis on the Strategic Air Command with its B-36 bombers at the expense of the more-traditional combat weapons of the Army and Navy, and continuing through the 1960s' Single Integrated Operational Plan and the Joint Strategic Target Planning Staff, the author summarizes what he calls bitter rivalry that has seen the official attitudes change toward nuclear war, that helps sustain the arms race, and that caused the multiplicity of nuclear weapons. He sees today's debate over the (Air Force) MX versus the (Navy) Trident II as evidence of the earlier RAND strategy, refined for the 1980s, of counterforce/no-cities targeting (that is, meeting Soviet aggression initially with a nuclear attack on military targets only).

  1. Nuclear Energy R&D Imperative 3: Enable a Transition Away from Fossil Fuel in the Transportation and Industrial Sectors

    SciTech Connect

    David Petti; J. Stephen Herring

    2010-03-01

    As described in the Department of Energy Office of Nuclear Energy’s Nuclear Energy R&D Roadmap, nuclear energy can play a significant role in supplying energy for a growing economy while reducing both our dependence on foreign energy supplies and emissions from the burning of fossil fuels. The industrial and transportation sectors are responsible for more than half of the greenhouse gas emissions in the U.S., and imported oil supplies 70% of the energy used in the transportation sector. It is therefore important to examine the various ways nuclear energy can facilitate a transition away from fossil fuels to secure environmentally sustainable production and use of energy in the transportation and manufacturing industry sectors. Imperative 3 of the Nuclear Energy R&D Roadmap, entitled “Enable a Transition Away from Fossil Fuels by Producing Process Heat for use in the Transportation and Industrial Sectors”, addresses this need. This document presents an Implementation Plan for R&D efforts related to this imperative. The expanded use of nuclear energy beyond the electrical grid will contribute significantly to overcoming the three inter-linked energy challenges facing U.S. industry: the rising and volatile prices for premium fossil fuels such as oil and natural gas, dependence on foreign sources for these fuels, and the risks of climate change resulting from carbon emissions. Nuclear energy could be used in the industrial and transportation sectors to: • Generate high temperature process heat and electricity to serve industrial needs including the production of chemical feedstocks for use in manufacturing premium fuels and fertilizer products, • Produce hydrogen for industrial processes and transportation fuels, and • Provide clean water for human consumption by desalination and promote wastewater treatment using low-grade nuclear heat as a useful additional benefit. Opening new avenues for nuclear energy will significantly enhance our nation’s energy

  2. Allowable shipment frequencies for the transport of toxic gases near nuclear power plants

    SciTech Connect

    Bennett, D.E.; Heath, D.C.

    1982-10-01

    One part of the safety analysis of offsite hazards for a nuclear power plant is consideration of accidents which could release toxic gases or vapors and thus jeopardize plant safety through incapacitation of the control room operators. The purpose of this work is to provide generic, bounding estimates of the maximum allowable shipping frequencies for the transport of a chemical near the plant, such that the regulatory criteria for the protection of the operators are met. A probabilistic methodology was developed and then applied to the truck and rail transport of an example chemical, chlorine. The current regulatory criteria are discussed in detail. For this study, a maximum allowable probability of occurrence of operator incapacitation of 10/sup -5/ per year was used in the example calculation for each mode of transport. Comprehensive tables of conditional probabilities are presented. Maximum allowable ahipping frequencies are then derived. These frequencies could be used as part of a generic, bounding criterion for the screening of toxic hazards safety analyses. Unless a transport survey assures shipping frequencies within 8 km of the plant on the order of or lower than 4/week for rail or 35/week for truck, the contol room should be isolatable and the shipping frequency then determines the degree of isolation needed. The need for isolation implies the need for toxic chemical detection at the air intake.For a self-detection case in which the smell threshold is significantly lower than the incapacitation threshold and the control room is isolatable, the corresponding trequencies are 11/week for rail or 115/week for truck. Self-contained breathing equipment is assumed to be used after 5 minutes.

  3. Hydrothermal Alteration of Glass from Underground Nuclear Tests: Formation and Transport of Pu-clay Colloids at the Nevada National Security Site

    SciTech Connect

    Zavarin, M.; Zhao, P.; Joseph, C.; Begg, J.; Boggs, M.; Dai, Z.; Kersting, A. B.

    2015-05-27

    The testing of nuclear weapons at the Nevada National Security Site (NNSS), formerly the Nevada Test Site (NTS), has led to the deposition of substantial quantities of plutonium into the environment. Approximately 2.8 metric tons (3.1×104 TBq) of Pu were deposited in the NNSS subsurface as a result of underground nuclear testing. While 3H is the most abundant anthropogenic radionuclide deposited in the NNSS subsurface (4.7×106 TBq), plutonium is the most abundant from a molar standpoint. The only radioactive elements in greater molar abundance are the naturally occurring K, Th, and U isotopes. 239Pu and 240Pu represent the majority of alpha-emitting Pu isotopes. The extreme temperatures associated with underground nuclear tests and the refractory nature of Pu results in most of the Pu (98%) being sequestered in melted rock, referred to as nuclear melt glass (Iaea, 1998). As a result, Pu release to groundwater is controlled, in large part, by the leaching (or dissolution) of nuclear melt glass over time. The factors affecting glass dissolution rates have been studied extensively. The dissolution of Pu-containing borosilicate nuclear waste glasses at 90ºC has been shown to lead to the formation of dioctahedral smectite colloids. Colloid-facilitated transport of Pu at the NNSS has been observed. Recent groundwater samples collected from a number of contaminated wells have yielded a wide range of Pu concentrations from 0.00022 to 2.0 Bq/L. While Pu concentrations tend to fall below the Maximum Contaminant Level (MCL) established by the Environmental Protection Agency (EPA) for drinking water (0.56 Bq/L), we do not yet understand what factors limit the Pu concentration or its transport behavior. To quantify the upper limit of Pu concentrations produced as a result of melt glass dissolution and determine the nature of colloids and Pu associations, we performed a 3 year nuclear melt glass dissolution experiment

  4. Light ion components of the galactic cosmic rays: Nuclear interactions and transport theory

    NASA Technical Reports Server (NTRS)

    Cucinotta, F. A.; Townsend, L. W.; Wilson, J. W.; Shinn, J. L.; Badhwar, G. D.; Dubey, R. R.

    1996-01-01

    Light nuclei are present in the primary galactic cosmic rays (GCR) and are produced in thick targets due to projectile or target fragmentation from both nucleon and heavy induced reactions. In the primary GCR, He-4 is the most abundant nucleus after H-1. However, there are also a substantial fluxes of H-2 and He-3. In this paper we describe theoretical models based on quantum multiple scattering theory for the description of light ion nuclear interactions. The energy dependence of the light ion fragmentation cross section is considered with comparisons of inclusive yields and secondary momentum distributions to experiments described. We also analyze the importance of a fast component of lights ions from proton and neutron induced target fragementation. These theoretical models have been incorporated into the cosmic ray transport code HZETRN and will be used to analyze the role of shielding materials in modulating the production and the energy spectrum of light ions.

  5. Light ion components of the galactic cosmic rays: Nuclear interactions and transport theory

    NASA Technical Reports Server (NTRS)

    Cucinotta, F. A.; Townsend, L. W.; Wilson, J. W.; Shinn, J. L.; Badhwar, G. D.; Dubey, R. R.

    1996-01-01

    Light nuclei are present in the primary galactic cosmic rays (GCR) and are produced in thick targets due to projectile or target fragmentation from both nucleon and heavy induced reactions. In the primary GCR, He-4 is the most abundant nucleus after H-1. However, there are also a substantial fluxes of H-2 and He-3. In this paper we describe theoretical models based on quantum multiple scattering theory for the description of light ion nuclear interactions. The energy dependence of the light ion fragmentation cross section is considered with comparisons of inclusive yields and secondary momentum distributions to experiments described. We also analyze the importance of a fast component of lights ions from proton and neutron induced target fragementation. These theoretical models have been incorporated into the cosmic ray transport code HZETRN and will be used to analyze the role of shielding materials in modulating the production and the energy spectrum of light ions.

  6. Nuclear fragmentation induced by low-energy antiprotons within a microscopic transport approach

    NASA Astrophysics Data System (ADS)

    Feng, Zhao-Qing

    2016-12-01

    Within the framework of the Lanzhou quantum molecular-dynamics transport model, the nuclear fragmentation induced by low-energy antiprotons has been investigated thoroughly. A coalescence approach is developed for constructing the primary fragments in phase space. The secondary decay process of the fragments is described by a well-known statistical code. It is found that the localized energy released in antibaryon-baryon annihilation is deposited in a nucleus mainly via pion-nucleon collisions, which leads to the emissions of pre-equilibrium particles, fission, evaporation of nucleons, light fragments, etc. The strangeness exchange reactions dominate the hyperon production. The averaged mass loss increases with the mass number of target nucleus. A bump structure in the domain of intermediate mass for heavy targets appears owing to the contribution of fission fragments.

  7. The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression

    PubMed Central

    Lee, Yoon-Kwang; Dell, Helen; Dowhan, Dennis H.; Hadzopoulou-Cladaras, Margarita; Moore, David D.

    2000-01-01

    The orphan nuclear hormone receptor SHP interacts with a number of other nuclear hormone receptors and inhibits their transcriptional activity. Several mechanisms have been suggested to account for this inhibition. Here we show that SHP inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (HNF-4) and the retinoid X receptor (RXR) by at least two mechanisms. SHP interacts with the same HNF-4 surface recognized by transcriptional coactivators and competes with them for binding in vivo. The minimal SHP sequences previously found to be required for interaction with other receptors are sufficient for interaction with HNF-4, although deletion results indicate that additional C-terminal sequences are necessary for full binding and coactivator competition. These additional sequences include those associated with direct transcriptional repressor activity of SHP. SHP also competes with coactivators for binding to ligand-activated RXR, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of SHP-mediated repression. The minimal receptor interaction domain of SHP is sufficient for full interaction with RXR, as previously described. This domain is also sufficient for full coactivator competition. Functionally, however, full inhibition of RXR transactivation requires the presence of the C-terminal repressor domain, with only weak inhibition associated with this receptor interaction domain. Overall, these results suggest that SHP represses nuclear hormone receptor-mediated transactivation via two separate steps: first by competition with coactivators and then by direct effects of its transcriptional repressor function. PMID:10594021

  8. Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos

    PubMed Central

    Miyamoto, Kei; Nagai, Kouhei; Kitamura, Naoya; Nishikawa, Tomoaki; Ikegami, Haruka; Binh, Nguyen T.; Tsukamoto, Satoshi; Matsumoto, Mai; Tsukiyama, Tomoyuki; Minami, Naojiro; Yamada, Masayasu; Ariga, Hiroyoshi; Miyake, Masashi; Kawarasaki, Tatsuo; Matsumoto, Kazuya; Imai, Hiroshi

    2011-01-01

    Nuclear reprogramming of differentiated cells can be induced by oocyte factors. Despite numerous attempts, these factors and mechanisms responsible for successful reprogramming remain elusive. Here, we identify one such factor, necessary for the development of nuclear transfer embryos, using porcine oocyte extracts in which some reprogramming events are recapitulated. After incubating somatic nuclei in oocyte extracts from the metaphase II stage, the oocyte proteins that were specifically and abundantly incorporated into the nuclei were identified by mass spectrometry. Among 25 identified proteins, we especially focused on a multifunctional protein, DJ-1. DJ-1 is present at a high concentration in oocytes from the germinal vesicle stage until embryos at the four-cell stage. Inhibition of DJ-1 function compromises the development of nuclear transfer embryos but not that of fertilized embryos. Microarray analysis of nuclear transfer embryos in which DJ-1 function is inhibited shows perturbed expression of P53 pathway components. In addition, embryonic arrest of nuclear transfer embryos injected with anti–DJ-1 antibody is rescued by P53 inhibition. We conclude that DJ-1 is an oocyte factor that is required for development of nuclear transfer embryos. This study presents a means for identifying natural reprogramming factors in mammalian oocytes and a unique insight into the mechanisms underlying reprogramming by nuclear transfer. PMID:21482765

  9. Nuclear waste transportation package testing: A review of selected programs in the United States and abroad

    SciTech Connect

    Snedeker, D F

    1990-12-01

    This report provides an overview of some recent nuclear waste transportation package development programs. This information is intended to aid the State of Nevada in its review of US Department of Energy (DOE) nuclear waste transportation programs. This report addresses cask testing programs in the United Kingdom and selected 1/4 and full scale testing in the US. Facilities that can provide cask testing services, both in the US and to a limited extent abroad, are identified. The costs for different type test programs are identified as a means to estimate costs for future test programs. Not addressed is the public impact such testing might have in providing an increased sense of safety or confidence. The British test program was apparently quite successful in demonstrating safety to the public at the time. There is no US test effort that is similar in scope for direct comparison. Also addressed are lessons learned from testing programs and areas that may merit possible future integrated examination. Areas that may require further examination are both technical and institutional. This report provides information which, when combined with other sources of information will enable the State of Nevada to assess the following areas: feasibility of full scale testing; costs of full scale tests; potential benefits of testing; limits that full scale testing impose; and disadvantages of emphasis on testing vs analytical solutions. This assessment will then allow the state to comment on DOE Office of Civilian Radioactive Waste Management (OCRWM) plans for the development and licensing of new shipping cask designs. These plans currently expect contractors to perform engineering testing for materials development, quarter scale model testing to validate analytical assessments and full scale prototype testing of operational features. DOE currently plans no full scale or extra-regulatory destructive testing to aid in cask licensing. 1 tab.

