Modeled Neutron and Charged-Particle Induced Nuclear Reaction Cross Sections for Radiochemistry in the Region of Yttrium, Zirconium, Niobium, and Molybdenum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffman, R D; Kelley, K; Dietrich, F S

2006-06-13

We have developed a set of modeled nuclear reaction cross sections for use in radiochemical diagnostics. Systematics for the input parameters required by the Hauser-Feshbach statistical model were developed and used to calculate neutron, proton, and deuteron induced nuclear reaction cross sections for targets ranging from strontium (Z = 38) to rhodium (Z = 45).

The Science of Nuclear Materials: A Modular, Laboratory-based Curriculum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cahill, C.L., E-mail: cahill@gwu.edu; Feldman, G.; Briscoe, W.J.

The development of a curriculum for nuclear materials courses targeting students pursuing Master of Arts degrees at The George Washington University is described. The courses include basic concepts such as radiation and radioactivity as well as more complex topics such the nuclear fuel cycle, nuclear weapons, radiation detection and technological aspects of non-proliferation.

Bubble chambers for experiments in nuclear astrophysics

DOE Office of Scientific and Technical Information (OSTI.GOV)

DiGiovine, B.; Henderson, D.; Holt, R. J.

A bubble chamber has been developed to be used as an active target system for low energy nuclear astrophysics experiments. Adopting ideas from dark matter detection with superheated liquids, a detector system compatible with gamma-ray beams has been developed. This detector alleviates some of the limitations encountered in standard measurements of the minute cross sections of interest to stellar environments. While the astrophysically relevant nuclear reaction processes at hydrostatic burning temperatures are dominated by radiative captures, in this experimental scheme we measure the time reversed processes. Such photodisintegrations allow us to compute the radiative capture cross sections when transitions tomore » excited states of the reaction products are negligible. Due to the transformation of phase space, the photodisintegration cross-sections are up to two orders of magnitude higher. The main advantage of the new target-detector system is a density several orders of magnitude higher than conventional gas targets. Also, the detector is virtually insensitive to the gamma-ray beam itself, thus allowing us to detect only the products of the nuclear reaction of interest. The development and the operation as well as the advantages and disadvantages of the bubble chamber are discussed.« less

Manufacturing of calcium, lithium and molybdenum targets for use in nuclear physics experiments

NASA Astrophysics Data System (ADS)

Kheswa, N. Y.; Papka, P.; Buthelezi, E. Z.; Lieder, R. M.; Neveling, R.; Newman, R. T.

2010-02-01

This paper describes methods used in the manufacturing of chemically reactive targets such as calcium ( natCa), lithium-6 ( 6Li) and molybdenum-97 ( 97Mo) for nuclear physics experiments at the iThemba LABS cyclotron facility (Faure, South Africa). Due to the chemical properties of these materials a suitable and controlled environment was established in order to minimize oxygen contamination of targets. Calcium was prepared by means of vacuum evaporation while lithium was cold rolled to a desired thickness. In the case of molybdenum, the metallic powder was melted under vacuum using an e-gun followed by cold rolling of the metal bead to a desired thickness. In addition, latest developments toward the establishment of a dedicated nuclear physics target laboratory are discussed.

Nuclear Data Covariances in the Indian Context – Progress, Challenges, Excitement and Perspectives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganesan, S., E-mail: gane-san555@gmail.com

We present a brief overview of progress, challenges, excitement and perspectives in developing nuclear data covariances in the Indian context in relation to target accuracies and sensitivity studies that are of great importance to Bhabha's 3-stage nuclear programme for energy and non-energy applications.

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chutiwitoonchai, Nopporn; Mano, Takafumi; Kakisaka

An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 bindsmore » at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. - Highlights: •DP2392-E10 inhibits replication of a broad range of influenza A subtypes. •DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. •DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.« less

Orphan Nuclear Receptors as Targets for Drug Development

PubMed Central

Mukherjee, Subhajit

2012-01-01

Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994

Schemes of detecting nuclear spin correlations by dynamical decoupling based quantum sensing

NASA Astrophysics Data System (ADS)

Ma, Wen-Long Ma; Liu, Ren-Bao

Single-molecule sensitivity of nuclear magnetic resonance (NMR) and angstrom resolution of magnetic resonance imaging (MRI) are the highest challenges in magnetic microscopy. Recent development in dynamical decoupling (DD) enhanced diamond quantum sensing has enabled NMR of single nuclear spins and nanoscale NMR. Similar to conventional NMR and MRI, current DD-based quantum sensing utilizes the frequency fingerprints of target nuclear spins. Such schemes, however, cannot resolve different nuclear spins that have the same noise frequency or differentiate different types of correlations in nuclear spin clusters. Here we show that the first limitation can be overcome by using wavefunction fingerprints of target nuclear spins, which is much more sensitive than the ''frequency fingerprints'' to weak hyperfine interaction between the targets and a sensor, while the second one can be overcome by a new design of two-dimensional DD sequences composed of two sets of periodic DD sequences with different periods, which can be independently set to match two different transition frequencies. Our schemes not only offer an approach to breaking the resolution limit set by ''frequency gradients'' in conventional MRI, but also provide a standard approach to correlation spectroscopy for single-molecule NMR.

Bmal1 is a direct transcriptional target of the orphan nuclear receptor, NR2F1

USDA-ARS?s Scientific Manuscript database

Orphan nuclear receptor NR2F1 (also known as COUP-TFI, Chicken Ovalbumin Upstream Promoter Transcription Factor I) is a highly conserved member of the nuclear receptor superfamily. NR2F1 plays a critical role during embryonic development, particularly in the central and peripheral nervous systems a...

Analysis of Power Planning Deviation Influence on the Non-fossil Energy Development Goal

NASA Astrophysics Data System (ADS)

Xu, Wei-ting; Li, Ting; Ye, Qiang; Mi, Zhu; Ying, Liu; Tao, Yu-xuan

2017-05-01

Due to the international circumstances changes and domestic economic restructuring, the policies and planning of energy development have been adjusting in recent years, especially in energy power industry. Under these influences, the Chinese energy development goal “non-fossil energy accounts for 15% of the primary energy consumption” which planned to be realized in 2020 becomes uncertain. To ensure the goal can be achieved, a new energy power planning scheme is provided. Based on this planning scheme, the sensitivity analysis method and the maximum deviation method are proposed to quantify the influence of planning deviation on the target percentage. At the same time, the energy replacement is provided to fill the deviation. Research results shows that the main influence factors of target percentage is the hydro and nuclear power develop scale and their output channel construction. If the hydro and nuclear power capacity can’t reach their target scale, wind and solar power capacity can fill the vacancy instead. But if the vacancy of hydropower exceeds 58GW, or vacancy of nuclear power exceeds 27GW, the “15% goal” would be very difficult to achieve. Accelerating the construction of the hydropower output transmission lines helps to guarantee the "15% goal".

Nuclear-effects model embedded stochastically in simulation (NEMESIS) summary report. Technical paper

DOE Office of Scientific and Technical Information (OSTI.GOV)

Youngren, M.A.

1989-11-01

An analytic probability model of tactical nuclear warfare in the theater is presented in this paper. The model addresses major problems associated with representing nuclear warfare in the theater. Current theater representations of a potential nuclear battlefield are developed in context of low-resolution, theater-level models or scenarios. These models or scenarios provide insufficient resolution in time and space for modeling a nuclear exchange. The model presented in this paper handles the spatial uncertainty in potentially targeted unit locations by proposing two-dimensional multivariate probability models for the actual and perceived locations of units subordinate to the major (division-level) units represented inmore » theater scenarios. The temporal uncertainty in the activities of interest represented in our theater-level Force Evaluation Model (FORCEM) is handled through probability models of the acquisition and movement of potential nuclear target units.« less

Design of an intelligent sub-50 nm nuclear-targeting nanotheranostic system for imaging guided intranuclear radiosensitization.

PubMed

Fan, Wenpei; Shen, Bo; Bu, Wenbo; Zheng, Xiangpeng; He, Qianjun; Cui, Zhaowen; Zhao, Kuaile; Zhang, Shengjian; Shi, Jianlin

2015-03-01

Clinically applied chemotherapy and radiotherapy is sometimes not effective due to the limited dose acting on DNA chains resident in the nuclei of cancerous cells. Herein, we develop a new theranostic technique of "intranuclear radiosensitization" aimed at directly damaging the DNA within the nucleus by a remarkable synergetic chemo-/radiotherapeutic effect based on intranuclear chemodrug-sensitized radiation enhancement. To achieve this goal, a sub-50 nm nuclear-targeting rattle-structured upconversion core/mesoporous silica nanotheranostic system was firstly constructed to directly transport the radiosensitizing drug Mitomycin C (MMC) into the nucleus for substantially enhanced synergetic chemo-/radiotherapy and simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging, which can lead to efficient cancer treatment as well as multi-drug resistance circumvention in vitro and in vivo . We hope the technique of intranuclear radiosensitization along with the design of nuclear-targeting nanotheranostics will contribute greatly to the development of cancer theranostics as well as to the improvement of the overall therapeutic effectiveness.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, Tatsunori; Yamamoto, Norio; Department of General Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421