  10. MODELING OF THE GROUNDWATER TRANSPORT AROUND A DEEP BOREHOLE NUCLEAR WASTE REPOSITORY

    SciTech Connect

    N. Lubchenko; M. Rodríguez-Buño; E.A. Bates; R. Podgorney; E. Baglietto; J. Buongiorno; M.J. Driscoll

    2015-04-01

    The concept of disposal of high-level nuclear waste in deep boreholes drilled into crystalline bedrock is gaining renewed interest and consideration as a viable mined repository alternative. A large amount of work on conceptual borehole design and preliminary performance assessment has been performed by researchers at MIT, Sandia National Laboratories, SKB (Sweden), and others. Much of this work relied on analytical derivations or, in a few cases, on weakly coupled models of heat, water, and radionuclide transport in the rock. Detailed numerical models are necessary to account for the large heterogeneity of properties (e.g., permeability and salinity vs. depth, diffusion coefficients, etc.) that would be observed at potential borehole disposal sites. A derivation of the FALCON code (Fracturing And Liquid CONvection) was used for the thermal-hydrologic modeling. This code solves the transport equations in porous media in a fully coupled way. The application leverages the flexibility and strengths of the MOOSE framework, developed by Idaho National Laboratory. The current version simulates heat, fluid, and chemical species transport in a fully coupled way allowing the rigorous evaluation of candidate repository site performance. This paper mostly focuses on the modeling of a deep borehole repository under realistic conditions, including modeling of a finite array of boreholes surrounded by undisturbed rock. The decay heat generated by the canisters diffuses into the host rock. Water heating can potentially lead to convection on the scale of thousands of years after the emplacement of the fuel. This convection is tightly coupled to the transport of the dissolved salt, which can suppress convection and reduce the release of the radioactive materials to the aquifer. The purpose of this work has been to evaluate the importance of the borehole array spacing and find the conditions under which convective transport can be ruled out as a radionuclide transport mechanism

  11. Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes.

    PubMed

    Rappa, Germana; Santos, Mark F; Green, Toni M; Karbanová, Jana; Hassler, Justin; Bai, Yongsheng; Barsky, Sanford H; Corbeil, Denis; Lorico, Aurelio

    2017-02-28

    Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication, but how the biomaterials they carry reach the target site in recipient cells is an open question. We report that subdomains of Rab7+ late endosomes and nuclear envelope invaginations come together to create a sub-nuclear compartment, where biomaterials associated with CD9+ EVs are delivered. EV-derived biomaterials were also found in the nuclei of host cells. The inhibition of nuclear import and export pathways abrogated the nuclear localization of EV-derived biomaterials or led to their accumulation therein, respectively, suggesting that their translocation is dependent on nuclear pores. Nuclear envelope invagination-associated late endosomes were observed in ex vivo biopsies in both breast carcinoma and associated stromal cells. The transcriptome of stromal cells exposed to cancer cell-derived CD9+ EVs revealed that the regulation of eleven genes, notably those involved in inflammation, relies on the nuclear translocation of EV-derived biomaterials. Our findings uncover a new cellular pathway used by EVs to reach nuclear compartment.

  12. Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes

    PubMed Central

    Rappa, Germana; Santos, Mark F.; Green, Toni M.; Karbanová, Jana; Hassler, Justin; Bai, Yongsheng; Barsky, Sanford H.; Corbeil, Denis; Lorico, Aurelio

    2017-01-01

    Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication, but how the biomaterials they carry reach the target site in recipient cells is an open question. We report that subdomains of Rab7+ late endosomes and nuclear envelope invaginations come together to create a sub-nuclear compartment, where biomaterials associated with CD9+ EVs are delivered. EV-derived biomaterials were also found in the nuclei of host cells. The inhibition of nuclear import and export pathways abrogated the nuclear localization of EV-derived biomaterials or led to their accumulation therein, respectively, suggesting that their translocation is dependent on nuclear pores. Nuclear envelope invagination-associated late endosomes were observed in ex vivo biopsies in both breast carcinoma and associated stromal cells. The transcriptome of stromal cells exposed to cancer cell-derived CD9+ EVs revealed that the regulation of eleven genes, notably those involved in inflammation, relies on the nuclear translocation of EV-derived biomaterials. Our findings uncover a new cellular pathway used by EVs to reach nuclear compartment. PMID:28129640

  13. Fluid Transport Driven by Heat-Generating Nuclear Waste in Bedded Salt

    NASA Astrophysics Data System (ADS)

    Jordan, A.; Harp, D. R.; Stauffer, P. H.; Ten Cate, J. A.; Labyed, Y.; Boukhalfa, H.; Lu, Z.; Person, M. A.; Robinson, B. A.

    2013-12-01

    The question of where to safely dispose high-level nuclear waste (HLW) provides ample motivation for scientific research on deep geologic disposal options. The goal of this study is to model the dominant heat and mass transport processes that would be driven by heat generating nuclear waste buried in bedded salt. The interaction between liquid brine flow towards the heat source, establishment of a heat pipe in the mine-run salt backfill, boiling, and vapor condensation leads to changes in porosity, permeability, saturation, thermal conductivity, and rheology of the salt surrounding potential waste canisters. The Finite Element Heat and Mass transfer code (FEHM) was used to simulate these highly coupled thermal, hydrological, and chemical processes. The numerical model has been tested against recent and historical experimental data to develop and improve the salt material model. We used the validated numerical model to make predictions of temperature gradients, porosity changes, and tracer behavior that will be testable in a future 2-year field-scale heater experiment to be carried out in an experimental test bed at the Waste Isolation Pilot Plant (WIPP) site near Carlsbad, NM.

  14. KPNA7, a nuclear transport receptor, promotes malignant properties of pancreatic cancer cells in vitro

    SciTech Connect

    Laurila, Eeva; Vuorinen, Elisa; Savinainen, Kimmo; Rauhala, Hanna; Kallioniemi, Anne

    2014-03-10

    Pancreatic cancer is an aggressive malignancy and one of the leading causes of cancer deaths. The high mortality rate is mostly due to the lack of appropriate tools for early detection of the disease and a shortage of effective therapies. We have previously shown that karyopherin alpha 7 (KPNA7), the newest member of the alpha karyopherin family of nuclear import receptors, is frequently amplified and overexpressed in pancreatic cancer. Here, we report that KPNA7 expression is absent in practically all normal human adult tissues but elevated in several pancreatic cancer cell lines. Inhibition of KPNA7 expression in AsPC-1 and Hs700T pancreatic cancer cells led to a reduction in cell growth and decreased anchorage independent growth, as well as increased autophagy. The cell growth effects were accompanied by an induction of the cell cycle regulator p21 and a G1 arrest of the cell cycle. Interestingly, the p21 induction was caused by increased mRNA synthesis and not defective nuclear transport. These data strongly demonstrate that KPNA7 silencing inhibits the malignant properties of pancreatic cancer cells in vitro and thereby provide the first evidence on the functional role for KPNA7 in human cancer. - Highlights: • KPNA7 expression is elevated in several pancreatic cancer cell lines. • KPNA7 silencing in high expressing cancer cells leads to growth inhibition. • The cell growth reduction is associated with p21 induction and G1 arrest. • KPNA7 silencing is also accompanied with increased autophagy.

  15. Nuclear Factor-Y is an adipogenic factor that regulates leptin gene expression

    PubMed Central

    Lu, Yi-Hsueh; Dallner, Olof Stefan; Birsoy, Kivanc; Fayzikhodjaeva, Gulya; Friedman, Jeffrey M.

    2015-01-01

    Objective Leptin gene expression is highly correlated with cellular lipid content in adipocytes but the transcriptional mechanisms controlling leptin expression in vivo are poorly understood. In this report, we set out to identify cis- and trans-regulatory elements controlling leptin expression. Methods Leptin-BAC luciferase transgenic mice combining with other computational and molecular techniques were used to identify transcription regulatory elements including a CCAAT-binding protein Nuclear Factor Y (NF-Y). The function of NF-Y in adipocyte was studied in vitro with 3T3-L1 cells and in vivo with adipocyte-specific knockout of NF-Y. Results Using Leptin-BAC luciferase mice, we showed that DNA sequences between −22 kb and +8.8 kb can confer quantitative expression of a leptin reporter. Computational analysis of sequences and gel shift assays identified a 32 bp sequence (chr6: 28993820–2899385) consisting a CCAAT binding site for Nuclear Factor Y (NF-Y) and this was confirmed by a ChIP assay in vivo. A deletion of this 32 bp sequence in the −22 kb to +8.8 kb leptin-luciferase BAC reporter completely abrogates luciferase reporter activity in vivo. RNAi mediated knockdown of NF-Y interfered with adipogenesis in vitro and adipocyte-specific knockout of NF-Y in mice reduced expression of leptin and other fat specific genes in vivo. Further analyses of the fat specific NF-Y knockout revealed that these animals develop a moderately severe lipodystrophy that is remediable with leptin therapy. Conclusions These studies advance our understanding of leptin gene expression and show that NF-Y controls the expression of leptin and other adipocyte genes and identifies a new form of lipodystrophy. PMID:25973387

  16. Featured Article: Hypoxia-inducible factor-1α dependent nuclear entry of factor inhibiting HIF-1

    PubMed Central

    Liang, Ke; Ding, Xue-qin; Lin, Chen

    2015-01-01

    The regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity in the nucleus is related to factor inhibiting HIF-1 (FIH-1). FIH-1 hydrolyzes asparagine at the C-terminal of HIF-1α, preventing the interaction between HIF-1α and its associated cofactors, and leading to suppressed activation of HIF-1. FIH-1 is a cytosolic protein and its entry to the nucleus has to be coordinated with HIF-1α. The present study was undertaken to examine the correlation between HIF-1α and FIH-1 in their nuclear entry. Human umbilical vein endothelial cells were treated with dimethyloxalylglycine at a final concentration of 100 µM for 4 h, resulting in an accumulation of HIF-1α and an increase of FIH-1 in the nucleus as determined by Western blot analysis. Pretreatment of the cells with copper (Cu) chelator tetraethylenepentamine at 50 µM in cultures for 24 h reduced both HIF-1α protein levels and the HIF-1α entry to the nucleus, along with decreased FIH-1 protein levels in the nucleus but no changes in the total FIH-1 protein levels in the cells. These effects were prevented by simultaneous addition of 50 µM CuSO4 with tetraethylenepentamine. Gene-silencing of HIF-1α significantly inhibited FIH-1 entry to the nucleus, but did not affect the total protein levels of FIH-1 in the cells. This work demonstrates that the nuclear entry of FIH-1 depends on HIF-1α. Cu deficiency caused a decrease of HIF-1α, leading to suppression of FIH-1 entry to the nucleus. PMID:25687434

  17. Featured Article: Hypoxia-inducible factor-1α dependent nuclear entry of factor inhibiting HIF-1.

    PubMed

    Liang, Ke; Ding, Xue-Qin; Lin, Chen; Kang, Y James

    2015-11-01

    The regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity in the nucleus is related to factor inhibiting HIF-1 (FIH-1). FIH-1 hydrolyzes asparagine at the C-terminal of HIF-1α, preventing the interaction between HIF-1α and its associated cofactors, and leading to suppressed activation of HIF-1. FIH-1 is a cytosolic protein and its entry to the nucleus has to be coordinated with HIF-1α. The present study was undertaken to examine the correlation between HIF-1α and FIH-1 in their nuclear entry. Human umbilical vein endothelial cells were treated with dimethyloxalylglycine at a final concentration of 100 µM for 4 h, resulting in an accumulation of HIF-1α and an increase of FIH-1 in the nucleus as determined by Western blot analysis. Pretreatment of the cells with copper (Cu) chelator tetraethylenepentamine at 50 µM in cultures for 24 h reduced both HIF-1α protein levels and the HIF-1α entry to the nucleus, along with decreased FIH-1 protein levels in the nucleus but no changes in the total FIH-1 protein levels in the cells. These effects were prevented by simultaneous addition of 50 µM CuSO4 with tetraethylenepentamine. Gene-silencing of HIF-1α significantly inhibited FIH-1 entry to the nucleus, but did not affect the total protein levels of FIH-1 in the cells. This work demonstrates that the nuclear entry of FIH-1 depends on HIF-1α. Cu deficiency caused a decrease of HIF-1α, leading to suppression of FIH-1 entry to the nucleus.