The development of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus (HIV) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. One such target is the interaction between Vpr, one of the accessory gene products of HIV-1 and Importin {alpha}, which is crucial, not only for the nuclear import of Vpr, but also for HIV-1 replication in macrophages. We have identified a potential parent compound, hematoxylin, which suppresses Vpr-Importin {alpha} interaction, thereby inhibiting HIV-1 replication in a Vpr-dependent manner. Analysis by real-time PCR demonstrated that hematoxylin specificallymore » inhibited nuclear import step of pre-integration complex. Thus, hematoxylin is a new anti-HIV-1 inhibitor that targets the nuclear import of HIV-1 via the Vpr-Importin {alpha} interaction, suggesting that a specific inhibitor of the interaction between viral protein and the cellular factor may provide a new strategy for HIV-1 therapy.« less

Simulation and Automation of Microwave Frequency Control in Dynamic Nuclear Polarization for Solid Polarized Targets

NASA Astrophysics Data System (ADS)

Perera, Gonaduwage; Johnson, Ian; Keller, Dustin

2017-09-01

Dynamic Nuclear Polarization (DNP) is used in most of the solid polarized target scattering experiments. Those target materials must be irradiated using microwaves at a frequency determined by the difference in the nuclear Larmor and electron paramagnetic resonance (EPR) frequencies. But the resonance frequency changes with time as a result of radiation damage. Hence the microwave frequency should be adjusted accordingly. Manually adjusting the frequency can be difficult, and improper adjustments negatively impact the polarization. In order to overcome these difficulties, two controllers were developed which automate the process of seeking and maintaining the optimal frequency: one being a standalone controller for a traditional DC motor and the other a LabVIEW VI for a stepper motor configuration. Further a Monte-Carlo simulation was developed which can accurately model the polarization over time as a function of microwave frequency. In this talk, analysis of the simulated data and recent improvements to the automated system will be presented. DOE.

NEWSdm: Nuclear Emulsions for WIMP Search with directional measurement

NASA Astrophysics Data System (ADS)

Di Crescenzo, A.

2017-12-01

Direct Dark Matter searches are nowadays one of the most exciting research topics. Several experimental efforts are concentrated on the development, construction, and operation of detectors looking for the scattering of target nuclei with Weakly Interactive Massive Particles (WIMPs). The measurement of the direction of WIMP-induced nuclear recoils is a challenging strategy to extend dark matter searches beyond the neutrino floor and provide an unambiguous signature of the detection of Galactic dark matter. Current directional experiments are based on the use of gas TPC whose sensitivity is strongly limited by the small achievable detector mass. We present an innovative directional experiment based on the use of a solid target made by newly developed nuclear emulsions and read-out systems reaching a position resolution of the order of 10 nm.

Designing an Active Target Test Projection Chamber

NASA Astrophysics Data System (ADS)

Koci, James; Tan Ahn Collaboration, Dr.; Nicolas Dixneuf Collaboration

2015-10-01

The development of instrumentation in nuclear physics is crucial for advancing our ability to measure the properties of exotic nuclei. One limitation of the use of exotic nuclei in experiment is their very low production intensities. Recently, detectors, called active-target dectectors, have been developed to address this issue. Active-target detectors use a gas medium to image charged-particle tracks that are emitted in nuclear reactions. Last semester, I designed a vacuum chamber to be used in developing Micro-Pattern Gas detectors that will upgrade the capabilities of an active-target detector called the Prototype AT-TPC. With the exterior of the chamber complete, I have now been using an electric field modeling program, Garfield, developed by CERN to design a field cage to be placed within the vacuum chamber. The field cage will be a box-like apparatus consisting of two parallel metal plates connected with a resistor chain and attached to wires wrapped between them. The cage will provide a uniform electric field within the chamber to drift electrons from nuclear reactions down to the detector in the bottom of the chamber. These signals are then amplified by a proportional counter, and the data is sent to a computer. For the long term, we would like to incorporate a Micro-Pattern Gas Detectors in the interior of the chamber and eventually use the AT-TPC to examine various nuclei. Dr. Ahn is my advising professor.

Solid-State Nuclear Power

NASA Technical Reports Server (NTRS)

George, Jeffrey A.

2012-01-01

A strategy for "Solid-State" Nuclear Power is proposed to guide development of technologies and systems into the second 50 years of nuclear spaceflight. The strategy emphasizes a simple and highly integrated system architecture with few moving parts or fluid loops; the leverage of modern advances in materials, manufacturing, semiconductors, microelectromechanical and nanotechnology devices; and the targeted advancement of high temperature nuclear fuels, materials and static power conversion to enable high performance from simple system topologies.

Target with a frozen nuclear polarization for experiments at low energies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borisov, N.S.; Matafonov, V.N.; Neganov, A.B.

1995-09-01

The short history of the development of frozen spin polarized targets at the Laboratory of Nuclear Problems JINR is given. The latest development is the target with a frozen spin polarization of protons in 1,2- propanediol with a paramagnetic Cr{sup {ital V}} impurity, intended for polarization parameter studies in np-scattering at approximately 15 MeV neutron energy. The target of cylindrical shape of 2 cm diameter and 6 cm long with an initial polarization of 95{plus_minus}3{percent} obtainable by the dynamic polarization technique is placed at a temperature about 20 mK in a magnetic field of 0.37 T generated by a magneticmore » system, which provides a large aperture for scattered particles. The relaxation time for the spin polarization is about 1000 hours. {copyright} {ital 1995 American Institute of Physics.}« less

Development of Cell‐Permeable, Non‐Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer

PubMed Central

Wiedmann, Mareike M.; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F.; Verma, Chandra S.; Itzhaki, Laura; Stewart, Murray; Brenton, James D.

2016-01-01

Abstract There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum‐based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA‐mediated knockdown of the target protein, HNF1β, in five high‐ and low‐HNF1β‐expressing CCC lines. To inhibit the protein function, cell‐permeable, non‐helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X‐ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. PMID:27918136

Th and U fuel photofission study by NTD for AD-MSR subcritical assembly

NASA Astrophysics Data System (ADS)

Sajo-Bohus, Laszlo; Greaves, Eduardo D.; Davila, Jesus; Barros, Haydn; Pino, Felix; Barrera, Maria T.; Farina, Fulvio

2015-07-01

During the last decade a considerable effort has been devoted for developing energy generating systems based on advanced nuclear technology within the design concepts of GEN-IV. Thorium base fuel systems such as accelerator driven nuclear reactors are one of the often mentioned attractive and affordable options. Several radiotherapy linear accelerators are on the market and due to their reliability, they could be employed as drivers for subcritical liquid fuel assemblies. Bremsstrahlung photons with energies above 5.5MeV, induce (γ,n) and (e,e'n) reactions in the W-target. Resulting gamma radiation and photo or fission neutrons may be absorbed in target materials such as thorium and uranium isotopes to induce sustained fission or nuclear transmutation in waste radioactive materials. Relevant photo driven and photo-fission reaction cross sections are important for actinides 232Th, 238U and 237Np in the radiotherapy machines energy range of 10-20 MV. In this study we employ passive nuclear track detectors (NTD) to determine fission rates and neutron production rates with the aim to establish the feasibility for gamma and photo-neutron driven subcritical assemblies. To cope with these objectives a 20 MV radiotherapy machine has been employed with a mixed fuel target. Results will support further development for a subcritical assembly employing a thorium containing liquid fuel. It is expected that acquired technological knowledge will contribute to the Venezuelan nuclear energy program.

Non-canonical modulators of nuclear receptors.

PubMed

Tice, Colin M; Zheng, Ya-Jun

2016-09-01

Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cross-species extrapolation of an adverse outcome pathway for ecdysone receptor activation

EPA Science Inventory

Different invertebrate nuclear receptors serve as targets for a variety of environmental contaminants. One of these is the ecdysteroid receptor (EcR). Due to the important role of this nuclear receptor in regulating development and reproduction in invertebrates, particularly duri...

Cross-species extrapolation of an adverse outcome pathway for ecdysteroid receptor activation

EPA Science Inventory

Different invertebrate nuclear receptors serve as targets for a variety of environmental contaminants. One of these is the ecdysteroid receptor (EcR). Due to the important role of this nuclear receptor in regulating development and reproduction in invertebrates, particularly duri...

Morphological and functional effects of graphene on the synthesis of uranium carbide for isotopes production targets.

PubMed

Biasetto, L; Corradetti, S; Carturan, S; Eloirdi, R; Amador-Celdran, P; Staicu, D; Blanco, O Dieste; Andrighetto, A

2018-05-29

The development of tailored targets for the production of radioactive isotopes represents an active field in nuclear research. Radioactive beams find applications in nuclear medicine, in astrophysics, matter physics and materials science. In this work, we study the use of graphene both as carbon source for UO 2 carbothermal reduction to produce UC x targets, and also as functional properties booster. At fixed composition, the UC x target grain size, porosity and thermal conductivity represent the three main points that affect the target production efficiency. UC x was synthesized using both graphite and graphene as the source of carbon and the target properties in terms of composition, grain size, porosity, thermal diffusivity and thermal conductivity were studied. The main output of this work is related to the remarkable enhancement achieved in thermal conductivity, which can profitably improve thermal dissipation during operational stages of UC x targets.

In silico prediction of escherichia coli proteins targeting the host cell nucleus, with special reference to their role in colon cancer etiology.

PubMed

Khan, Abdul Arif

2014-06-01

The potential role of Escherichia coli in the development of colorectal carcinoma (CRC) has been investigated in many studies. Although the exact mechanism is not clear, chronic inflammation caused by E. coli and other related events are suggested as possible causes behind E. coli-induced colon cancer. It has been found that CRC cells, but not normal cells, are colonized by an intracellular form of E. coli. We predicted nuclear targeting of bacterial proteins in the host cell through computational tools nuclear localization signal (NLS) mapper and balanced subcellular localization predictor (BaCeILo). During intracellular E. coli residence, such targeting is highly likely and may have a possible role in colon cancer etiology. We observed that several gene expression-associated proteins of E. coli can migrate to the host nucleus during intracellular infections. This situation provides an opportunity for competitive interaction of host and pathogen proteins with similar cellular substrates, thereby increasing the chances of development of colon cancer. Moreover, the results indicated that proteins localized in the membrane of E. coli mostly act as secretary proteins in host cells. No exact correlation was observed between NLS prediction and nuclear localization prediction by BaCeILo. This is partly because of a number of reasons, including that only 30% of nuclear proteins carry NLS and that proteins <40 kDa molecular weight can passively target the host nucleus. This study concludes that detection of gene expression-specific E. coli proteins and their targeting of the nucleus may have a profound impact on CRC etiology.

Lujan Center Mark-IV Target Neutronics Design Internal Review Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lisowski, Paul W.; Gallmeier, Franz; Guber, Klaus

The 1L Target Moderator Reflector System (TMRS) at the Lujan Center will need to be replaced before the CY 2020 operating cycle. A Physics Division design team investigated options for improving the overall target performance for nuclear science research with minimal reduction in performance for materials science. This review concluded that devoting an optimized arrangement of the Lujan TMRS upper tier to nuclear science and using the lower tier for materials science can achieve those goals. This would open the opportunity for enhanced nuclear science research in an important neutron energy range for NNSA. There will be no other facilitymore » in the US that will compete in the keV energy range provided flight paths and instrumentation are developed to take advantage of the neutron flux and resolution.« less

New bomb, no mission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mello, G.

1997-05-01

The cold war may be over, but the nuclear arms race has not quite ended. The United States is fielding a new nuclear weapon-a bomb that was used to threaten Libya, a non-nuclear nation, even before it was deployed. The B61 {open_quotes}mod-11{close_quotes} gravity bomb is the first nuclear capability added to the US arsenal since 1989. It was developed and deployed secretly, without public or congressional debate, and in apparent contradiction to official domestic and international assurances that no new nuclear weapons were being developed in the United States. The B61-11`s unique earth-penetrating characteristic and wide range of yields allowmore » it to threaten otherwide indestructible targets from the air-or, in Pentagonese, to hold such targets {open_quotes}at risk.{close_quotes} That makes the B61-11 a uniquely useful warfighting tool. The 1,200-pound B61-11 replaces the B53, a 8,900-pound, nine-megaton bomb that was developed as a {open_quotes}city buster{close_quotes} and was later designated as a substitute for an earth-penetrating weapon. The B53 was deliverable only by vulnerable B-52s; in contrast, the smaller and lighter B61-11 can be delivered the the stealthier B-2A bomber, or even by F16 fighters.« less

Applications of nuclear physics

NASA Astrophysics Data System (ADS)

Hayes, A. C.

2017-02-01

Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applications of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.

Applications of nuclear physics

DOE PAGES

Hayes-Sterbenz, Anna Catherine

2017-01-10

Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applicationsmore » of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Lastly, each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.« less

Applications of nuclear physics.

PubMed

Hayes, A C

2017-02-01

Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applications of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.

Applications of nuclear physics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayes-Sterbenz, Anna Catherine

Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applicationsmore » of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Lastly, each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.« less

Design of the Next Generation Target at the Lujan Neutron Scattering Center, LANSCE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferres, Laurent

Los Alamos National Laboratory (LANL) supports scientific research in many diverse fields such as biology, chemistry, and nuclear science. The Laboratory was established in 1943 during the Second World War to develop nuclear weapons. Today, LANL is one of the largest laboratories dedicated to nuclear defense and operates an 800 MeV proton linear accelerator for basic and applied research including: production of high- and low-energy neutrons beams, isotope production for medical applications and proton radiography. This accelerator is located at the Los Alamos Neutron Science Center (LANSCE). The work performed involved the redesign of the target for the low-energy neutronmore » source at the Lujan Neutron Scattering Center, which is one of the facilities built around the accelerator. The redesign of the target involves modeling various arrangements of the moderator-reflector-shield for the next generation neutron production target. This is done using Monte Carlo N-Particle eXtended (MCNPX), and ROOT analysis framework, a C++ based-software, to analyze the results.« less

Intranuclear biophotonics by smart design of nuclear-targeting photo-/radio-sensitizers co-loaded upconversion nanoparticles.

PubMed

Fan, Wenpei; Shen, Bo; Bu, Wenbo; Zheng, Xiangpeng; He, Qianjun; Cui, Zhaowen; Ni, Dalong; Zhao, Kuaile; Zhang, Shengjian; Shi, Jianlin

2015-11-01

Biophotonic technology that uses light and ionizing radiation for positioned cancer therapy is a holy grail in the field of biomedicine because it can overcome the systemic toxicity and adverse side effects of conventional chemotherapy. However, the existing biophotonic techniques fail to achieve the satisfactory treatment efficacy, which remains a big challenge for clinical implementation. Herein, we develop a novel theranostic technique of "intranuclear biophotonics" by the smart design of a nuclear-targeting biophotonic system based on photo-/radio-sensitizers covalently co-loaded upconversion nanoparticles. These nuclear-targeting biophotonic agents can not only generate a great deal of multiple cytotoxic reactive oxygen species in the nucleus by making full use of NIR/X-ray irradiation, but also produce greatly enhanced intranuclear synergetic radio-/photodynamic therapeutic effects under the magnetic/luminescent bimodal imaging guidance, which may achieve the optimal efficacy in treating radio-resistant tumors. We anticipate that the highly effective intranuclear biophotonics will contribute significantly to the development of biophotonic techniques and open new perspectives for a variety of cancer theranostic applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Physics division. Progress report for period ending September 30, 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ball, S.J.

1997-04-01

This report covers the research and development activities of the Physics Division for the 1995 and 1996 fiscal years, beginning October 1, 1994, and ending September 30, 1996. The activities of the Division continue to be concentrated in the areas of experimental nuclear physics, experimental atomic physics, and theoretical nuclear and atomic physics. In addition, there are smaller programs in plasma diagnostics and data compilation and evaluation. During the period of this report, there has been considerable success in bringing the Holifield Radioactive Ion Beam Facility (HRIBF) into routine operation. The budgets of the nuclear physics portion of the Divisionmore » have increased each year in nearly all areas, and several new members have been added to the Division research and development staff. On August 30, 1996, the HRIBF successfully accelerated its first radioactive ion beams, {sup 69}As and {sup 70}As. Prior to this, the heart of the facility, the RIB injector system, was completed, including installation of a remote handling system for the target/ion source assembly. Target and ion source development is likely to be the technical key to success of the HRIBF. We have expanded our efforts in those development areas. Of special note is the development of highly permeable composite targets which have now been shown to allow release of difficult-to-produce radioactive ions such as {sup 17,18}F. A summary of the HRIBF work is provided in Chapter 1, along with supporting activities of the Joint Institute for Heavy Ion Research.« less

Fabrication of light water reactor tritium targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pilger, J.P.

1991-11-01

The mission of the Fabrication Development Task of the Tritium Target Development Project is: to produce a documented technology basis, including specifications and procedures for target rod fabrication; to demonstrate that light water tritium targets can be manufactured at a rate consistent with tritium production requirements; and to develop quality control methods to evaluate target rod components and assemblies, and establish correlations between evaluated characteristics and target rod performance. Many of the target rod components: cladding tubes, end caps, plenum springs, etc., have similar counterparts in LWR fuel rods. High production rate manufacture and inspection of these components has beenmore » adequately demonstrated by nuclear fuel rod manufacturers. This summary describes the more non-conventional manufacturing processes and inspection techniques developed to fabricate target rod components whose manufacturability at required production rates had not been previously demonstrated.« less

Human resource development for nuclear generation - from the perspective of a utility company

NASA Astrophysics Data System (ADS)

Kahar, Wan Shakirah Wan Abdul; Mostafa, Nor Azlan; Salim, Mohd Faiz

2017-01-01

Malaysia is currently in the planning phase of its nuclear power program, with the first unit targeted to be operational in 2030. Training of nuclear power plant (NPP) staffs are usually long and rigorous due to the complexity and safety aspects of nuclear power. As the sole electricity utility in the country, it is therefore essential that Tenaga Nasional Berhad (TNB) prepares early in developing its human resource and nuclear expertise as a potential NPP owner-operator. A utility also has to be prudent in managing its work force efficiently and effectively, while ensuring that adequate preparations are being made to acquire the necessary nuclear knowledge with sufficient training lead time. There are several approaches to training that can be taken by a utility company with no experience in nuclear power. These include conducting feasibility studies and benchmarking exercises, preparing long term human resource development, increasing the exposure on nuclear power technology to both the top management and general staff, and employing the assistance of relevant agencies locally and abroad. This paper discusses the activities done and steps taken by TNB in its human resource development for Malaysia's nuclear power program.