  18. Rifampicin Attenuated Global Cerebral Ischemia Injury via Activating the Nuclear Factor Erythroid 2-Related Factor Pathway

    PubMed Central

    Chen, Beibei; Cao, Huimin; Chen, Lili; Yang, Xuemei; Tian, Xiaoyan; Li, Rong; Cheng, Oumei

    2016-01-01

    Background: Recent studies have found that rifampicin has neuroprotective properties in neurodegenerative diseases. However, the exact mechanisms of action remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) has been considered a potential target for neuroprotection. In this study, we examined whether rifampicin exhibits beneficial effects mediated by the Nrf2 pathway after global cerebral ischemia (GCI). Methods: Rats were randomly assigned to four groups that included a sham group and three treatment groups with global ischemia-reperfusion [control, rifampicin, and rifampicin plus brusatol (an inhibitor of Nrf2)]. Rats were subjected to transient GCI induced by bilateral common carotid artery occlusion for 20 min with systemic hypotension by blood withdrawal. The Morris water maze test was performed for neurobehavioral testing, whereas the pathological changes were investigated using HE and TUNEL staining. The protein expression of Nrf2, hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) in the hippocampus were analyzed by Western blotting. The immunofluorescence staining was used to determine the distribution of Nrf2. Results: Rifampicin treatment significantly improved spatial learning ability compared with the control group, which was consistent with the pathological changes. In addition, rifampicin significantly elevated the nuclear expression of Nrf2, Nrf2 downstream anti-oxidant protein, HO-1 compared with the control group, and it simultaneously downregulated the expression of COX-2 in the hippocampus on day 3 after ischemia-reperfusion. Interestingly, the forenamed effects of rifampicin were abolished by pretreatment with brusatol, a specific inhibitor of Nrf2 activation. Conclusions: Rifampicin exerts neuroprotective effects against global cerebral ischemia, which may be attributed to activation of the Nrf2 pathway. PMID:27965540

  19. Nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated protein quality control in cardiomyocytes.

    PubMed

    Cui, Taixing; Lai, Yimu; Janicki, Jospeh S; Wang, Xuejun

    2016-01-01

    Protein quality control (PQC) acts to minimize the level and toxicity of malfolded proteins in the cell. It is performed by an elaborate network of molecular chaperones and targeted protein degradation pathways. PQC monitors and maintains protein homeostasis or proteostasis in the cells. Whilst chaperones may actively promote refolding of malfolded proteins, the malfolded proteins which cannot be correctly refolded are degraded by the ubiquitin proteasome system (UPS) and the autophagic-lysosome pathway (ALP). The UPS degrades individual misfolded protein molecules, whereas the ALP removes large and less soluble protein aggregates and organelles. Emerging evidence indicates that dysregulated and inadequate PQC play an important role in the pathogenesis of not only classic conformational disease but more common forms of cardiac pathology such as cardiac pathological hypertrophy and heart failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor of cellular defense, appears to regulate the USP and the ALP by directly controlling the expression of UPS- and ALP- related genes. This article highlights an emerging role of Nrf2 in the regulation of intracellular PQC as well as its potential involvement in cardiac pathology.

  20. Nuclear Factor of Activated T Cells Transcription Factor Nfatp Controls Superantigen-Induced Lethal Shock

    PubMed Central

    Tsytsykova, Alla V.; Goldfeld, Anne E.

    2000-01-01

    Tumor necrosis factor α (TNF-α) is the key mediator of superantigen-induced T cell lethal shock. Here, we show that nuclear factor of activated T cells transcription factor, NFATp, controls susceptibility to superantigen-induced lethal shock in mice through its activation of TNF-α gene transcription. In NFATp-deficient mice, T cell stimulation leads to delayed induction and attenuation of TNF-α mRNA levels, decreased TNF-α serum levels, and resistance to superantigen-induced lethal shock. By contrast, after lipopolysaccharide (LPS) challenge, serum levels of TNF-α and susceptibility to shock are unaffected. These results demonstrate that NFATp is an essential activator of immediate early TNF-α gene expression in T cells and they present in vivo evidence of the inducer- and cell type–specific regulation of TNF-α gene expression. Furthermore, they suggest NFATp as a potential selective target in the treatment of superantigen-induced lethal shock. PMID:10952728

  1. Exact factorization of the full electron-nuclear wavefunction: A quantum-classical study

    NASA Astrophysics Data System (ADS)

    Agostini, Federica; Abedi, Ali; Gross, Eberhard

    2012-02-01

    It was recently shown in [1] that the solution of the time-dependent Schr"odinger equation for a molecular system can be exactly factorized to an electronic and a nuclear contribution. In [1], the authors derived exact equations of motion for the coupled evolution of the electronic and nuclear wavefunctions, which are a good starting point to develop approximations, systematically. Based on this exact decomposition of the electron and nuclear motion, we present a quantum-classical scheme for the coupled electron-nuclear dynamics. Nuclear degrees of freedom evolve along a classical trajectory, affecting electronic motion and inducing quantum transitions, which in turn alter nuclear dynamics. Applications of the proposed method to model systems will be presented.[4pt] [1] A. Abedi, N.T. Maitra and E.K.U. Gross, Phys. Rev. Lett. 105 123002 (2010).

  2. Nuclear factor E2-related factor 2 knockdown enhances glucose uptake and alters glucose metabolism in AML12 hepatocytes.

    PubMed

    Yuan, Xiaoyang; Huang, Huijing; Huang, Yi; Wang, Jinli; Yan, Jinhua; Ding, Ling; Zhang, Cuntai; Zhang, Le

    2017-05-01

    Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce the expression of a variety of antioxidant and detoxification genes. Recently, increasing evidence has revealed roles for Nrf2 in glucose, lipid, and energy metabolism; however, the exact functions of Nrf2 in hepatocyte biology are largely unclear. In the current study, the transient knockdown of Nrf2 via siRNA transfection enhanced the glucose uptake of fasting AML12 hepatocytes to 325.3 ± 11.1% ( P < 0.05) of that of untransfected control cells. The impacts of Nrf2 knockdown (NK) on the antioxidant system, inflammatory response, and glucose metabolism were then examined in AML12 cells under both high-glucose (33 mmol/L) and low-glucose (4.5 mmol/L) conditions. NK lowered the gene and protein expression of the anti-oxidases heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 and increased p-eukaryotic initiation factor-2α(S51), p-nuclear factor-κB p65(S276), and its downstream proinflammatory factors, including interleukin-1 beta, tumor necrosis factor-α, matrix metalloproteinase 2, and matrix metalloproteinase 9, at the protein level. NK also altered the protein expression of fibroblast growth factor 21, glucose transporter type 4, insulin-like growth factor 1, forkhead box protein O1, p-AKT(S473), and p-GSK3α/β(Y279/Y216), which are involved in glucose uptake, glycogenesis, and gluconeogenesis in AML12 cells. Our results provide a comprehensive understanding of the central role of Nrf2 in the regulation of glucose metabolism in AML12 hepatocytes, in addition to its classical roles in the regulation of redox signaling, endoplasmic reticulum stress and proinflammatory responses, and support the potential of Nrf2 as a therapeutic target for the prevention and treatment of obesity and other associated metabolic syndromes. Impact statement Increasing evidence supports the complexity of Nrf2 functions beyond the antioxidant and detoxification response. Previous in

  3. Interlayer transport of nuclear spin polarization in ν = 2/3 quantum Hall states

    SciTech Connect

    Tsuda, S.; Nguyen, M. H.; Terasawa, D.; Fukuda, A.; Zheng, Y. D.; Arai, T.; Sawada, A.

    2013-12-04

    We investigated the interlayer diffusion of nuclear spin polarization (NSP) by using the phase transition point of quantum Hall states at a Landau level filling factor of ν ν 2/3 in a double quantum well sample. When the NSP is current-pumped in one layer, the magnetoresistance in the other layer is enhanced after a delay of 150 s and the raising speed of this layer is lower than that of the pumped layer. The delay and lower value of the raising speed are explained by the diffusion of NSP.

  4. Nuclear factor-κ B inducing kinase is required for graft-versus-host disease

    PubMed Central

    Sánchez-Valdepeñas, Carmen; Casanova, Lucía; Colmenero, Isabel; Arriero, Mar; González, África; Lozano, Nieves; González-Vicent, Marta; Díaz, Miguel A.; Madero, Luís; Fresno, Manuel; Ramírez, Manuel

    2010-01-01

    Background Donor T lymphocytes are directly responsible for graft-versus-host disease. Molecules important in T-cell function may, therefore, be appropriate targets for graft-versus-host disease therapy and/or prophylaxis. Here we analyzed whether nuclear factor-κ B inducing kinase might have a role in graft-versus-host disease. Design and Methods We studied the expression of nuclear factor-κ B inducing kinase in human samples from patients with graft-versus-host disease. We also explored the effect of nuclear factor-κ B inducing kinase in a murine model of graft-versus-host disease using donor cells from aly/aly mice (deficient in nuclear factor-κ B inducing kinase) and C57BL/6 mice (control). Results We detected expression of nuclear factor-κ B inducing kinase in T-lymphocytes in the pathological lesions of patients with acute graft-versus-host disease. Mice transplanted with aly/aly T lymphocytes did not develop graft-versus-host disease at all, while mice receiving C57BL/6 cells died of a lethal form of the disease. Deficiency of nuclear factor-κ B inducing kinase did not affect the engrafting ability of donor T cells, but severely impaired their expansion capacity early after transplantation, and aly/aly T cells showed a higher proportion of apoptosis than did C57BL/6 T cells. Effector T lymphocytes were the T-cell subset most affected by nuclear factor-κ B inducing kinase deficiency. We also detected lower amounts of inflammatory cytokines in the serum of mice receiving aly/aly T cells than in the serum of mice receiving C57BL/6 T cells. Conclusions Our results show that nuclear factor-κ B inducing kinase has a role in graft-versus-host disease by maintaining the viability of activated alloreactive T lymphocytes. PMID:20823135

  5. Nuclear pulse. I - Awakening to the chaos factor

    NASA Astrophysics Data System (ADS)

    Broad, W. J.

    1981-05-01

    The discovery of the significance of the high-voltage wave termed electromagnetic pulse (EMP), which occurs following the high-altitude detonation of a nuclear device, is discussed. The disruptions to the street lights, burglar alarms and circuit breakers of Hawaii caused by the detonation of a nuclear device 248 mi above Johnson Island in the Pacific in July, 1962 are described and attributed to the Compton electrons produced by the impact of gamma rays from the nuclear explosion on air in the upper atmosphere. It is pointed out, however, that at the time of the explosion, most communications systems were based on vacuum tube and electromechanical technology, which is about 10,000,000 times harder against EMP than integrated solid-state circuitry, and thus the threat posed by EMP to the power grid and communications capabilities was not apparent. Efforts undertaken to harden discrete (missile) and communications systems against EMP are outlined for the example of the Safeguard ABM system, and difficulties are pointed out. Soviet awareness of EMP is considered, and the discovery of vacuum tubes on board the state-of-the-art Foxbat MiG interceptor flown into Japan is noted as a possible indicator of this awareness. It is concluded that the problem of EMP will increase in significance as semiconductor electronics proliferates.

  6. Homeostatic restitution of cell membranes. Nuclear membrane lipid biogenesis and transport of protein from cytosol to intranuclear spaces.

    PubMed

    Slomiany, Amalia; Grabska, Maria; Slomiany, Bronislaw L

    2006-08-30

    Our studies on homeostatic restitution of cellular and subcellular membranes showed that vesicular intracellular transport is engaged in systematic and coordinated replacement of lipids and proteins in the membranes of the secretory, non-dividing epithelial cells (Slomiany et al., J. Physiol. Pharmacol. 2004; 55: 837-860). In this report, we present evidence on the homeostatic restitution of lipids in the biomembranes that constitute nuclear envelopes. We investigated nuclear membranes lipid synthesis by employing purified intact nuclei (IN), the outer nuclear membrane (ONM), the inner nuclear membrane (INM) and the cell cytosol (CC). In contrast to Endoplasmic Reticulum (ER) which in the presence of CC generates new biomembrane that forms ER vesicles transporting ER products to Golgi, the IN, ONM and INM are not producing transport vesicles. Instead, the newly synthesized lipids remain in the nuclear membranes. The membranes (INM, ONM) of IN incubated with CC become enriched with newly synthesized phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylinositol phosphates (PIPs) and phosphatidic acid (PA). The incubation of separated ONM and INM with CC also enriched the membranes with IN specific lipids identified above. Moreover, the incubation of IN or its membranes with CC afforded retention of numerous CC proteins on the nuclear membrane. Here, we concentrated on 30kDa CC protein that displayed affinity to nuclear membrane PIP2. The 30kDa CC protein bound to PIP2 of IN, INM, and ONM. With IN, initially the PIP2-30kDa CC protein complex was detected on ONM, after 30-120 min of incubation, was found on INM and in nuclear contents. At the same time when the 30 kDa protein was released from INM and found in nuclear contents, the PIP2 of INM and ONM became undetectable, while the lipid extract from the membrane displaced from IN contained labeled PI only. Since ONM is an uninterrupted continuum of ER and INM, we speculate that the synthesis of the lipids

  7. The adiabatic limit of the exact factorization of the electron-nuclear wave function.

    PubMed

    Eich, F G; Agostini, Federica

    2016-08-07

    We propose a procedure to analyze the relation between the exact factorization of the electron-nuclear wave function and the Born-Oppenheimer approximation. We define the adiabatic limit as the limit of infinite nuclear mass. To this end, we introduce a unit system that singles out the dependence on the electron-nuclear mass ratio of each term appearing in the equations of the exact factorization. We observe how non-adiabatic effects induced by the coupling to the nuclear motion affect electronic properties and we analyze the leading term, connecting it to the classical nuclear momentum. Its dependence on the mass ratio is tested numerically on a model of proton-coupled electron transfer in different non-adiabatic regimes.

  8. Environmental Baseline File: National Transportation

    SciTech Connect

    1999-05-22

    This Environmental Baseline File summarizes and consolidates information related to the national-level transportation of commercial spent nuclear fuel. Topics address include: shipmnents of commercial spent nuclear fuel based on mostly truck and mostly rail shipping scenarios; transportation routing for commercial spent nuclear fuel sites and DOE sites; radionuclide inventories for various shipping container capacities; transportation routing; populations along transportation routes; urbanized area population densities; the impacts of historical, reasonably foreseeable, and general transportation; state-level food transfer factors; Federal Guidance Report No. 11 and 12 radionuclide dose conversion factors; and national average atmospheric conditions.