Angstrom-Resolution Magnetic Resonance Imaging of Single Molecules via Wave-Function Fingerprints of Nuclear Spins

NASA Astrophysics Data System (ADS)

Ma, Wen-Long; Liu, Ren-Bao

2016-08-01

Single-molecule sensitivity of nuclear magnetic resonance (NMR) and angstrom resolution of magnetic resonance imaging (MRI) are the highest challenges in magnetic microscopy. Recent development in dynamical-decoupling- (DD) enhanced diamond quantum sensing has enabled single-nucleus NMR and nanoscale NMR. Similar to conventional NMR and MRI, current DD-based quantum sensing utilizes the "frequency fingerprints" of target nuclear spins. The frequency fingerprints by their nature cannot resolve different nuclear spins that have the same noise frequency or differentiate different types of correlations in nuclear-spin clusters, which limit the resolution of single-molecule MRI. Here we show that this limitation can be overcome by using "wave-function fingerprints" of target nuclear spins, which is much more sensitive than the frequency fingerprints to the weak hyperfine interaction between the targets and a sensor under resonant DD control. We demonstrate a scheme of angstrom-resolution MRI that is capable of counting and individually localizing single nuclear spins of the same frequency and characterizing the correlations in nuclear-spin clusters. A nitrogen-vacancy-center spin sensor near a diamond surface, provided that the coherence time is improved by surface engineering in the near future, may be employed to determine with angstrom resolution the positions and conformation of single molecules that are isotope labeled. The scheme in this work offers an approach to breaking the resolution limit set by the "frequency gradients" in conventional MRI and to reaching the angstrom-scale resolution.

Upgrade of the MIT Linear Electrostatic Ion Accelerator (LEIA) for nuclear diagnostics development for Omega, Z and the NIF.

PubMed

Sinenian, N; Manuel, M J-E; Zylstra, A B; Rosenberg, M; Waugh, C J; Rinderknecht, H G; Casey, D T; Sio, H; Ruszczynski, J K; Zhou, L; Gatu Johnson, M; Frenje, J A; Séguin, F H; Li, C K; Petrasso, R D; Ruiz, C L; Leeper, R J

2012-04-01

The MIT Linear Electrostatic Ion Accelerator (LEIA) generates DD and D(3)He fusion products for the development of nuclear diagnostics for Omega, Z, and the National Ignition Facility (NIF). Significant improvements to the system in recent years are presented. Fusion reaction rates, as high as 10(7) s(-1) and 10(6) s(-1) for DD and D(3)He, respectively, are now well regulated with a new ion source and electronic gas control system. Charged fusion products are more accurately characterized, which allows for better calibration of existing nuclear diagnostics. In addition, in situ measurements of the on-target beam profile, made with a CCD camera, are used to determine the metrology of the fusion-product source for particle-counting applications. Finally, neutron diagnostics development has been facilitated by detailed Monte Carlo N-Particle Transport (MCNP) modeling of neutrons in the accelerator target chamber, which is used to correct for scattering within the system. These recent improvements have resulted in a versatile platform, which continues to support the existing nuclear diagnostics while simultaneously facilitating the development of new diagnostics in aid of the National Ignition Campaign at the National Ignition Facility. © 2012 American Institute of Physics

Upgrade of the MIT Linear Electrostatic Ion Accelerator (LEIA) for nuclear diagnostics development for Omega, Z and the NIF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sinenian, N.; Manuel, M. J.-E.; Zylstra, A. B.

2012-04-15

The MIT Linear Electrostatic Ion Accelerator (LEIA) generates DD and D{sup 3}He fusion products for the development of nuclear diagnostics for Omega, Z, and the National Ignition Facility (NIF). Significant improvements to the system in recent years are presented. Fusion reaction rates, as high as 10{sup 7} s{sup -1} and 10{sup 6} s{sup -1} for DD and D{sup 3}He, respectively, are now well regulated with a new ion source and electronic gas control system. Charged fusion products are more accurately characterized, which allows for better calibration of existing nuclear diagnostics. In addition, in situ measurements of the on-target beam profile,more » made with a CCD camera, are used to determine the metrology of the fusion-product source for particle-counting applications. Finally, neutron diagnostics development has been facilitated by detailed Monte Carlo N-Particle Transport (MCNP) modeling of neutrons in the accelerator target chamber, which is used to correct for scattering within the system. These recent improvements have resulted in a versatile platform, which continues to support the existing nuclear diagnostics while simultaneously facilitating the development of new diagnostics in aid of the National Ignition Campaign at the National Ignition Facility.« less

Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.

PubMed

Wiedmann, Mareike M; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F; Verma, Chandra S; Itzhaki, Laura; Stewart, Murray; Brenton, James D; Spring, David R

2017-01-09

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nuclear Receptor TLX in Development and Diseases.

PubMed

Sun, Guoqiang; Cui, Qi; Shi, Yanhong

2017-01-01

The nuclear receptor TLX (NR2E1) is a transcription factor that is critical for neural development and adult neurogenesis through its actions in regulating neural stem cell proliferation, self-renewal, and fate determination. These roles are primarily executed by regulating TLX downstream target genes involved in myriad pathways such as cell cycle progression, RNA processing, angiogenesis, and senescence. Recent studies suggest that dysregulation of TLX pathways plays an important role in the pathogenesis of human neurological disorders and brain tumors. Here, we will highlight recent progress in the roles of TLX in brain development and adult neurogenesis, and the relevance of TLX to neurological diseases and brain tumors. We will also discuss the potential of TLX as a therapeutic target for these disorders. © 2017 Elsevier Inc. All rights reserved.

A new approach for manufacturing and processing targets to produce 99mTc with cyclotrons

NASA Astrophysics Data System (ADS)

Matei, L.; McRae, G.; Galea, R.; Niculae, D.; Craciun, L.; Leonte, R.; Surette, G.; Langille, S.; Louis, C. St.; Gelbart, W.; Abeysekera, B.; Johnson, R. R.

2017-06-01

The most important radioisotope for nuclear medicine is 99mTc. After the supply crisis of 99Mo starting in 2008, the availability of 99mTc became a worldwide concern. Alternative methods for producing the medical imaging isotope 99mTc are actively being developed around the world. The reaction 100Mo(p, 2n)99mTc provides a direct route that can be incorporated into routine production in nuclear medicine centers that possess medical cyclotrons for production of other isotopes, such as those used for Positron Emission Tomography. This paper describes a new approach for manufacturing targets for the (p, 2n) nuclear reaction on 100Mo and the foundation for the subsequent commercial separation and purification of the 99mTc produced. Two designs of targets are presented. The targets used to produce 99mTc are subject to a number of operational constraints.They must withstand the temperatures generated by the irradiation, accommodate temperature gradients from cooling system of the target, must be resilient and must be easily post-processed to separate the 99mTc. After irradiation, the separation of Tc from Mo was carried out using an innovative two-step approach. The process described in this paper can be automated with modules that easily fit in standard production hot cells found in nuclear medicine facilities.

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

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 asmore » 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.« less

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

PubMed Central

Sun, Xingshen; Yan, Ziying; Yi, Yaling; Li, Ziyi; Lei, Diana; Rogers, Christopher S.; Chen, Juan; Zhang, Yulong; Welsh, Michael J.; Leno, Gregory H.; Engelhardt, John F.

2008-01-01

Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene–deficient model in the domestic ferret using recombinant adeno-associated virus–mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases. PMID:18324338

Novel approach for the simultaneous detection of DNA from different fish species based on a nuclear target: quantification potential.

PubMed

Prado, Marta; Boix, Ana; von Holst, Christoph

2012-07-01

The development of DNA-based methods for the identification and quantification of fish in food and feed samples is frequently focused on a specific fish species and/or on the detection of mitochondrial DNA of fish origin. However, a quantitative method for the most common fish species used by the food and feed industry is needed for official control purposes, and such a method should rely on the use of a single-copy nuclear DNA target owing to its more stable copy number in different tissues. In this article, we report on the development of a real-time PCR method based on the use of a nuclear gene as a target for the simultaneous detection of fish DNA from different species and on the evaluation of its quantification potential. The method was tested in 22 different fish species, including those most commonly used by the food and feed industry, and in negative control samples, which included 15 animal species and nine feed ingredients. The results show that the method reported here complies with the requirements concerning specificity and with the criteria required for real-time PCR methods with high sensitivity.

Development of single-copy nuclear intron markers for species-level phylogenetics: Case study with Paullinieae (Sapindaceae).

PubMed

Chery, Joyce G; Sass, Chodon; Specht, Chelsea D

2017-09-01

We developed a bioinformatic pipeline that leverages a publicly available genome and published transcriptomes to design primers in conserved coding sequences flanking targeted introns of single-copy nuclear loci. Paullinieae (Sapindaceae) is used to demonstrate the pipeline. Transcriptome reads phylogenetically closer to the lineage of interest are aligned to the closest genome. Single-nucleotide polymorphisms are called, generating a "pseudoreference" closer to the lineage of interest. Several filters are applied to meet the criteria of single-copy nuclear loci with introns of a desired size. Primers are designed in conserved coding sequences flanking introns. Using this pipeline, we developed nine single-copy nuclear intron markers for Paullinieae. This pipeline is highly flexible and can be used for any group with available genomic and transcriptomic resources. This pipeline led to the development of nine variable markers for phylogenetic study without generating sequence data de novo.

Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development.

PubMed

Schmouth, Jean-François; Arenillas, David; Corso-Díaz, Ximena; Xie, Yuan-Yun; Bohacec, Slavita; Banks, Kathleen G; Bonaguro, Russell J; Wong, Siaw H; Jones, Steven J M; Marra, Marco A; Simpson, Elizabeth M; Wasserman, Wyeth W

2015-07-24

Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development.

Localization of a bacterial group II intron-encoded protein in eukaryotic nuclear splicing-related cell compartments.

PubMed

Nisa-Martínez, Rafael; Laporte, Philippe; Jiménez-Zurdo, José Ignacio; Frugier, Florian; Crespi, Martin; Toro, Nicolás

2013-01-01

Some bacterial group II introns are widely used for genetic engineering in bacteria, because they can be reprogrammed to insert into the desired DNA target sites. There is considerable interest in developing this group II intron gene targeting technology for use in eukaryotes, but nuclear genomes present several obstacles to the use of this approach. The nuclear genomes of eukaryotes do not contain group II introns, but these introns are thought to have been the progenitors of nuclear spliceosomal introns. We investigated the expression and subcellular localization of the bacterial RmInt1 group II intron-encoded protein (IEP) in Arabidopsis thaliana protoplasts. Following the expression of translational fusions of the wild-type protein and several mutant variants with EGFP, the full-length IEP was found exclusively in the nucleolus, whereas the maturase domain alone targeted EGFP to nuclear speckles. The distribution of the bacterial RmInt1 IEP in plant cell protoplasts suggests that the compartmentalization of eukaryotic cells into nucleus and cytoplasm does not prevent group II introns from invading the host genome. Furthermore, the trafficking of the IEP between the nucleolus and the speckles upon maturase inactivation is consistent with the hypothesis that the spliceosomal machinery evolved from group II introns.

Localization of a Bacterial Group II Intron-Encoded Protein in Eukaryotic Nuclear Splicing-Related Cell Compartments

PubMed Central

Nisa-Martínez, Rafael; Laporte, Philippe; Jiménez-Zurdo, José Ignacio; Frugier, Florian; Crespi, Martin; Toro, Nicolás

2013-01-01

Some bacterial group II introns are widely used for genetic engineering in bacteria, because they can be reprogrammed to insert into the desired DNA target sites. There is considerable interest in developing this group II intron gene targeting technology for use in eukaryotes, but nuclear genomes present several obstacles to the use of this approach. The nuclear genomes of eukaryotes do not contain group II introns, but these introns are thought to have been the progenitors of nuclear spliceosomal introns. We investigated the expression and subcellular localization of the bacterial RmInt1 group II intron-encoded protein (IEP) in Arabidopsis thaliana protoplasts. Following the expression of translational fusions of the wild-type protein and several mutant variants with EGFP, the full-length IEP was found exclusively in the nucleolus, whereas the maturase domain alone targeted EGFP to nuclear speckles. The distribution of the bacterial RmInt1 IEP in plant cell protoplasts suggests that the compartmentalization of eukaryotic cells into nucleus and cytoplasm does not prevent group II introns from invading the host genome. Furthermore, the trafficking of the IEP between the nucleolus and the speckles upon maturase inactivation is consistent with the hypothesis that the spliceosomal machinery evolved from group II introns. PMID:24391881

Radiological Aspects of Heavy Metal Liquid Targets for Accelerator-Driven Systems as Intense Neutron Sources

NASA Astrophysics Data System (ADS)

Gai, E. V.; Ignatyuk, A. V.; Lunev, V. P.; Shubin, Yu. N.

2001-11-01

General problems arising in development of intense neutron sources as a part of accelerator-driven systems and first experience accumulated in IPPE during last several years are briefly discussed. The calculation and analysis of nuclear-physical properties of the targets, such as the accumulation of spallation reaction products, activity and heat release for various versions of heavy liquid metal targets were performed in IPPE. The sensitivity of the results of calculations to the various sets of nuclear data was considered. The main radiology characteristics of the lead-bismuth target, which is now under construction in the frame of ISTC Project # 559, are briefly described. The production of short-lived nuclides was estimated, the total activity and volatile nuclide accumulation, residual heat release, the energies of various decay modes were analysed.

ROR nuclear receptors: structures, related diseases, and drug discovery

PubMed Central

Zhang, Yan; Luo, Xiao-yu; Wu, Dong-hai; Xu, Yong

2015-01-01

Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs. PMID:25500868

Efficient Subcellular Targeting to the Cell Nucleus of Quantum Dots Densely Decorated with a Nuclear Localization Sequence Peptide.

PubMed

Maity, Amit Ranjan; Stepensky, David

2016-01-27

Organelle-targeted drug delivery can enhance the efficiency of the intracellularly acting drugs and reduce their toxicity. We generated core-shell type CdSe-ZnS quantum dots (QDs) densely decorated with NLS peptidic targeting residues using a 3-stage decoration approach and investigated their endocytosis and nuclear targeting efficiencies. The diameter of the generated QDs increased following the individual decoration stages (16.3, 18.9, and 21.9 nm), the ζ-potential became less negative (-33.2, -17.5, and -11.9 mV), and characteristic changes appeared in the FTIR spectra following decoration with the linker and NLS peptides. Quantitative analysis of the last decoration stage revealed that 37.9% and 33.2% of the alkyne-modified NLS groups that were added to the reaction mix became covalently attached or adsorbed to the QDs surface, respectively. These numbers correspond to 63.6 and 55.7 peptides conjugated or adsorbed to a single QD (the surface density of 42 and 37 conjugated and adsorbed peptides per 1000 nm(2) of the QDs surface), which is higher than in the majority of previous studies that reported decoration efficiencies of formulations intended for nuclear-targeted drug delivery. QDs decorated with NLS peptides undergo more efficient endocytosis, as compared to other investigated QDs formulations, and accumulated to a higher extent in the cell nucleus or in close vicinity to it (11.9%, 14.6%, and 56.1% of the QDs endocytosed by an average cell for the QD-COOH, QD-azide, and QD-NLS formulations, respectively). We conclude that dense decoration of QDs with NLS residues increased their endocytosis and led to their nuclear targeting (preferential accumulation in the cells nuclei or in close vicinity to them). The experimental system and research tools that were used in this study allow quantitative investigation of the mechanisms that govern the QDs nuclear targeting and their dependence on the formulation properties. These findings will contribute to the development of subcellularly targeted DDSs that will deliver specific drugs to the nuclei of the target cells and will enhance efficacy and reduce toxicity of these drugs.

Resonant scattering experiments with radioactive nuclear beams - Recent results and future plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teranishi, T.; Sakaguchi, S.; Uesaka, T.

2013-04-19

Resonant scattering with low-energy radioactive nuclear beams of E < 5 MeV/u have been studied at CRIB of CNS and at RIPS of RIKEN. As an extension to the present experimental technique, we will install an advanced polarized proton target for resonant scattering experiments. A Monte-Carlo simulation was performed to study the feasibility of future experiments with the polarized target. In the Monte-Carlo simulation, excitation functions and analyzing powers were calculated using a newly developed R-matrix calculation code. A project of a small-scale radioactive beam facility at Kyushu University is also briefly described.

Nuclear weapons in the 1980s: MAD versus NUTS. Mutual hostage relationship of the superpowers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keeny, S.M. Jr.; Panofsky, W.K.H.

Critics of the strategic relationship of Mutual Assured Destruction (MAD) developed during the 1960s claim it immorally holds entire civilian populations hostage. Some advocate the Nuclear Utilization Target Selection (NUTS) concept, while others argue for a defense-oriented military posture. The interrelationships of these concepts are examined against the background of stockpiled nuclear weapons capable of massive devastation, the technical limits to defense, and the uncertainty that a nuclear war could be controlled. The evidence shows that a MAD world prevails despite NUTS proposals, which may have increased the danger by giving nuclear war the illusion of acceptability. (DCK)

The Proliferation Security Initiative: A Means to an End for the Operational Commander

DTIC Science & Technology

2009-05-04

The Reduced Enrichment for Research and Test Reactors ( RERTR ) Program develops technology necessary to enable the conversion of civilian...facilities using high enriched uranium (HEU) to low enriched uranium (LEU) fuels and targets. The RERTR Program was initiated by the U.S. Department of...processes have been developed for producing radioisotopes with LEU targets. The RERTR Program is managed by the Office of Nuclear Material Threat

Cell Nucleus-Targeting Zwitterionic Carbon Dots.

PubMed

Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

2015-12-22

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.

Cell Nucleus-Targeting Zwitterionic Carbon Dots

PubMed Central

Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

2015-01-01

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation. PMID:26689549

Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1β (HNF1β) transcription factor is imported into the nucleus via a monopartite NLS sequence.