  9. Reconstruction of adenovirus replication origins with a human nuclear factor I binding site.

    PubMed

    Adhya, S; Shneidman, P S; Hurwitz, J

    1986-03-05

    Nuclear factor I is a host-coded DNA-binding protein that stimulates initiation of adenovirus DNA replication. To understand the mechanism of action of nuclear factor I, we have constructed, by recombinant DNA techniques, origins of replication in which the adenovirus type 5 nuclear factor I binding site (FIB site) has been replaced by a FIB site isolated from human genomic DNA (Gronostajski, R. M., Nagata, K., and Hurwitz, J. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 4013-4017). Assays of such recombinants for initiation and elongation in vitro showed that nuclear factor I was active only when the FIB site was relatively close to the DNA terminus, i.e. the FIB site was centered at nucleotides 30-36 from the end of the DNA. Nuclear factor I was active in either orientation within this distance range. The presence of one or two additional FIB sites in the downstream region had no effect. The implications of these results for the mechanism of nuclear factor I action are discussed.

  10. Shuanghuanglian injection downregulates nuclear factor-kappa B expression in mice with viral encephalitis★

    PubMed Central

    Gu, Naibing; Tian, Ye; Di, Zhengli; Han, Caiping; Lei, Hui; Zhang, Gejuan

    2012-01-01

    A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis. PMID:25368635

  11. Shuanghuanglian injection downregulates nuclear factor-kappa B expression in mice with viral encephalitis.

    PubMed

    Gu, Naibing; Tian, Ye; Di, Zhengli; Han, Caiping; Lei, Hui; Zhang, Gejuan

    2012-11-25

    A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.

  12. Effects of molybdenum and silver on iodine transport in primary circuit on severe nuclear accidents

    SciTech Connect

    Kalilainen, J.; Rantanen, P.; Karkela, T.; Lipponen, M.; Auvinen, A.; Jokiniemi, J.

    2012-07-01

    This experimental study was a continuation of the study conducted at VTT to investigate the effects of reactions on primary circuit surfaces to transport of gaseous and aerosol phase iodine during the hypothetical severe nuclear accident. Cesium iodide was used as a precursor in every experiment. In the experiments it was observed that the hydrogen in the atmosphere decreased the fraction of released gaseous iodine. As the temperature was lowered, less iodine was released, but the fraction of gaseous iodine from the overall released iodine was increased. As molybdenum trioxide was introduced to the precursor, the fraction of gaseous iodine from the overall released iodine was increased significantly. Also, Mo decreased the transport of Cs and caused significant depositions to the reaction furnace. Addition of silver to the CsI precursor at 650 deg. C decreased the release of iodine as well as the fraction of gaseous iodine. At 400 deg. C, Ag + CsI as well as Ag + MoO{sub 3} + CsI precursor significantly increased the release of gaseous iodine, where almost no aerosol particles were released. With B{sub 2}O{sub 3} + CsI precursor it was observed that in the atmosphere without H{sub 2}O, the released iodine was mostly in gaseous form. (authors)

  13. Finite element analysis of ion transport in solid state nuclear waste form materials

    NASA Astrophysics Data System (ADS)

    Rabbi, F.; Brinkman, K.; Amoroso, J.; Reifsnider, K.

    2017-09-01

    Release of nuclear species from spent fuel ceramic waste form storage depends on the individual constituent properties as well as their internal morphology, heterogeneity and boundary conditions. Predicting the release rate is essential for designing a ceramic waste form, which is capable of effectively storing the spent fuel without contaminating the surrounding environment for a longer period of time. To predict the release rate, in the present work a conformal finite element model is developed based on the Nernst Planck Equation. The equation describes charged species transport through different media by convection, diffusion, or migration. And the transport can be driven by chemical/electrical potentials or velocity fields. The model calculates species flux in the waste form with different diffusion coefficient for each species in each constituent phase. In the work reported, a 2D approach is taken to investigate the contributions of different basic parameters in a waste form design, i.e., volume fraction, phase dispersion, phase surface area variation, phase diffusion co-efficient, boundary concentration etc. The analytical approach with preliminary results is discussed. The method is postulated to be a foundation for conformal analysis based design of heterogeneous waste form materials.

  14. Radioecological consequences of a potential accident during transport of spent nuclear fuel along an Arctic coastline.

    PubMed

    Iosjpe, M; Reistad, O; Amundsen, I B

    2009-02-01

    This article presents results pertaining to a risk assessment of the potential consequences of a hypothetical accident occurring during the transportation by ship of spent nuclear fuel (SNF) along an Arctic coastline. The findings are based on modelling of potential releases of radionuclides, radionuclide transport and uptake in the marine environment. Modelling work has been done using a revised box model developed at the Norwegian Radiation Protection Authority. Evaluation of the radioecological consequences of a potential accident in the southern part of the Norwegian Current has been made on the basis of calculated collective dose to man, individual doses for the critical group, concentrations of radionuclides in seafood and doses to marine organisms. The results of the calculations indicate a large variability in the investigated parameters above mentioned. On the basis of the calculated parameters the maximum total activity ("accepted accident activity") in the ship, when the parameters that describe the consequences after the examined potential accident are still in agreement with the recommendations and criterions for protection of the human population and the environment, has been evaluated.

  15. The optimization of mechanical properties for nuclear transportation casks in ASTM A350 LF5

    SciTech Connect

    Price, S.; Honeyman, G.A.

    1997-12-31

    Transport flasks are required for the movement of spent nuclear fuel. Due to their nature of operation, it is necessary that these flasks are produced from forged steels with exceptional toughness properties. The material specification generally cited for flask manufacture is ASTM A350 Grade LF5 Class 1, a carbon-manganese-nickel alloy. The range of chemical analysis permitted by this specification is very broad and it is the responsibility of the material manufacturer to select a composition within this range which will satisfy all the mechanical properties requirements, and to ensure safe and reliable performance. Forgemasters Steel and Engineering Limited have experience in the manufacture of large high integrity fuel element flask forgings which extend over several decades. This experience and involvement in international standards in US, Europe and Japan has facilitated the development of an optimized analysis with a low carbon content, nickel levels towards the top end of the allowed range, a deliberate aluminum addition to control grain size and strictly controlled residual element levels. The resultant steel has excellent low temperature impact properties which greatly exceed the requirements of the specification. This analysis is now being adopted for the manufacture of all current transport flasks.

  16. Barometric gas transport along faults and its application to nuclear test-ban monitoring

    SciTech Connect

    Carrigan, C. R.; Heinle, R. A.; Hudson, G. B.; Nitao, J. J.; Zucca, J. J.

    1997-06-01

    Underground nuclear explosions produce a unique but evanescent set of radionuclide gases that potentially can be used in the context of an on-site, test-ban monitoring program to differentiate them from other detected events such as earthquakes or mining activity. In Part I of this report we describe an experiment to evaluate the upward transport of gases from an underground explosion using two gas tracers with very different diffusivities that were released in a 400- m-deep, chemical explosive detonation. The less diffusive (more massive) tracer was detected on a nearby geologic fault 50 days following the detonation while the more diffusive tracer was-- detected 375 days after release. Computer simulations indicate that the arrival time and the chromatographic behavior of transport are characteristic of barometrically induced flow in a fractured, porous matrix regime. For a hypothetical 1-kiloton fission explosion subject to the same weather and gas transport conditions of the chemical explosion, simulations predict the delectability of argon-37 after 80 days in spite of depletion by radioactive decay. Largely because of the earlier arrival of xenon-133, owing to its lower binary gas diffusivity, the exceedingly short lived isotope should also be detectable-arriving about 30 days earlier than argon. in Part II we consider that our prediction of the delectability of argon and xenon is based upon the small volume (0.00001 M3) sampling technique of the NPE tracer-gas sampling study while actual sampling for radionuclides would involve drawing much larger volume (possibly 0.1- 1 M3) gas samples from the near-surface.

  17. Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury.

    PubMed

    Collins, Alan R; Gupte, Anisha A; Ji, Ruirui; Ramirez, Maricela R; Minze, Laurie J; Liu, Joey Z; Arredondo, Magda; Ren, Yuelan; Deng, Tuo; Wang, Jun; Lyon, Christopher J; Hsueh, Willa A

    2012-12-01

    To determine the impact of hematopoietic deletion of nuclear factor- (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model. Two-month-old male low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2(-/-)) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2(-/-) bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%; P=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency. Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity.

  18. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data. © The Author(s) 2014.

  19. The convergent roles of the nuclear factor I transcription factors in development and cancer.

    PubMed

    Chen, Kok-Siong; Lim, Jonathan W C; Richards, Linda J; Bunt, Jens

    2017-09-26

    The nuclear factor I (NFI) transcription factors play important roles during normal development and have been associated with developmental abnormalities in humans. All four family members, NFIA, NFIB, NFIC and NFIX, have a homologous DNA binding domain and function by regulating cell proliferation and differentiation via the transcriptional control of their target genes. More recently, NFI genes have also been implicated in cancer based on genomic analyses and studies of animal models in a variety of tumours across multiple organ systems. However, the association between their functions in development and in cancer is not well described. In this review, we summarise the evidence suggesting a converging role for the NFI genes in development and cancer. Our review includes all cancer types in which the NFI genes are implicated, focusing predominantly on studies demonstrating their oncogenic or tumour-suppressive potential. We conclude by presenting the challenges impeding our understanding of NFI function in cancer biology, and demonstrate how a developmental perspective may contribute towards overcoming such hurdles. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Modeling most likely pathways for smuggling radioactive and special nuclear materials on a worldwide multimodal transportation network

    SciTech Connect

    Saeger, Kevin J; Cuellar, Leticia

    2010-01-01

    Nuclear weapons proliferation is an existing and growing worldwide problem. To help with devising strategies and supporting decisions to interdict the transport of nuclear material, we developed the Pathway Analysis, Threat Response and Interdiction Options Tool (PATRIOT) that provides an analytical approach for evaluating the probability that an adversary smuggling radioactive or special nuclear material will be detected during transit. We incorporate a global, multi-modal transportation network, explicit representation of designed and serendipitous detection opportunities, and multiple threat devices, material types, and shielding levels. This paper presents the general structure of PATRIOT, and focuses on the theoretical framework used to model the reliabilities of all network components that are used to predict the most likely pathways to the target.

  1. Modeling most likely pathways for smuggling radioactive and special nuclear materials on a worldwide multi-modal transportation network

    SciTech Connect

    Saeger, Kevin J; Cuellar, Leticia

    2010-10-28

    Nuclear weapons proliferation is an existing and growing worldwide problem. To help with devising strategies and supporting decisions to interdict the transport of nuclear material, we developed the Pathway Analysis, Threat Response and Interdiction Options Tool (PATRIOT) that provides an analytical approach for evaluating the probability that an adversary smuggling radioactive or special nuclear material will be detected during transit. We incorporate a global, multi-modal transportation network, explicit representation of designed and serendipitous detection opportunities, and multiple threat devices, material types, and shielding levels. This paper presents the general structure of PATRIOT, all focuses on the theoretical framework used to model the reliabilities of all network components that are used to predict the most likely pathways to the target.

  2. GATA transcription factors associate with a novel class of nuclear bodies in erythroblasts and megakaryocytes.

    PubMed Central

    Elefanty, A G; Antoniou, M; Custodio, N; Carmo-Fonseca, M; Grosveld, F G

    1996-01-01

    The nuclear distribution of GATA transcription factors in murine haemopoietic cells was examined by indirect immunofluorescence. Specific bright foci of GATA-1 fluorescence were observed in erythroleukaemia cells and primary murine erythroblasts and megakaryocytes, in addition to diffuse nucleoplasmic localization. These foci, which were preferentially found adjacent to nucleoli or at the nuclear periphery, did not represent sites of active transcription or binding of GATA-1 to consensus sites in the beta-globin loci. Immunoelectron microscopy demonstrated the presence of intensely labelled structures likely to represent the GATA-1 foci seen by immunofluorescence. The GATA-1 nuclear bodies differed from previously described nuclear structures and there was no co-localization with nuclear antigens involved in RNA processing or other ubiquitous (Spl, c-Jun and TBP) or haemopoietic (NF-E2) transcription factors. Interestingly, GATA-2 and GATA-3 proteins also localized to the same nuclear bodies in cell lines co-expressing GATA-1 and -2 or GATA-1 and -3 gene products. This pattern of distribution is, thus far, unique to the GATA transcription factors and suggests a protein-protein interaction with other components of the nuclear bodies via the GATA zinc finger domain. Images PMID:8617207

  3. GCR Transport in the Brain: Assessment of Self-Shielding, Columnar Damage, and Nuclear Reactions on Cell Inactivation Rates

    NASA Technical Reports Server (NTRS)

    Shavers, M. R.; Atwell, W.; Cucinotta, F. A.; Badhwar, G. D. (Technical Monitor)

    1999-01-01

    Radiation shield design is driven by the need to limit radiation risks while optimizing risk reduction with launch mass/expense penalties. Both limitation and optimization objectives require the development of accurate and complete means for evaluating the effectiveness of various shield materials and body-self shielding. For galactic cosmic rays (GCR), biophysical response models indicate that track structure effects lead to substantially different assessments of shielding effectiveness relative to assessments based on LET-dependent quality factors. Methods for assessing risk to the central nervous system (CNS) from heavy ions are poorly understood at this time. High-energy and charge (HZE) ion can produce tissue events resulting in damage to clusters of cells in a columnar fashion, especially for stopping heavy ions. Grahn (1973) and Todd (1986) have discussed a microlesion concept or model of stochastic tissue events in analyzing damage from HZE's. Some tissues, including the CNS, maybe sensitive to microlesion's or stochastic tissue events in a manner not illuminated by either conventional dosimetry or fluence-based risk factors. HZE ions may also produce important lateral damage to adjacent cells. Fluences of high-energy proton and alpha particles in the GCR are many times higher than HZE ions. Behind spacecraft and body self-shielding the ratio of protons, alpha particles, and neutrons to HZE ions increases several-fold from free-space values. Models of GCR damage behind shielding have placed large concern on the role of target fragments produced from tissue atoms. The self-shielding of the brain reduces the number of heavy ions reaching the interior regions by a large amount and the remaining light particle environment (protons, neutrons, deuterons. and alpha particles) may be the greatest concern. Tracks of high-energy proton produce nuclear reactions in tissue, which can deposit doses of more than 1 Gv within 5 - 10 cell layers. Information on rates of