PubMed

Wiedmann, Mareike M; Aibara, Shintaro; Spring, David R; Stewart, Murray; Brenton, James D

2016-09-01

The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in ovarian clear cell carcinoma (CCC) and is a potential therapeutic target. To explore potential approaches that block HNF1β transcription we have identified and characterised extensively the nuclear localisation signal (NLS) for HNF1β and its interactions with the nuclear protein import receptor, Importin-α. Pull-down assays demonstrated that the DNA binding domain of HNF1β interacted with a spectrum of Importin-α isoforms and deletion constructs tagged with eGFP confirmed that the HNF1β (229)KKMRRNR(235) sequence was essential for nuclear localisation. We further characterised the interaction between the NLS and Importin-α using complementary biophysical techniques and have determined the 2.4Å resolution crystal structure of the HNF1β NLS peptide bound to Importin-α. The functional, biochemical, and structural characterisation of the nuclear localisation signal present on HNF1β and its interaction with the nuclear import protein Importin-α provide the basis for the development of compounds targeting transcription factor HNF1β via its nuclear import pathway. Copyright © 2016. Published by Elsevier Inc.

Human peroxisome proliferator-activated receptor mRNA and protein expression during development

EPA Science Inventory

The peroxisome proliferator-activated receptors (PPAR) are nuclear hormone receptors that regulate lipid and glucose homeostasis and are important in reproduction and development. PPARs are targets ofpharmaceuticals and are also activated by environmental contaminants, including ...

Facility Targeting, Protection and Mission Decision Making Using the VISAC Code

NASA Technical Reports Server (NTRS)

Morris, Robert H.; Sulfredge, C. David

2011-01-01

The Visual Interactive Site Analysis Code (VISAC) has been used by DTRA and several other agencies to aid in targeting facilities and to predict the associated collateral effects for the go, no go mission decision making process. VISAC integrates the three concepts of target geometric modeling, damage assessment capabilities, and an event/fault tree methodology for evaluating accident/incident consequences. It can analyze a variety of accidents/incidents at nuclear or industrial facilities, ranging from simple component sabotage to an attack with military or terrorist weapons. For nuclear facilities, VISAC predicts the facility damage, estimated downtime, amount and timing of any radionuclides released. Used in conjunction with DTRA's HPAC code, VISAC also can analyze transport and dispersion of the radionuclides, levels of contamination of the surrounding area, and the population at risk. VISAC has also been used by the NRC to aid in the development of protective measures for nuclear facilities that may be subjected to attacks by car/truck bombs.

Loss of intracellular lipid binding proteins differentially impacts saturated fatty acid uptake and nuclear targeting in mouse hepatocytes

PubMed Central

Storey, Stephen M.; McIntosh, Avery L.; Huang, Huan; Martin, Gregory G.; Landrock, Kerstin K.; Landrock, Danilo; Payne, H. Ross; Kier, Ann B.

2012-01-01

The liver expresses high levels of two proteins with high affinity for long-chain fatty acids (LCFAs): liver fatty acid binding protein (L-FABP) and sterol carrier protein-2 (SCP-2). Real-time confocal microscopy of cultured primary hepatocytes from gene-ablated (L-FABP, SCP-2/SCP-x, and L-FABP/SCP-2/SCP-x null) mice showed that the loss of L-FABP reduced cellular uptake of 12-N-methyl-(7-nitrobenz-2-oxa-1,3-diazo)-aminostearic acid (a fluorescent-saturated LCFA analog) by ∼50%. Importantly, nuclear targeting of the LCFA was enhanced when L-FABP was upregulated (SCP-2/SCP-x null) but was significantly reduced when L-FABP was ablated (L-FABP null), thus impacting LCFA nuclear targeting. These effects were not associated with a net decrease in expression of key membrane proteins involved in LCFA or glucose transport. Since hepatic LCFA uptake and metabolism are closely linked to glucose uptake, the effect of glucose on L-FABP-mediated LCFA uptake and nuclear targeting was examined. Increasing concentrations of glucose decreased cellular LCFA uptake and even more extensively decreased LCFA nuclear targeting. Loss of L-FABP exacerbated the decrease in LCFA nuclear targeting, while loss of SCP-2 reduced the glucose effect, resulting in enhanced LCFA nuclear targeting compared with control. Simply, ablation of L-FABP decreases LCFA uptake and even more extensively decreases its nuclear targeting. PMID:22859366

Nuclear Forensic Science: Analysis of Nuclear Material Out of Regulatory Control

NASA Astrophysics Data System (ADS)

Kristo, Michael J.; Gaffney, Amy M.; Marks, Naomi; Knight, Kim; Cassata, William S.; Hutcheon, Ian D.

2016-06-01

Nuclear forensic science seeks to identify the origin of nuclear materials found outside regulatory control. It is increasingly recognized as an integral part of a robust nuclear security program. This review highlights areas of active, evolving research in nuclear forensics, with a focus on analytical techniques commonly employed in Earth and planetary sciences. Applications of nuclear forensics to uranium ore concentrates (UOCs) are discussed first. UOCs have become an attractive target for nuclear forensic researchers because of the richness in impurities compared to materials produced later in the fuel cycle. The development of chronometric methods for age dating nuclear materials is then discussed, with an emphasis on improvements in accuracy that have been gained from measurements of multiple radioisotopic systems. Finally, papers that report on casework are reviewed, to provide a window into current scientific practice.

Can the HIV-1 splicing machinery be targeted for drug discovery?

PubMed Central

Dlamini, Zodwa; Hull, Rodney

2017-01-01

HIV-1 is able to express multiple protein types and isoforms from a single 9 kb mRNA transcript. These proteins are also expressed at particular stages of viral development, and this is achieved through the control of alternative splicing and the export of these transcripts from the nucleus. The nuclear export is controlled by the HIV protein Rev being required to transport incompletely spliced and partially spliced mRNA from the nucleus where they are normally retained. This implies a close relationship between the control of alternate splicing and the nuclear export of mRNA in the control of HIV-1 viral proliferation. This review discusses both the processes. The specificity and regulation of splicing in HIV-1 is controlled by the use of specific splice sites as well as exonic splicing enhancer and exonic splicing silencer sequences. The use of these silencer and enhancer sequences is dependent on the serine arginine family of proteins as well as the heterogeneous nuclear ribonucleoprotein family of proteins that bind to these sequences and increase or decrease splicing. Since alternative splicing is such a critical factor in viral development, it presents itself as a promising drug target. This review aims to discuss the inhibition of splicing, which would stall viral development, as an anti-HIV therapeutic strategy. In this review, the most recent knowledge of splicing in human immunodeficiency viral development and the latest therapeutic strategies targeting human immunodeficiency viral splicing are discussed. PMID:28331370

Nuclear clustering and the electron screening puzzle

NASA Astrophysics Data System (ADS)

Bertulani, C. A.; Spitaleri, C.

2018-01-01

Electron screening changes appreciably the magnitude of astrophysical nuclear reactions within stars. This effect is also observed in laboratory experiments on Earth, where atomic electrons are present in the nuclear targets. Theoretical models were developed over the past 30 years and experimental measurements have been carried out to study electron screening in thermonuclear reactions. None of the theoretical models were able to explain the high values of the experimentally determined screening potentials. We explore the possibility that the "electron screening puzzle" is due to nuclear clusterization and polarization e_ects in the fusion reactions. We will discuss the supporting arguments for this scenario.

Perspectives in molecular imaging through translational research, human medicine, and veterinary medicine.

PubMed

Berry, Clifford R; Garg, Predeep

2014-01-01

The concept of molecular imaging has taken off over the past 15 years to the point of the renaming of the Society of Nuclear Medicine (Society of Nuclear Medicine and Molecular Imaging) and Journals (European Journal of Nuclear Medicine and Molecular Imaging) and offering of medical fellowships specific to this area of study. Molecular imaging has always been at the core of functional imaging related to nuclear medicine. Even before the phrase molecular imaging came into vogue, radionuclides and radiopharmaceuticals were developed that targeted select physiological processes, proteins, receptor analogs, antibody-antigen interactions, metabolites and specific metabolic pathways. In addition, with the advent of genomic imaging, targeted genomic therapy, and theranostics, a number of novel radiopharmaceuticals for the detection and therapy of specific tumor types based on unique biological and cellular properties of the tumor itself have been realized. However, molecular imaging and therapeutics as well as the concept of theranostics are yet to be fully realized. The purpose of this review article is to present an overview of the translational approaches to targeted molecular imaging with application to some naturally occurring animal models of human disease. © 2013 Published by Elsevier Inc.

Nuclear Methods for Transmutation of Nuclear Waste: Problems, Perspextives, Cooperative Research - Proceedings of the International Workshop

NASA Astrophysics Data System (ADS)

Khankhasayev, Zhanat B.; Kurmanov, Hans; Plendl, Mikhail Kh.