  4. GCR Transport in the Brain: Assessment of Self-Shielding, Columnar Damage, and Nuclear Reactions on Cell Inactivation Rates

    NASA Technical Reports Server (NTRS)

    Shavers, M. R.; Atwell, W.; Cucinotta, F. A.; Badhwar, G. D. (Technical Monitor)

    1999-01-01

    Radiation shield design is driven by the need to limit radiation risks while optimizing risk reduction with launch mass/expense penalties. Both limitation and optimization objectives require the development of accurate and complete means for evaluating the effectiveness of various shield materials and body-self shielding. For galactic cosmic rays (GCR), biophysical response models indicate that track structure effects lead to substantially different assessments of shielding effectiveness relative to assessments based on LET-dependent quality factors. Methods for assessing risk to the central nervous system (CNS) from heavy ions are poorly understood at this time. High-energy and charge (HZE) ion can produce tissue events resulting in damage to clusters of cells in a columnar fashion, especially for stopping heavy ions. Grahn (1973) and Todd (1986) have discussed a microlesion concept or model of stochastic tissue events in analyzing damage from HZE's. Some tissues, including the CNS, maybe sensitive to microlesion's or stochastic tissue events in a manner not illuminated by either conventional dosimetry or fluence-based risk factors. HZE ions may also produce important lateral damage to adjacent cells. Fluences of high-energy proton and alpha particles in the GCR are many times higher than HZE ions. Behind spacecraft and body self-shielding the ratio of protons, alpha particles, and neutrons to HZE ions increases several-fold from free-space values. Models of GCR damage behind shielding have placed large concern on the role of target fragments produced from tissue atoms. The self-shielding of the brain reduces the number of heavy ions reaching the interior regions by a large amount and the remaining light particle environment (protons, neutrons, deuterons. and alpha particles) may be the greatest concern. Tracks of high-energy proton produce nuclear reactions in tissue, which can deposit doses of more than 1 Gv within 5 - 10 cell layers. Information on rates of

  5. Hepatocyte Nuclear Factor-1β Regulates Urinary Concentration and Response to Hypertonicity.

    PubMed

    Aboudehen, Karam; Noureddine, Lama; Cobo-Stark, Patricia; Avdulov, Svetlana; Farahani, Shayan; Gearhart, Micah D; Bichet, Daniel G; Pontoglio, Marco; Patel, Vishal; Igarashi, Peter

    2017-10-01

    The transcription factor hepatocyte nuclear factor-1β (HNF-1β) is essential for normal kidney development and function. Inactivation of HNF-1β in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1β specifically in renal collecting ducts (CDs). CD-specific HNF-1β mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1β mutant mice exhibited polyuria and polydipsia. Before the development of significant renal structural abnormalities, mutant mice exhibited low urine osmolality at baseline and after water restriction and administration of desmopressin. However, mutant and wild-type mice had similar plasma vasopressin and solute excretion levels. HNF-1β mutant kidneys showed increased expression of aquaporin-2 mRNA but mislocalized expression of aquaporin-2 protein in the cytoplasm of CD cells. Mutant kidneys also had decreased expression of the UT-A urea transporter and collectrin, which is involved in apical membrane vesicle trafficking. Treatment of HNF-1β mutant mIMCD3 cells with hypertonic NaCl inhibited the induction of osmoregulated genes, including Nr1h4, which encodes the transcription factor FXR that is required for maximal urinary concentration. Chromatin immunoprecipitation and sequencing experiments revealed HNF-1β binding to the Nr1h4 promoter in wild-type kidneys, and immunoblot analysis revealed downregulated expression of FXR in HNF-1β mutant kidneys. These findings reveal a novel role of HNF-1β in osmoregulation and identify multiple mechanisms, whereby mutations of HNF-1β produce defects in urinary concentration. Copyright © 2017 by the American Society of Nephrology.

  6. Characterization of a multiple endogenously expressed adenosine triphosphate-binding cassette transporters using nuclear and cellular membrane affinity chromatography columns.

    PubMed

    Habicht, K-L; Singh, N S; Khadeer, M A; Shimmo, R; Wainer, I W; Moaddel, R

    2014-04-25

    Glioblastoma multiforme is an aggressive form of human astrocytoma, with poor prognosis due to multi-drug resistance to a number of anticancer drugs. The observed multi-drug resistance is primarily due to the efflux activity of ATP-Binding Cassette (ABC) efflux transporters such as Pgp, MRP1 and BCRP. The expression of these transporters has been demonstrated in nuclear and cellular membranes of the LN-229 human glioblastoma cell line. Nuclear membrane and cellular membrane fragments from LN-229 cells were immobilized on the IAM stationary phase to create nuclear and cellular membrane affinity chromatography columns, (NMAC(LN-229)) and (CMAC(LN-229)), respectively. Pgp, MRP1 and BCRP transporters co-immobilized on both columns were characterized and compared by establishing the binding affinities for estrone-3-sulfate (3.8 vs. 3.7μM), verapamil (0.6 vs. 0.7μM) and prazosin (0.099 vs. 0.033μM) on each column and no significant differences were observed. Since the marker ligands had overlapping selectivities, the selective characterization of each transporter was carried out by saturation of the binding sites of the non-targeted transporters. The addition of verapamil (Pgp and MRP1 substrate) to the mobile phase allowed the comparative screening of eight compounds at the nuclear and cellular BCRP using etoposide as the marker ligand. AZT increased the retention of etoposide (+15%), a positive allosteric interaction, on the CMAC(LN-229) column and decreased it (-5%) on the NMAC(LN-229), while the opposite effect was produced by rhodamine. The results indicate that there are differences between the cellular and nuclear membrane expressed BCRP and that NMAC and CMAC columns can be used to probe these differences.

  7. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis.

    PubMed

    Parviz, Fereshteh; Matullo, Christine; Garrison, Wendy D; Savatski, Laura; Adamson, John W; Ning, Gang; Kaestner, Klaus H; Rossi, Jennifer M; Zaret, Kenneth S; Duncan, Stephen A

    2003-07-01

    Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.

  8. Analysis of nuclear mitochondrial DNAs and factors affecting patterns of integration in plant species.

    PubMed

    Yoshida, Takanori; Furihata, Hazuka Y; Kawabe, Akira

    2017-09-12

    Sequences homologous to organellar DNA that have been integrated into nuclear genomes are referred to as nuclear mitochondrial DNAs (NUMTs) and nuclear plastid DNAs (NUPTs). NUMTs in nine plant species were analyzed to reveal the integration patterns and possible factors involved. The cumulative lengths of NUMTs in two-thirds of species analyzed were greater than those of NUPTs observed in a previous study. The age distribution of NUMTs was similar to that of NUPTs, suggesting similar mechanisms for integration and degradation of both NUPTs and NUMTs. Nuclear genome size and the cumulative length of NUMTs showed a significant positive correlation for older but not younger NUMTs. The same correlation was also found between nuclear genome size and older NUPTs in 17 species. These results suggested that genome size is a key factor to determine the cumulative length of relatively older NUPTs/NUMTs. Although the factor(s) determining the cumulative length of younger NUPTs/NUMTs is unclear, these sequences may be more deleterious, which could explain the different manner of determining the cumulative length of younger NUPTs/NUMTs in nuclear genomes. In addition, a relationship between the cumulative length of integrated NUMTs and complexity of mitochondrial genomes (i.e., the number of repeats) was found. The results indicate that the structural complexity of both NUMTs and their original mitochondrial sequences affects integration and degradation processes.

  9. Source term estimation of radioxenon released from the Fukushima Dai-ichi nuclear reactors using measured air concentrations and atmospheric transport modeling.

    PubMed

    Eslinger, P W; Biegalski, S R; Bowyer, T W; Cooper, M W; Haas, D A; Hayes, J C; Hoffman, I; Korpach, E; Yi, J; Miley, H S; Rishel, J P; Ungar, K; White, B; Woods, V T

    2014-01-01

    Systems designed to monitor airborne radionuclides released from underground nuclear explosions detected radioactive fallout across the northern hemisphere resulting from the Fukushima Dai-ichi Nuclear Power Plant accident in March 2011. Sampling data from multiple International Modeling System locations are combined with atmospheric transport modeling to estimate the magnitude and time sequence of releases of (133)Xe. Modeled dilution factors at five different detection locations were combined with 57 atmospheric concentration measurements of (133)Xe taken from March 18 to March 23 to estimate the source term. This analysis suggests that 92% of the 1.24 × 10(19) Bq of (133)Xe present in the three operating reactors at the time of the earthquake was released to the atmosphere over a 3 d period. An uncertainty analysis bounds the release estimates to 54-129% of available (133)Xe inventory.

  10. Identification of a nuclear transport inhibitory signal (NTIS) in the basic domain of HIV-1 Vif protein.

    PubMed

    Friedler, A; Zakai, N; Karni, O; Friedler, D; Gilon, C; Loyter, A

    1999-06-11

    The HIV-1 auxiliary protein Vif contains a basic domain within its sequence. This basic region,90RKKR93, is similar to the prototypic nuclear localization signal (NLS). However, Vif is not a nuclear protein and does not function in the nucleus. Here we have studied the karyophilic properties of this basic region. We have synthesized peptides corresponding to this positively charged NLS-like region and observed that these peptides inhibited nuclear transport via the importin pathway in vitro with IC50values in the micromolar range. Inhibition was observed only with peptides derived from the positively charged region, but not from other regions of the Vif protein, showing sequence specificity. On the other hand, the Vif inhibitory peptide Vif88-98 did not confer karyophilic properties when conjugated to BSA. The inactive Vif conjugate and the active SV40-NLS-BSA conjugate both contained a similar number of peptides conjugated to each BSA molecule, as was determined by amino acid analysis of the peptide-BSA conjugates. Thus, the lack of nuclear import of the Vif peptide-BSA conjugate cannot be attributed to insufficient number of conjugated peptide molecules per BSA molecule. Our results suggest that the HIV-1 Vif protein carries an NLS-like sequence that inhibits, but does not mediate, nuclear import via the importin pathway. We have termed such signals as nuclear transport inhibitory signals (NTIS). The possible role of NTIS in controlling nuclear uptake, and specifically during virus infection, is discussed herein. Our results raise the possibility that NLS-like sequences of certain low molecular weight viral proteins may serve as regulators of nucleocytoplasmic trafficking and not neccessarily as mediators of nuclear import.

  11. Intra-nuclear mobility and target search mechanisms of transcription factors: a single-molecule perspective on gene expression.

    PubMed

    Normanno, Davide; Dahan, Maxime; Darzacq, Xavier

    2012-06-01

    Precise expression of specific genes in time and space is at the basis of cellular viability as well as correct development of organisms. Understanding the mechanisms of gene regulation is fundamental and still one of the great challenges for biology. Gene expression is regulated also by specific transcription factors that recognize and bind to specific DNA sequences. Transcription factors dynamics, and especially the way they sample the nucleoplasmic space during the search for their specific target in the genome, are a key aspect for regulation and it has been puzzling researchers for forty years. The scope of this review is to give a state-of-the-art perspective over the intra-nuclear mobility and the target search mechanisms of specific transcription factors at the molecular level. Going through the seminal biochemical experiments that have raised the first questions about target localization and the theoretical grounds concerning target search processes, we describe the most recent experimental achievements and current challenges in understanding transcription factors dynamics and interactions with DNA using in vitro assays as well as in live prokaryotic and eukaryotic cells. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. The effect of transverse flow on the nuclear modification factor at RHIC and LHC

    SciTech Connect

    Betz, Barbara; Gyulassy, Miklos

    2016-01-22

    We determine the nuclear modification factor at RHIC and LHC energies using a generic jet-energy loss model that is expanded by an additional flow factor accounting for the impact of transverse flow. We consider a pQCD-based ansatz with and without jet-energy loss fluctuations that is coupled to a state-of-the-art hydrodynamic prescription and includes a running coupling effect. We show that the nuclear modification factor is a rather insensitive quantity that is barely affected by the flow dynamics of the medium created in a heavy-ion collision.

  13. Neutron Transport Characteristics of a Nuclear Reactor Based Dynamic Neutron Imaging System

    SciTech Connect

    Khaial, Anas M.; Harvel, Glenn D.; Chang, Jen-Shih

    2006-07-01

    An advanced dynamic neutron imaging system has been constructed in the McMaster Nuclear Reactor (MNR) for nondestructive testing and multi-phase flow studies in energy and environmental applications. A high quality neutron beam is required with a thermal neutron flux greater than 5.0 x 10{sup 6} n/cm{sup 2}-s and a collimation ratio of 120 at image plane to promote high-speed neutron imaging up to 2000 frames per second. Neutron source strength and neutron transport have been experimentally and numerically investigated. Neutron source strength at the beam tube entrance was evaluated experimentally by measuring the thermal and fast neutron fluxes, and simple analytical neutron transport calculations were performed based upon these measured neutron fluxes to predict facility components in accordance with high-speed dynamic neutron imaging and operation safety requirements. Monte-Carlo simulations (using MCNP-4B code) with multiple neutron energy groups have also been used to validate neutron beam parameters and to ensure shielding capabilities of facility shutter and cave walls. Neutron flux distributions at the image plane and the neutron beam characteristics were experimentally measured by irradiating a two-dimensional array of Copper foils and using a real-time neutron radiography system. The neutron image characteristics -- such as neutron flux, image size, beam quality -- measured experimentally and predicted numerically for beam tube, beam shutter and radiography cave are compared and discussed in detail in this paper. The experimental results show that thermal neutron flux at image plane is nearly uniform over an imaging area of 20.0-cm diameter and its magnitude ranges from 8.0 x 10{sup 6} - 1.0 x 10{sup 7} n/cm{sup 2}-sec while the neutron-to-gamma ratio is 6.0 x 10{sup 5} n/cm{sup 2}-{mu}Sv. (authors)

  14. Atmospheric transport of neutrons and gamma rays from a high-altitude nuclear detonation

    SciTech Connect

    Byrd, R.C.

    1995-07-01

    Although radiation outputs from nuclear detonations in free space are well established, few studies exist of effect of atmospheric transport on the resulting intensity, energy, and time signatures. This report presents calculations for generic sources at high altitudes, 20-50 km above the Earth`s surface, in an atmosphere whose density decreases almost exponentially with height. The sources are instantaneous time bursts with simple energy dependences: gamma rays use an evaporation spectrum; neutrons use either a Gaussian fusion or a Maxwell fission spectrum. The observation angles vary from vertical to 5{degrees} below the horizon, and detectors are placed in either geosynchronous or low Earth orbits (100 km). All calculations use the Monte Carlo N-Particle (MCNP) transport code in either its photon, neutron, or coupled neutron-photon modes, with the coupled mode being applied to the production of gamma rays by neutron inelastic scattering. The standard MCNP outputs are analyzed to extract the intensity, energy, and time dependences of the fluence as functions of either source altitude or observation angle. In general, the intensities drop rapidly below about 30-km source altitude or +5` slant angle. Above these limits, the gamma-ray signal loses substantial intensity but still contains most of the original source information. In contrast, neutron scattering produces little or no decrease in intensity, but it rapidly degrades much of the information about the original source spectrum. Finally, although there is abundant gamma-ray production from neutron inelastic scattering, the resulting signatures appear to provide little additional information.

  15. Regulation of the Drosophila hypoxia-inducible factor alpha Sima by CRM1-dependent nuclear export.

    PubMed

    Romero, Nuria M; Irisarri, Maximiliano; Roth, Peggy; Cauerhff, Ana; Samakovlis, Christos; Wappner, Pablo

    2008-05-01

    Hypoxia-inducible factor alpha (HIF-alpha) proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional coactivator recruitment, and subcellular localization. It was previously reported that these transcription factors are mainly nuclear in hypoxia and cytoplasmic in normoxia, but so far the molecular basis of this regulation is unclear. We show here that the Drosophila melanogaster HIF-alpha protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal and two functional nuclear export signals (NESs). These NESs are in the Sima basic helix-loop-helix (bHLH) domain and promote CRM1-dependent nuclear export. Site-directed mutagenesis of either NES provoked Sima nuclear retention and increased transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and probably functional in the bHLH domains of several bHLH-PAS proteins. We propose that rapid nuclear export of Sima regulates the duration of cellular responses to hypoxia.

  16. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates airway epithelial barrier integrity.

    PubMed

    Shintani, Yoshitaka; Maruoka, Shuichiro; Gon, Yasuhiro; Koyama, Daisuke; Yoshida, Akiko; Kozu, Yutaka; Kuroda, Kazumichi; Takeshita, Ikuko; Tsuboi, Eriko; Soda, Kaori; Hashimoto, Shu

    2015-09-01

    Inhaled corticosteroids enhance airway epithelial barrier integrity. However, the mechanism by which they accomplish this is unclear. Therefore, we investigated steroid-inducible genes and signaling pathways that were involved in enhancing airway epithelial barrier integrity. A human bronchial epithelial cell line (16HBE cells) was cultured with 10(-6) M dexamethasone (DEX) for 3 days to enhance epithelial barrier integrity. After measuring transepithelial electrical resistance (TER) and paracellular permeability, we extracted total RNA from 16HBE cells and performed microarray and pathway analysis. After we identified candidate genes and a canonical pathway, we measured TER and immunostained for tight junction (TJ) and adherent junction (AJ) proteins in cells that had been transfected with specific small interfering RNAs (siRNAs) for these genes. We identified a nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response pathway which was primarily involved in the steroid-induced enhancement of airway epithelial barrier integrity. Transfecting cells with Nrf2 specific siRNA reduced the steroid-induced enhancement of airway epithelial barrier integrity and the accumulation of TJ and AJ proteins at sites of cell-cell contact. Moreover, based on pathway analysis, aldehyde oxidase 1 (AOX1) was identified as a downstream enzyme of Nrf2. Transfecting cells with AOX1-specific siRNA also reduced the steroid-induced enhancement of airway epithelial barrier integrity. Our results indicated that the Nrf2/AOX1 pathway was important for enhancing airway epithelial barrier integrity. Because the airway epithelium of asthmatics is susceptible to reduced barrier integrity, this pathway might be a new therapeutic target for asthma. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1

    PubMed Central

    Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina; Ciurea, Stefan; Yamamoto, Shinichi; Kikkawa, Mika; Kazuno, Saiko; Taka, Hikari; Kaga, Naoko; Arai, Hajime; Miida, Takashi; Andreeff, Michael; Konopleva, Marina; Tabe, Yoko

    2017-01-01

    Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, characterized by aberrant expression of growth-regulating and oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is associated with its pathogenesis. mTOR signaling, a central regulator of cell metabolism, is frequently activated in MCL and is also an important therapeutic target in this cancer. This study investigated the antitumor effects and molecular/metabolic changes induced by the combination of the small-molecule selective inhibitor XPO1 inhibitor KPT-185 and the dual mTORC1/2 kinase inhibitor AZD-2014 on MCL cells. AZD-2014 enhanced the KPT-185–induced inhibition of cell growth and repression of cell viability. The combination of KPT-185 and AZD-2014 downregulated c-Myc and heat shock factor 1 (HSF1) with its target heat shock protein 70 (HSP70). As a consequence, the combination caused repression of ribosomal biogenesis demonstrated by iTRAQ proteomic analyses. Metabolite assay by CETOF-MS showed that AZD-2014 enhanced the KPT-185–induced repression of MCL cellular energy metabolism through the TCA (Krebs) cycle, and further repressed KPT-185–caused upregulation of glycolysis. Thus the simultaneous inhibition of XPO1 and mTOR signaling is a novel and promising strategy targeting prosurvival metabolism in MCL. PMID:28388555

  18. Towards high precision measurements of nuclear g-factors for the Be isotopes

    NASA Astrophysics Data System (ADS)

    Takamine, A.; Wada, M.; Okada, K.; Ito, Y.; Schury, P.; Arai, F.; Katayama, I.; Imamura, K.; Ichikawa, Y.; Ueno, H.; Wollnik, H.; Schuessler, H. A.

    2016-06-01

    We describe the present status of future high-precision measurements of nuclear g-factors utilizing laser-microwave double and laser-microwave-rf triple resonance methods for online-trapped, laser-cooled radioactive beryllium isotope ions. These methods have applicability to other suitably chosen isotopes and for beryllium show promise in deducing the hyperfine anomaly of 11Be with a sufficiently high precision to study the nuclear magnetization distribution of this one-neutron halo nucleus in a nuclear-model-independent manner.

  19. Human factors design review guidelines for advanced nuclear control room technologies

    SciTech Connect

    O'Hara, J.; Brown, W. ); Granda, T.; Baker, C. )

    1991-01-01

    Advanced control rooms (ACRs) for future nuclear power plants are being designed utilizing computer-based technologies. The US Nuclear Regulatory Commission reviews the human engineering aspects of such control rooms to ensure that they are designed to good human factors engineering principles and that operator performance and reliability are appropriately supported in order to protect public health and safety. This paper describes the rationale, general approach, and initial development of an NRC Advanced Control Room Design Review Guideline. 20 refs., 1 fig.

  20. Information needs for siting new, and evaluating current, nuclear facilities: ecology, fate and transport, and human health.

    PubMed

    Burger, Joanna; Clarke, James; Gochfeld, Michael

    2011-01-01

    The USA is entering an era of energy diversity, and increasing nuclear capacity and concerns focus on accidents, security, waste, and pollution. Physical buffers that separate outsiders from nuclear facilities often support important natural ecosystems but may contain contaminants. The US Nuclear Regulatory Commission (NRC) licenses nuclear reactors; the applicant provides environmental assessments that serve as the basis for Environmental Impact Statements developed by NRC. We provide a template for the types of information needed for safe siting of nuclear facilities with buffers in three categories: ecological, fate and transport, and human health information that can be used for risk evaluations. Each item on the lists is an indicator for evaluation, and individual indicators can be selected for specific region. Ecological information needs include biodiversity (species, populations, communities) and structure and functioning of ecosystems, habitats, and landscapes, in addition to common, abundant, and unique species and endangered and rare ones. The key variables of fate and transport are sources of release for radionuclides and other chemicals, nature of releases (atmospheric vapors, subsurface liquids), features, and properties of environmental media (wind speed, direction and atmospheric stability, hydraulic gradient, hydraulic conductivity, groundwater chemistry). Human health aspects include receptor populations (demography, density, dispersion, and distance), potential pathways (drinking water sources, gardening, fishing), and exposure opportunities (lifestyle activities). For each of the three types of information needs, we expect that only a few of the indicators will be applicable to a particular site and that stakeholders should agree on a site-specific suite.

  1. Reassessment of selected factors affecting siting of Nuclear Power Plants

    SciTech Connect

    Davis, R.E.; Hanson, A.L.; Mubayi, V.; Nourbakhsh, H.P.

    1997-02-01

    Brookhaven National Laboratory has performed a series of probabilistic consequence assessment calculations for nuclear reactor siting. This study takes into account recent insights into severe accident source terms and examines consequences in a risk based format consistent with the quantitative health objectives (QHOs) of the NRC`s Safety Goal Policy. Simplified severe accident source terms developed in this study are based on the risk insights of NUREG-1150. The results of the study indicate that both the quantity of radioactivity released in a severe accident as well as the likelihood of a release are lower than those predicted in earlier studies. The accident risks using the simplified source terms are examined at a series of generic plant sites, that vary in population distribution, meteorological conditions, and exclusion area boundary distances. Sensitivity calculations are performed to evaluate the effects of emergency protective action assumptions on the risk of prompt fatality and latent cancers fatality, and population relocation. The study finds that based on the new source terms the prompt and latent fatality risks at all generic sites meet the QHOs of the NRC`s Safety Goal Policy by margins ranging from one to more than three orders of magnitude. 4 refs., 17 figs., 24 tabs.

  2. Understanding the reaction of nuclear graphite with molecular oxygen: Kinetics, transport, and structural evolution

    NASA Astrophysics Data System (ADS)

    Kane, Joshua J.; Contescu, Cristian I.; Smith, Rebecca E.; Strydom, Gerhard; Windes, William E.

    2017-09-01

    For the next generation of nuclear reactors, HTGRs specifically, an unlikely air ingress warrants inclusion in the license applications of many international regulators. Much research on oxidation rates of various graphite grades under a number of conditions has been undertaken to address such an event. However, consequences to the reactor result from the microstructural changes to the graphite rather than directly from oxidation. The microstructure is inherent to a graphite's properties and ultimately degradation to the graphite's performance must be determined to establish the safety of reactor design. To understand the oxidation induced microstructural change and its corresponding impact on performance, a thorough understanding of the reaction system is needed. This article provides a thorough review of the graphite-molecular oxygen reaction in terms of kinetics, mass and energy transport, and structural evolution: all three play a significant role in the observed rate of graphite oxidation. These provide the foundations of a microstructurally informed model for the graphite-molecular oxygen reaction system, a model kinetically independent of graphite grade, and capable of describing both the observed and local oxidation rates under a wide range of conditions applicable to air-ingress.

  3. Understanding the reaction of nuclear graphite with molecular oxygen: Kinetics, transport, and structural evolution

    DOE PAGES

    Kane, Joshua J.; Contescu, Cristian I.; Smith, Rebecca E.; ...

    2017-06-08

    A thorough understanding of oxidation is important when considering the health and integrity of graphite components in graphite reactors. For the next generation of graphite reactors, HTGRs specifically, an unlikely air ingress has been deemed significant enough to have made its way into the licensing applications of many international licensing bodies. While a substantial body of literature exists on nuclear graphite oxidation in the presence of molecular oxygen and significant efforts have been made to characterize oxidation kinetics of various grades, the value of existing information is somewhat limited. Often, multiple competing processes, including reaction kinetics, mass transfer, and microstructuralmore » evolution, are lumped together into a single rate expression that limits the ability to translate this information to different conditions. This article reviews the reaction of graphite with molecular oxygen in terms of the reaction kinetics, gas transport, and microstructural evolution of graphite. It also presents the foundations of a model for the graphite-molecular oxygen reaction system that is kinetically independent of graphite grade, and is capable of describing both the bulk and local oxidation rates under a wide range of conditions applicable to air-ingress.« less

  4. Correlated Biofilm Imaging, Transport and Metabolism Measurements via Combined Nuclear Magnetic Resonance and Confocal Microscopy

    SciTech Connect

    Mclean, Jeffrey S.; Ona, Ositadinma; Majors, Paul D.