1996-12-01

The Table of Contents for the full book PDF is as follows: * Preface * I. Review of Current Status of Nuclear Transmutation Projects * Accelerator-Driven Systems — Survey of the Research Programs in the World * The Los Alamos Accelerator-Driven Transmutation of Nuclear Waste Concept * Nuclear Waste Transmutation Program in the Czech Republic * Tentative Results of the ISTC Supported Study of the ADTT Plutonium Disposition * Recent Neutron Physics Investigations for the Back End of the Nuclear Fuel Cycle * Optimisation of Accelerator Systems for Transmutation of Nuclear Waste * Proton Linac of the Moscow Meson Factory for the ADTT Experiments * II. Computer Modeling of Nuclear Waste Transmutation Methods and Systems * Transmutation of Minor Actinides in Different Nuclear Facilities * Monte Carlo Modeling of Electro-nuclear Processes with Nonlinear Effects * Simulation of Hybrid Systems with a GEANT Based Program * Computer Study of 90Sr and 137Cs Transmutation by Proton Beam * Methods and Computer Codes for Burn-Up and Fast Transients Calculations in Subcritical Systems with External Sources * New Model of Calculation of Fission Product Yields for the ADTT Problem * Monte Carlo Simulation of Accelerator-Reactor Systems * III. Data Basis for Transmutation of Actinides and Fission Products * Nuclear Data in the Accelerator Driven Transmutation Problem * Nuclear Data to Study Radiation Damage, Activation, and Transmutation of Materials Irradiated by Particles of Intermediate and High Energies * Radium Institute Investigations on the Intermediate Energy Nuclear Data on Hybrid Nuclear Technologies * Nuclear Data Requirements in Intermediate Energy Range for Improvement of Calculations of ADTT Target Processes * IV. Experimental Studies and Projects * ADTT Experiments at the Los Alamos Neutron Science Center * Neutron Multiplicity Distributions for GeV Proton Induced Spallation Reactions on Thin and Thick Targets of Pb and U * Solid State Nuclear Track Detector and Radiochemical Studies on the Transmutation of Nuclei Using Relativistic Heavy Ions * Experimental and Theoretical Study of Radionuclide Production on the Electronuclear Plant Target and Construction Materials Irradiated by 1.5 GeV and 130 MeV Protons * Neutronics and Power Deposition Parameters of the Targets Proposed in the ISTC Project 17 * Multicycle Irradiation of Plutonium in Solid Fuel Heavy-Water Blanket of ADS * Compound Neutron Valve of Accelerator-Driven System Sectioned Blanket * Subcritical Channel-Type Reactor for Weapon Plutonium Utilization * Accelerator Driven Molten-Fluoride Reactor with Modular Heat Exchangers on PB-BI Eutectic * A New Conception of High Power Ion Linac for ADTT * Pions and Accelerator-Driven Transmutation of Nuclear Waste? * V. Problems and Perspectives * Accelerator-Driven Transmutation Technologies for Resolution of Long-Term Nuclear Waste Concerns * Closing the Nuclear Fuel-Cycle and Moving Toward a Sustainable Energy Development * Workshop Summary * List of Participants

The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision.

PubMed

Yu, R T; Chiang, M Y; Tanabe, T; Kobayashi, M; Yasuda, K; Evans, R M; Umesono, K

2000-03-14

Although the development of the vertebrate eye is well described, the number of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addition to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with associated blindness. An extensive screen of Tlx-positive and Tlx-negative P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade.

The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision

PubMed Central

Yu, Ruth T.; Chiang, Ming-Yi; Tanabe, Teruyo; Kobayashi, Mime; Yasuda, Kunio; Evans, Ronald M.; Umesono, Kazuhiko

2000-01-01

Although the development of the vertebrate eye is well described, the number of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addition to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with associated blindness. An extensive screen of Tlx-positive and Tlx-negative P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade. PMID:10706625

MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition.

PubMed

He, Qianjun; Shi, Jianlin

2014-01-22

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simulation study of neutron production in thick beryllium targets by 35 MeV and 50.5 MeV proton beams

NASA Astrophysics Data System (ADS)

Shin, Jae Won; Park, Tae-Sun

2017-09-01

A data-driven nuclear model dedicated to an accurate description of neutron productions in beryllium targets bombarded by proton beams is developed as a custom development that can be used as an add-on to GEANT4 code. The developed model, G4Data(Endf7.1), takes as inputs the total and differential cross section data of ENDF/B-VII.1 for not only the charge-exchange 9Be(p,n)9B reaction which produces discrete neutrons but also the nuclear reactions relevant for the production of continuum neutrons such as 9Be(p,pn)8Be and 9Be(p,n α) 5Li . In our benchmarking simulations for two experiments with 35 MeV and 50.5 MeV proton beams impinged on 1.16 and 1.05 cm thick beryllium targets, respectively, we find that the G4Data(Endf7.1) model can reproduce both the total amounts and the spectral shapes of the measured neutron yield data in a satisfactory manner, while all the considered hadronic models of GEANT4 cannot.

Targeting nuclear receptors for the treatment of fatty liver disease.

PubMed

Tanaka, Naoki; Aoyama, Toshifumi; Kimura, Shioko; Gonzalez, Frank J

2017-11-01

Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH. Copyright © 2017 Elsevier Inc. All rights reserved.

Neutron-rich isotope production using a uranium carbide - carbon nanotubes SPES target prototype

NASA Astrophysics Data System (ADS)

Corradetti, S.; Biasetto, L.; Manzolaro, M.; Scarpa, D.; Carturan, S.; Andrighetto, A.; Prete, G.; Vasquez, J.; Zanonato, P.; Colombo, P.; Jost, C. U.; Stracener, D. W.

2013-05-01

The SPES (Selective Production of Exotic Species) project, under development at the Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro (INFN-LNL), is a new-generation Isotope Separation On-Line (ISOL) facility for the production of radioactive ion beams by means of the proton-induced fission of uranium. In the framework of the research on the SPES target, seven uranium carbide discs, obtained by reacting uranium oxide with graphite and carbon nanotubes, were irradiated with protons at the Holifield Radioactive Ion Beam Facility (HRIBF) of Oak Ridge National Laboratory (ORNL). In the following, the yields of several fission products obtained during the experiment are presented and discussed. The experimental results are then compared to those obtained using a standard uranium carbide target. The reported data highlights the capability of the new type of SPES target to produce and release isotopes of interest for the nuclear physics community.

Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1

PubMed Central

Nambiar, Dhanya K.; Deep, Gagan; Singh, Rana P.; Agarwal, Chapla; Agarwal, Rajesh

2014-01-01

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis. PMID:25294820

Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1.

PubMed

Nambiar, Dhanya K; Deep, Gagan; Singh, Rana P; Agarwal, Chapla; Agarwal, Rajesh

2014-10-30

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.

The role of general nuclear medicine in breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greene, Lacey R, E-mail: lgreene@csu.edu.au; Wilkinson, Deborah; Faculty of Science, Charles Sturt University, Wagga Wagga, New South Wales

The rising incidence of breast cancer worldwide has prompted many improvements to current care. Routine nuclear medicine is a major contributor to a full gamut of clinical studies such as early lesion detection and stratification; guiding, monitoring, and predicting response to therapy; and monitoring progression, recurrence or metastases. Developments in instrumentation such as the high-resolution dedicated breast device coupled with the diagnostic versatility of conventional cameras have reinserted nuclear medicine as a valuable tool in the broader clinical setting. This review outlines the role of general nuclear medicine, concluding that targeted radiopharmaceuticals and versatile instrumentation position nuclear medicine as amore » powerful modality for patients with breast cancer.« less

Extended methods using thick-targets for nuclear reaction data of radioactive isotopes

NASA Astrophysics Data System (ADS)

Ebata, Shuichiro; Aikawa, Masayuki; Imai, Shotaro

2017-09-01

The nuclear transmutation is a technology to dispose of radioactive wastes. However, we do not have enough basic data for its developments, such as thick-target yields (TTY) and the interaction cross sections for radioactive material. We suggest two methods to estimate the TTY using inverse kinematics and to obtain the excitation function of the interaction cross sections which is named the thick-target transmission (T3) method. We deduce the energy-dependent conversion relation between the TTYs of the original system and its inverse kinematics, which can be replaced to a constant coefficient in the high energy region. Furthermore we show the usefulness of the T3 method to investigate the excitation function of the 12C + 27Al reaction in the simulation.

piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire.

PubMed

Senti, Kirsten-André; Jurczak, Daniel; Sachidanandam, Ravi; Brennecke, Julius

2015-08-15

PIWI clade Argonaute proteins silence transposon expression in animal gonads. Their target specificity is defined by bound ∼23- to 30-nucleotide (nt) PIWI-interacting RNAs (piRNAs) that are processed from single-stranded precursor transcripts via two distinct pathways. Primary piRNAs are defined by the endonuclease Zucchini, while biogenesis of secondary piRNAs depends on piRNA-guided transcript cleavage and results in piRNA amplification. Here, we analyze the interdependencies between these piRNA biogenesis pathways in developing Drosophila ovaries. We show that secondary piRNA-guided target slicing is the predominant mechanism that specifies transcripts—including those from piRNA clusters—as primary piRNA precursors and defines the spectrum of Piwi-bound piRNAs in germline cells. Post-transcriptional silencing in the cytoplasm therefore enforces nuclear transcriptional target silencing, which ensures the tight suppression of transposons during oogenesis. As target slicing also defines the nuclear piRNA pool during mouse spermatogenesis, our findings uncover an unexpected conceptual similarity between the mouse and fly piRNA pathways. © 2015 Senti et al.; Published by Cold Spring Harbor Laboratory Press.

Nuclear fusion at heavy water clusters collision with deuterized targets

NASA Astrophysics Data System (ADS)

Bolotin, Yu. L.; Inopin, E. V.; Lyashko, Yu. V.; Slabospitskij, R. P.

A review of research developed in different laboratories on animal heavy particle yield in D-D fusion reactions induced by heavy water cluster collisions with deuterized targets is presented. Analysis of data shows, on one hand, nontriviality of experimental results and inadequacy of their interpretation and, on the other hand, the multipromising prospects of such a research.