    2008-02-18

    Bacterial biofilms are complex, three-dimensional, communities that are found nearly everywhere in nature1 and are being recognized as the cause of treatment-resistant infections1 2. Advanced methods are required to characterize their collective and spatial patterns of metabolism however most techniques are invasive or destructive. Here we describe the use of a combined confocal laser scanning microscopy (CLSM) and nuclear magnetic resonance (NMR) microscopy system to monitor structure, mass transport, and metabolism in active biofilms. Non-invasive NMR methods provide macroscopic structure along with spatially-resolved metabolite profiles and diffusion measurements. CLSM enables monitoring of cells by fluorescent protein reporters to investigate biofilm structure and gene expression concurrently. A planar sample chamber design facilitates depth-resolved measurements on 140 nL sample volumes under laminar flow conditions. The techniques and approaches described here are applicable to environmental and medically relevant microbial communities, thus providing key metabolic information for promoting beneficial biofilms and treating associated diseases.

  5. Extended Burnup Credit for BWR Spent Nuclear Fuel in Storage and Transportation Systems

    SciTech Connect

    Ade, Brian J; Bowman, Stephen M; Gauld, Ian C; Ilas, Germina; Martinez, J. S.

    2015-01-01

    [Full Text] Oak Ridge National Laboratory and the United States Nuclear Regulatory Commission have initiated a multiyear project to investigate the application of burnup credit (BUC) for boiling-water reactor (BWR) fuel in storage and transportation casks. This project includes two phases. The first phase investigates the applicability of peak reactivity methods currently used for spent fuel pools to spent fuel storage and transportation casks and the validation of reactivity (keff) calculations and depleted fuel compositions. The second phase focuses on extending BUC beyond peak reactivity. This paper documents work performed to date, investigating some aspects of extended BUC, and it also describes the plan to complete the evaluations. The technical basis for application of peak reactivity methods to BWR fuel in storage and transportation systems is presented in a companion paper. Two reactor operating parameters are being evaluated to establish an adequate basis for extended BWR BUC, including investigation of the axial void profile effect and the effect of control blade utilization during operation. A detailed analysis of core simulator data for one cycle of an operating BWR plant was performed to determine the range of void profiles and the variability of the profile experienced during irradiation. While a single cycle does not provide complete data, the data obtained are sufficient to use to determine the primary effects and identify conservative modeling approaches. Using data resulting from a single cycle, the axial void profile is studied by first determining the temporal fidelity necessary in depletion modeling, and then using multiple void profiles to examine the effect of the void profile on cask reactivity. The results of these studies are being used to develop recommendations for conservatively modeling the void profile effects for BWR depletion calculations. The second operational parameter studied is control blade exposure. Control blades

  6. Krüppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine

    PubMed Central

    Liuzzi, Juan P.; Guo, Liang; Chang, Shou-Mei; Cousins, Robert J.

    2009-01-01

    Epithelial cells of the small intestine are the site of zinc absorption. Intestinal uptake of zinc is inversely proportional to the dietary supply of this essential micronutrient. The mechanism responsible for this adaptive differential in apical zinc transport is not known. The zinc transporter Zip4 (Slc39a4) is essential for adequate enteric zinc uptake. In mice, Zip4 expression is upregulated at low zinc intakes with a concomitant ZIP4 localization to the apical enterocyte plasma membrane. With the present experiments, we show that the zinc finger transcription factor Krüppel-like factor 4 (KLF4), produced in high abundance in the intestine, is expressed at elevated levels in mice fed a low-zinc diet. In the murine intestinal epithelial cell (IEC) line MODE-K, zinc depletion of culture medium with cell-permeant and cell-impermeant chelators increased Zip4 and Klf4 mRNA and Zip4 heterogeneous nuclear RNA expression. Zinc depletion led to increased KLF4 in nuclear extracts. Knockdown of KLF4 using small interfering RNA transfection drastically limited ZIP4 induction upon zinc depletion and reduced 65Zn uptake by depleted IECs. EMSAs with nuclear extracts of IECs showed KLF4 binding to cis elements of the mouse Zip4 promoter, with increased binding under zinc-limited conditions. Reporter constructs with the Zip4 promoter and mutation studies further demonstrated that Zip4 is regulated through a KLF4 response element. These data from experiments with mice and murine IECs demonstrate that KLF4 is induced during zinc restriction and is a transcription factor involved in adaptive regulation of the zinc transporter ZIP4. PMID:19147802

  7. Nuclear/cytoplasmic shuttling of the transcription factor FoxO1 is regulated by neurotrophic factors.

    PubMed

    Gan, Lixia; Zheng, Wenhua; Chabot, Jean-Guy; Unterman, Terry G; Quirion, Remi

    2005-06-01

    FoxO1, a member of the FoxO subfamily of forkhead transcription factors, is an important target for insulin and growth factor signaling in the regulation of metabolism, cell cycle and proliferation, and survival in peripheral tissues. However, its role in the central nervous system is mostly unknown. In this study, we examined the effect of neurotrophic factors on nuclear/cytoplasmic shuttling of FoxO1. We showed that insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF) potently induced the nuclear exclusion of FoxO1-green fluorescent protein (GFP) while neurotrophin (NT)-3 and NT-4 were much weaker and brain-derived neurotrophic factor (BDNF) failed to induce FoxO1 translocation in PC12 cells. FoxO1 translocation was inhibited by LY294002, a well-established PI3K/Akt kinase inhibitor. Moreover, FoxO1 was phosphorylated at Thr24 and Ser256 residues by the above neurotrophic factors, with the exception of BDNF. Triple mutant FoxO1, in which three Akt/PKB phosphorylation sites (Thr24, Ser256 and Ser319) were mutated to alanine, resulted in the complete nuclear targeting of the expressed FoxO1-GFP fusion protein in the presence of the above neurotrophic factors in both PC12 cells and cultured hippocampal and cortical neurons. Taken together, these findings demonstrate that neurotrophic factors are able to regulate nuclear/cytoplasmic shuttling of FoxO1 via the PI3K/Akt pathway in neuronal cells.

  8. Involvement of nuclear factor I transcription/replication factor in the early stage of chondrocytic differentiation.

    PubMed

    Uchihashi, Takayuki; Kimata, Masaaki; Tachikawa, Kanako; Koshimizu, Takao; Okada, Tomoko; Ihara-Watanabe, Miyuki; Sakai, Norio; Kogo, Mikihiko; Ozono, Keiichi; Michigami, Toshimi

    2007-12-01

    Gene-trap mutagenesis is based on the notion that the random insertion of a trapping vector may disturb the function of inserted genes. To identify the genes involved in chondrocytic differentiation, we applied this method to a murine mesenchymal cell line, ATDC5, which differentiate into mature chondrocytes in the presence of insulin, and isolated a clone in which the gene encoding a transcription/replication factor, nuclear factor I-B (NFIB), was trapped. In this particular clone, named #7-57, the trap vector pPT1-geo was inserted into intron 6 of the NFIB gene in one of the alleles. As a result, both wild-type NFIB and a mutant protein lacking the carboxyl-terminal transactivation/repression domain were expressed in the clone. Immunoprecipitation/Western blotting confirmed the interaction between wild-type NFIB and the truncated protein derived from the trapped allele, suggesting that the mutant protein formed a heterodimer with wild-type NFI proteins. When cultured in the differentiation medium, #7-57 exhibited impaired nodule formation and less accumulation of cartilageous matrices compared with the parental ATDC5 cells. In addition, the expression of marker genes for proliferating chondrocytes, including type II collagen (Col2a1), matrillin-1, and PTHrP, was reduced in the clone. The expression of SOX9 was also slightly decreased in the clone #7-57 compared with the parental cells. The overexpression of wild-type NFIB in parental ATDC5 cells resulted in the increased expression of Col2a1, and a series of reporter assays using a Col2a1 promoter/enhancer-luciferase construct demonstrated the transcriptional regulation of the gene by NFIB and the dominant-negative effect of the truncated mutant derived from the trapped allele. Interestingly, mutation in the SOX9-binding site in the 48-bp cis-element located in intron 1 failed to abolish the transactivation of Col2a1 gene by NFIB, suggesting that NFI regulates the transactivation of Col2a1, at least in part

  9. Prognostic value of nuclear hepatoma-derived growth factor (HDGF) localization in patients with breast cancer.

    PubMed

    Chen, Xiaoyan; Yun, Jun; Fei, Fei; Yi, Jun; Tian, Ruifeng; Li, Sanzhong; Gan, Xiaoqiang

    2012-08-15

    Hepatoma-derived growth factor (HDGF) plays an important role in tumor progression. Highly expressed HDGF has been found to indicate poor prognosis in many cancers. However, no information is available regarding the prognostic value of nuclear or cytoplasmic HDGF staining level in breast cancer. In the present study, the nuclear or cytoplasmic HDGF staining level was investigated in 86 patients with primary breast cancer by immunohistochemistry; the relationship between nuclear or cytoplasmic HDGF staining level and clinicopathological parameters was examined by Two-tailed Mann-Whitney U-test or Krustal-Wallis. The prognostic value of nuclear or cytoplasmic HDGF staining level in disease-free survival and overall survival was analyzed by Kaplan-Meier methods and log-rank test. We found that the percentage of cases with strong nuclear HDGF staining level was significantly higher in the cases with high tumor grade, high stage, high proliferation index (Ki-67 index>20%), as well as in those with lymph node invasion and recurrence (p<0.05) compared to those without. No significant correlation was found between cytoplasmic HDGF expression and any clinicopathological variables. In addition, disease-free survival and overall survival were significantly lower in patients with high nuclear HDGF expression (level 2) than in those with low nuclear HDGF expression (level 0 and level 1). Further Cox multivariate analysis showed that high nuclear HDGF expression is an independent factor for indicating poor prognosis in breast cancer patients. No significant difference in disease-free survival rate and overall survival was found between different cytoplasmic HDGF staining levels. All these findings suggest that increased nuclear HDGF expression is involved in tumor progression and might be used as a new prognosticator for breast cancer. Crown Copyright © 2012. Published by Elsevier GmbH. All rights reserved.

  10. Endogenous axoplasmic proteins and proteins containing nuclear localization signal sequences use the retrograde axonal transport/nuclear import pathway in Aplysia neurons.

    PubMed

    Schmied, R; Huang, C C; Zhang, X P; Ambron, D A; Ambron, R T

    1993-09-01

    When the nuclear localization signal peptide (sp) of the SV 40 large T antigen was coupled to human serum albumin (HSA), rhodaminated (r), and microinjected into axons of Aplysia neurons in vitro, the rHSA-sp was conveyed through the axon to the cell body and then into the nucleus (Ambron et al., 1992). But since rHSA-sp is an artificial construct, we needed to determine whether naturally occurring nuclear proteins use this pathway. We therefore injected calf thymus histone H-1 and Xenopus oocyte nucleoplasmin into axons. By 3 hr both were retrogradely transported and targeted into the nucleus, though histone H-1 less efficiently than rHSA-sp or nucleoplasmin. In contrast, neither rHSA, nor rHSA conjugated to a peptide with a random distribution of basic amino acids, was transported or imported. To see if proteins that use the pathway remain intact, we coupled sp to HRP. When injected into varicosities, the HRP-sp was transported/imported to the nucleus, where it was enzymatically active. A key issue was to determine whether endogenous proteins use this pathway. Consequently, axoplasm was extruded from Aplysia nerves and the proteins were fractionated by size. SDS-PAGE and Western blots showed that two fractions contained proteins that were recognized by an affinity-purified antibody to sp: fraction 3 included sp83, and fraction 4 contained sp75. In addition, these two proteins were found in nuclei isolated from neurons. To assess transport, the total proteins in the fractions were rhodaminated and injected into varicosities. Fraction 3, but not fraction 4, contained protein that was transported through the axon to the nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Trans-oceanic transport of 137Cs from the Fukushima nuclear accident and impact of hypothetical Fukushima-like events of future nuclear plants in Southern China.

    PubMed

    Wai, Ka-Ming; Yu, Peter K N

    2015-03-01

    A Lagrangian model was adopted to assess the potential impact of (137)Cs released from hypothetical Fukushima-like accidents occurring on three potential nuclear power plant sites in Southern China in the near future (planned within 10 years) in four different seasons. The maximum surface (0-500 m) (137)Cs air concentrations would be reached 10 Bq m(-3) near the source, comparable to the Fukushima case. In January, Southeast Asian countries would be mostly affected by the radioactive plume due to the effects of winter monsoon. In April, the impact would be mainly on Southern and Northern China. Debris of radioactive plume (~1 mBq m(-3)) would carry out long-range transport to North America. The area of influence would be the smallest in July due to the frequent and intense wet removal events by trough of low pressure and tropical cyclone. The maximum worst-case areas of influence were 2382000, 2327000, 517000 and 1395000 km(2) in January, April, July and October, respectively. Prior to the above calculations, the model was employed to simulate the trans-oceanic transport of (137)Cs from the Fukushima nuclear accident. Observed and modeled (137)Cs concentrations were comparable. Sensitivity runs were performed to optimize the wet scavenging parameterization. The adoption of higher-resolution (1° × 1°) meteorological fields improved the prediction. The computed large-scale plume transport pattern over the Pacific Ocean was compared with that reported in the literature.

  12. Increased glucose transport in response to phorbol ester growth factors, and insulin: relationship to phosphorylation of the glucose transporter

    SciTech Connect

    Allard, W.J.; Gibbs, E.M.; Witters, L.A.; Lienhard, G.E.

    1986-05-01

    The authors have examined the relationship between the increase in glucose transport induced by phorbol myristate acetate (PMA), EGF, PDGF, and insulin and the phosphorylation state of the glucose transporter in human fibroblasts. To assay transport, cells were cultured in medium with 10% serum for 5 days and then for 2 days in phosphate-free medium with 5% serum. Exposure to each agonist stimulated transport, as measured by the uptake of /sup 3/H-2-deoxyglucose over a 2 min period. Values for maximal percent stimulation, time needed to reach maximal stimulation, and concentration required to achieve half-maximal stimulation were as follows: PMA, 80%, 30 min, 2 nM; EGF, 30%, 10 min, 0.2 nM; Insulin, 45%, 10 min, 17 nM. In the case of PDGF, uptake was stimulated 65% by treatment with 0.7 or 1.4 nM for 20 min. Phosphorylation of the glucose transporter was measured in cells cultured for 5-7 days in medium with 10% serum and exposed to 670 ..mu..Ci/ml /sup 32/P/sub i/ for 100 min. The agonist was then added at a saturating dose for 20 min, and the glucose transporter was immunoprecipitated from cell lysates using a monoclonal antibody. Under these conditions, no basal phosphorylation of the transporter was detected, and only phorbol ester stimulated significant incorporation of phosphate into the transport protein. Experiments are currently in progress to quantitate transporter phosphorylation under conditions identical to those used for the assay of transport. These results suggest that while the transporter is a substrate for protein kinase C in vivo, phosphorylation of the transporter is not required for increased transport in response to growth factors and insulin.

  13. Cloning, characterization and subcellular localization of Nuclear LIM interactor interacting factor gene from Leishmania donovani.

    PubMed

    Ravinder, R; Goyal, N

    2017-05-05

    LIM domains are zinc-binding motifs that mediate protein-protein interactions and are found in a wide variety of cytoplasmic and nuclear proteins. The nuclear LIM domain family members have a number of different functions including transcription factors, gene regulation, cell fate determination, organization of the cytoskeleton and tumour formation exerting their function through various LIM domain interacting protein partners/cofactors. Nuclear LIM domain interacting proteins/factors have not been reported in any protozoan parasites including Leishmania. Here, we report for the first time cloning, characterization and subcellular localization of nuclear LIM interactor-interacting factor (NLI) like protein from Leishmania donovani, the causative agent of Indian Kala-azar. Primary sequence analysis of LdNLI revealed presence of characteristic features of nuclear LIM interactor-interacting factor. However, leishmanial NLI represents a distinct kinetoplastid group, clustered in a separate branch of the phylogenic tree. The sub-cellular distribution of LdNLI revealed the discreet localization in nucleus and kinetoplast only, suggesting that the gene may have a role in parasite gene expression.

  14. Factors of bacteria and virus transport in groundwater

    NASA Astrophysics Data System (ADS)

    Pekdeger, A.; Matthess, G.

    1983-06-01

    The underground transport of pathogenic bacteria and viruses may be described by the general transport equation considering dispersion, adsorption, and biological elimination. The survival time of bacteria and viruses in groundwater is different for the specific species and for the specific groundwater environment. Dispersion causes a distribution of pollutants in time and space, thus their concentration decreases over time and with transport distance. Microorganisms are reversibly adsorbed on underground particles, which causes a retardation of their transport velocity with respect to groundwater flow velocity. An additional approach is provided by the filter theory.

  15. A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy

    PubMed Central

    Gothwal, Monika; Wehrle, Julius; Aumann, Konrad; Zimmermann, Vanessa; Gründer, Albert; Pahl, Heike L.

    2016-01-01

    We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy. PMID:27479815

  16. Identification and characterization of potential discharge areas for radionuclide transport by groundwater from a nuclear waste repository in Sweden.

    PubMed

    Berglund, Sten; Bosson, Emma; Selroos, Jan-Olof; Sassner, Mona

    2013-05-01

    This paper describes solute transport modeling carried out as a part of an assessment of the long-term radiological safety of a planned deep rock repository for spent nuclear fuel in Forsmark, Sweden. Specifically, it presents transport modeling performed to locate and describe discharge areas for groundwater potentially carrying radionuclides from the repository to the surface where man and the environment could be affected by the contamination. The modeling results show that topography to large extent determines the discharge locations. Present and future lake and wetland objects are central for the radionuclide transport and dose calculations in the safety assessment. Results of detailed transport modeling focusing on the regolith and the upper part of the rock indicate that the identification of discharge areas and objects considered in the safety assessment is robust in the sense that it does not change when a more detailed model representation is used.

  17. Working Group 7.1 on environmental transport, US-USSR Joint Coordinating Committee on Civilian Nuclear Reactor Safety. Progress report update

    SciTech Connect

    Anspaugh, L.R.; Hendrickson, S.M.

    1991-09-07

    This report contains brief summaries of the status of projects of the Environmental Transport Group of the US-USSR Joint Coordinating Committee of Civilian Nuclear Reactor Safety. Projects reported on include: Management and Administration; Atmospheric Transport; Resuspension; External Dose; Terrestrial Food Chains; Aquatic Food Chains; Hydrological Transport; and Intercalibration

  18. Brownian Dynamics Simulation of Nucleocytoplasmic Transport: A Coarse-Grained Model for the Functional State of the Nuclear Pore Complex

    PubMed Central

    Moussavi-Baygi, Ruhollah; Jamali, Yousef; Karimi, Reza; Mofrad, Mohammad R. K.

    2011-01-01

    The nuclear pore complex (NPC) regulates molecular traffic across the nuclear envelope (NE). Selective transport happens on the order of milliseconds and the length scale of tens of nanometers; however, the transport mechanism remains elusive. Central to the transport process is the hydrophobic interactions between karyopherins (kaps) and Phe-Gly (FG) repeat domains. Taking into account the polymeric nature of FG-repeats grafted on the elastic structure of the NPC, and the kap-FG hydrophobic affinity, we have established a coarse-grained model of the NPC structure that mimics nucleocytoplasmic transport. To establish a foundation for future works, the methodology and biophysical rationale behind the model is explained in details. The model predicts that the first-passage time of a 15 nm cargo-complex is about 2.6±0.13 ms with an inverse Gaussian distribution for statistically adequate number of independent Brownian dynamics simulations. Moreover, the cargo-complex is primarily attached to the channel wall where it interacts with the FG-layer as it passes through the central channel. The kap-FG hydrophobic interaction is highly dynamic and fast, which ensures an efficient translocation through the NPC. Further, almost all eight hydrophobic binding spots on kap-β are occupied simultaneously during transport. Finally, as opposed to intact NPCs, cytoplasmic filaments-deficient NPCs show a high degree of permeability to inert cargos, implying the defining role of cytoplasmic filaments in the selectivity barrier. PMID:21673865

  19. Bohmian mechanics in the exact factorization of electron-nuclear wave functions

    NASA Astrophysics Data System (ADS)

    Suzuki, Yasumitsu; Watanabe, Kazuyuki

    2016-09-01

    The exact factorization of an electron-nuclear wave function [A. Abedi, N. T. Maitra, and E. K. U. Gross, Phys. Rev. Lett. 105, 123002 (2010), 10.1103/PhysRevLett.105.123002] allows us to define the rigorous nuclear time-dependent Schrödinger equation (TDSE) with a time-dependent potential-energy surface (TDPES) that fully accounts for the coupling to the electronic motion and drives the nuclear wave-packet dynamics. Here, we study whether the propagation of multiple classical trajectories can reproduce the quantum nuclear motion in strong-field processes when their motions are governed by the quantum Hamilton-Jacobi equation derived by applying Bohmian mechanics to this exact nuclear TDSE. We demonstrate that multiple classical trajectories propagated by the force from the gradient of the exact TDPES plus the Bohmian quantum potential can reproduce the strong-field dissociation dynamics of a one-dimensional model of the H2 + molecule. Our results show that the force from the Bohmian quantum potential plays a non-negligible role in yielding quantum nuclear dynamics in the strong-field process studied here, where ionization and/or splitting of nuclear probability density occurs.

  20. Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).

    PubMed

    Terranova, Christopher; Narla, Sridhar T; Lee, Yu-Wei; Bard, Jonathan; Parikh, Abhirath; Stachowiak, Ewa K; Tzanakakis, Emmanuel S; Buck, Michael J; Birkaya, Barbara; Stachowiak, Michal K

    2015-01-01

    Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

  1. Modeling and Simulation of Used Nuclear Fuel During Transportation with Consideration of Hydride Effects and Cyclic Fatigue

    SciTech Connect

    Chakraborty, Pritam; Sabharwall, Piyush; Spears, Robert Edward; Coleman, Justin Leigh; Sener, Kadir; Varma, Amit H.

    2015-09-30

    The objective of this work is to understand the integrity of Used Nuclear Fuel (UNF) during transportation. Previous analysis work has been performed to look at the integrity of UNF during transportation but these analyses have neglected to analyze the effect of hydrides and flaws (fracture mechanics models to capture radial cracking in the cladding). In this study, the clad regions of interest are near the pellet-pellet interfaces. These regions can experience more complex stress-states than the rest of the clad during cooling and have a greater possibility to develop radially reoriented hydrides during vacuum drying.

  2. 48 CFR 247.372 - DD Form 1654, Evaluation of Transportation Cost Factors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false DD Form 1654, Evaluation... Transportation in Supply Contracts 247.372 DD Form 1654, Evaluation of Transportation Cost Factors. Contracting personnel may use the DD Form 1654 to furnish information to the transportation office for development...

  3. 48 CFR 247.372 - DD Form 1654, Evaluation of Transportation Cost Factors.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false DD Form 1654, Evaluation... Transportation in Supply Contracts 247.372 DD Form 1654, Evaluation of Transportation Cost Factors. Contracting personnel may use the DD Form 1654 to furnish information to the transportation office for development...

  4. 48 CFR 1847.305 - Solicitation provisions, contract clauses, and transportation factors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Solicitation provisions, contract clauses, and transportation factors. 1847.305 Section 1847.305 Federal Acquisition Regulations System NATIONAL AERONAUTICS AND SPACE ADMINISTRATION CONTRACT MANAGEMENT TRANSPORTATION Transportation...

  5. 48 CFR 847.305 - Solicitation provisions, contract clauses, and transportation factors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Solicitation provisions, contract clauses, and transportation factors. 847.305 Section 847.305 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS CONTRACT MANAGEMENT TRANSPORTATION Transportation in...

  6. 48 CFR 847.306 - Transportation factors in the evaluation of offers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Transportation factors in the evaluation of offers. 847.306 Section 847.306 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS CONTRACT MANAGEMENT TRANSPORTATION Transportation in Supply Contracts...

  7. 41 CFR 109-40.112 - Transportation factors in the location of Government facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Management Federal Property Management Regulations System (Continued) DEPARTMENT OF ENERGY PROPERTY MANAGEMENT REGULATIONS AVIATION, TRANSPORTATION, AND MOTOR VEHICLES 40-TRANSPORTATION AND TRAFFIC MANAGEMENT... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Transportation factors...

  8. 41 CFR 109-40.112 - Transportation factors in the location of Government facilities.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Management Federal Property Management Regulations System (Continued) DEPARTMENT OF ENERGY PROPERTY MANAGEMENT REGULATIONS AVIATION, TRANSPORTATION, AND MOTOR VEHICLES 40-TRANSPORTATION AND TRAFFIC MANAGEMENT... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Transportation factors...

  9. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway

    PubMed Central

    Ha, Ae Wha

    2017-01-01

    BACKGROUN/OBJECTIVES Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2)-Keap1 complex. METHODS/MATERIALS After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8-isoprostaglandin F2α (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S-transferase alpha 2 (GSTA2) were examined. RESULTS Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. CONCLUSIONS The improvements of blood glucose homeostasis and

  10. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway.

    PubMed

    Ha, Ae Wha; Kim, Woo Kyoung

    2017-06-01

    Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2)-Keap1 complex. After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8-isoprostaglandin F2α (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S-transferase alpha 2 (GSTA2) were examined. Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. The improvements of blood glucose homeostasis and antioxidant systems in rats fed with black garlic extract were

  11. Modelling the global atmospheric transport and deposition of radionuclides from the Fukushima Dai-ichi nuclear accident.

    NASA Astrophysics Data System (ADS)

    Christoudias, Theodoros; Lelieveld, Jos

    2013-04-01

    We modeled the global atmospheric dispersion and deposition of radionuclides released from the Fukushima Dai-ichi nuclear power plant accident. The EMAC atmospheric chemistry - general circulation model was used, with circulation dynamics nudged towards ERA-Interim reanalysis data. We applied a resolution of approximately 0.5 degrees in latitude and longitude (T255). The model accounts for emissions and transport of the radioactive isotopes 131I and 137Cs, and removal processes through precipitation, particle sedimentation and dry deposition. In addition, we simulated the release of 133Xe, a noble gas that can be regarded as a passive transport tracer of contaminated air. The source terms are based on Chino et al. (2011) and Stohl et al. (2012); especially the emission estimates of 131I are associated with a high degree of uncertainty. The calculated concentrations have been compared to station observations by the Comprehensive Nuclear-Test-Ban Treaty Organisation (CTBTO).

  12. Factors Of Environmental Safety And Environmentally Efficient Technologies Transportation Facilities Gas Transportation Industry

    NASA Astrophysics Data System (ADS)

    Vasiliev, Bogdan U.

    2017-01-01

    The stable development of the European countries depends on a reliable and efficient operation of the gas transportation system (GTS). With high reliability of GTS it is necessary to ensure its industrial and environmental safety. In this article the major factors influencing on an industrial and ecological safety of GTS are analyzed, sources of GTS safety decreasing is revealed, measures for providing safety are proposed. The article shows that use of gas-turbine engines of gas-compressor units (GCU) results in the following phenomena: emissions of harmful substances in the atmosphere; pollution by toxic waste; harmful noise and vibration; thermal impact on environment; decrease in energy efficiency. It is shown that for the radical problem resolution of an industrial and ecological safety of gas-transmission system it is reasonable to use gas-compressor units driven by electric motors. Their advantages are shown. Perspective technologies of these units and experience of their use in Europe and the USA are given in this article.