Phylogenetic marker development for target enrichment from transcriptome and genome skim data: the pipeline and its application in southern African Oxalis (Oxalidaceae)

Treesearch

Roswitha Schmickl; Aaron Liston; Vojtěch Zeisek; Kenneth Oberlander; Kevin Weitemier; Shannon C. K. Straub; Richard C. Cronn; Léanne L. Dreyer; Jan Suda

2016-01-01

Phylogenetics benefits from using a large number of putatively independent nuclear loci and their combination with other sources of information, such as the plastid and mitochondrial genomes. To facilitate the selection of orthologous low-copy nuclear (LCN) loci for phylogenetics in nonmodel organisms, we created an automated and interactive script to select hundreds...

A Random Variable Approach to Nuclear Targeting and Survivability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Undem, Halvor A.

We demonstrate a common mathematical formalism for analyzing problems in nuclear survivability and targeting. This formalism, beginning with a random variable approach, can be used to interpret past efforts in nuclear-effects analysis, including targeting analysis. It can also be used to analyze new problems brought about by the post Cold War Era, such as the potential effects of yield degradation in a permanently untested nuclear stockpile. In particular, we illustrate the formalism through four natural case studies or illustrative problems, linking these to actual past data, modeling, and simulation, and suggesting future uses. In the first problem, we illustrate themore » case of a deterministically modeled weapon used against a deterministically responding target. Classic "Cookie Cutter" damage functions result. In the second problem, we illustrate, with actual target test data, the case of a deterministically modeled weapon used against a statistically responding target. This case matches many of the results of current nuclear targeting modeling and simulation tools, including the result of distance damage functions as complementary cumulative lognormal functions in the range variable. In the third problem, we illustrate the case of a statistically behaving weapon used against a deterministically responding target. In particular, we show the dependence of target damage on weapon yield for an untested nuclear stockpile experiencing yield degradation. Finally, and using actual unclassified weapon test data, we illustrate in the fourth problem the case of a statistically behaving weapon used against a statistically responding target.« less

C. elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity

PubMed Central

Zhang, Yanmei; Xu, Jinling; Puscau, Cristina; Kim, Yongsoon; Wang, Xi; Alam, Hena; Hu, Patrick J.

2008-01-01

SUMMARY Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals. PMID:18241854

Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells

PubMed Central

Nguyen, Minh M.; Dar, Javid A.; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z.; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P.; Hua, Yun; Huryn, Donna M.; Wilson, Gabriela Mustata; Lazo, John S.; Nelson, Joel B.; Wipf, Peter

2016-01-01

Abstract Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

Cyclotron Production of Radionuclides for Nuclear Medicine at Academic Centers

NASA Astrophysics Data System (ADS)

Lapi, Suzanne

2016-09-01

The increase in use of radioisotopes for medical imaging has led to the development of new accelerator targetry and separation techniques for isotope production. For example, the development of longer-lived position emitting radionuclides has been explored to allow for nuclear imaging agents based on peptides, antibodies and nanoparticles. These isotopes (64Cu, 89Zr, 86Y) are typically produced via irradiation of solid targets on smaller cyclotrons (10-25 MeV) at academic or hospital based facilities. Recent research has further expanded the toolbox of PET tracers to include additional isotopes such as 52Mn, 55Co, 76Br and others. The smaller scale of these types of facilities can enable the straightforward involvement of students, thus adding to the next generation of nuclear science leaders. Research pertaining to development of robust and larger scale production technologies including solid target systems and remote systems for transport and purification of these isotopes has enabled both preclinical and clinical imaging research for many diseases. In particular, our group has focused on the use of radiolabeled antibodies for imaging of receptor expression in preclinical models and in a clinical trial of metastatic breast cancer patients.

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

DTIC Science & Technology

2011-09-01

breast-cancer-targeted nuclear drug delivery carriers , but we found that the ability of the PEI to disrupt the endosome/lysosome membrane was not...AD_________________ Award Number: W81XWH-09-1-0502 TITLE: Breast Cancer-Targeted Nuclear Drug ...Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy PRINCIPAL INVESTIGATOR: Youqing Shen, Ph.D

Efficient protein targeting to the inner nuclear membrane requires Atlastin-dependent maintenance of ER topology

PubMed Central

Pawar, Sumit; Ungricht, Rosemarie; Tiefenboeck, Peter; Leroux, Jean-Christophe

2017-01-01

Newly synthesized membrane proteins are targeted to the inner nuclear membrane (INM) by diffusion within the membrane system of the endoplasmic reticulum (ER), translocation through nuclear pore complexes (NPCs) and retention on nuclear partners. Using a visual in vitro assay we previously showed that efficient protein targeting to the INM depends on nucleotide hydrolysis. We now reveal that INM targeting is GTP-dependent. Exploiting in vitro reconstitution and in vivo analysis of INM targeting, we establish that Atlastins, membrane-bound GTPases of the ER, sustain the efficient targeting of proteins to the INM by their continued activity in preserving ER topology. When ER topology is altered, the long-range diffusional exchange of proteins in the ER network and targeting efficiency to the INM are diminished. Highlighting the general importance of proper ER topology, we show that Atlastins also influence NPC biogenesis and timely exit of secretory cargo from the ER. PMID:28826471

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kristo, Michael J.; Gaffney, Amy M.; Marks, Naomi

Nuclear forensic science seeks to identify the origin of nuclear materials found outside regulatory control. It is increasingly recognized as an integral part of a robust nuclear security program. Our review highlights areas of active, evolving research in nuclear forensics, with a focus on analytical techniques commonly employed in Earth and planetary sciences. Applications of nuclear forensics to uranium ore concentrates (UOCs) are discussed first. UOCs have become an attractive target for nuclear forensic researchers because of the richness in impurities compared to materials produced later in the fuel cycle. Furthermore, the development of chronometric methods for age dating nuclearmore » materials is then discussed, with an emphasis on improvements in accuracy that have been gained from measurements of multiple radioisotopic systems. Finally, papers that report on casework are reviewed, to provide a window into current scientific practice.« less

A Fungal Effector With Host Nuclear Localization and DNA-Binding Properties Is Required for Maize Anthracnose Development.

PubMed

Vargas, Walter A; Sanz-Martín, José M; Rech, Gabriel E; Armijos-Jaramillo, Vinicio D; Rivera, Lina P; Echeverria, María Mercedes; Díaz-Mínguez, José M; Thon, Michael R; Sukno, Serenella A

2016-02-01

Plant pathogens have the capacity to manipulate the host immune system through the secretion of effectors. We identified 27 putative effector proteins encoded in the genome of the maize anthracnose pathogen Colletotrichum graminicola that are likely to target the host's nucleus, as they simultaneously contain sequence signatures for secretion and nuclear localization. We functionally characterized one protein, identified as CgEP1. This protein is synthesized during the early stages of disease development and is necessary for anthracnose development in maize leaves, stems, and roots. Genetic, molecular, and biochemical studies confirmed that this effector targets the host's nucleus and defines a novel class of double-stranded DNA-binding protein. We show that CgEP1 arose from a gene duplication in an ancestor of a lineage of monocot-infecting Colletotrichum spp. and has undergone an intense evolution process, with evidence for episodes of positive selection. We detected CgEP1 homologs in several species of a grass-infecting lineage of Colletotrichum spp., suggesting that its function may be conserved across a large number of anthracnose pathogens. Our results demonstrate that effectors targeted to the host nucleus may be key elements for disease development and aid in the understanding of the genetic basis of anthracnose development in maize plants.

Isotope production and target preparation for nuclear astrophysics data

NASA Astrophysics Data System (ADS)

Schumann, Dorothea; Dressler, Rugard; Maugeri, Emilio Andrea; Heinitz, Stephan

2017-09-01

Targets are in many cases an indispensable ingredient for successful experiments aimed to produce nuclear data. With the recently observed shift to study nuclear reactions on radioactive targets, this task can become extremely challenging. Concerted actions of a certain number of laboratories able to produce isotopes and manufacture radioactive targets are urgently needed. We present here some examples of successful isotope and target production at PSI, in particular the production of 60Fe samples used for half-life measurements and neutron capture cross section experiments, the chemical processing and fabrication of lanthanide targets for capture cross section experiments at n_TOF (European Organization for Nuclear Research (CERN), Switzerland) as well as the recently performed manufacturing of highly-radioactive 7Be targets for the measurement of the 7Be(n,α)4He cross section in the energy range of interest for the Big-Bang nucleosynthesis contributing to the solving of the cosmological Li-problem. The two future projects: "Determination of the half-life and experiments on neutron capture cross sections of 53Mn" and "32Si - a new chronometer for nuclear dating" are briefly described. Moreover, we propose to work on the establishment of a dedicated network on isotope and target producing laboratories.

Nuclear Targeting Terms for Engineers and Scientists

DOE Office of Scientific and Technical Information (OSTI.GOV)

St Ledger, John W.

The Department of Defense has a methodology for targeting nuclear weapons, and a jargon that is used to communicate between the analysts, planners, aircrews, and missile crews. The typical engineer or scientist in the Department of Energy may not have been exposed to the nuclear weapons targeting terms and methods. This report provides an introduction to the terms and methodologies used for nuclear targeting. Its purpose is to prepare engineers and scientists to participate in wargames, exercises, and discussions with the Department of Defense. Terms such as Circular Error Probable, probability of hit and damage, damage expectancy, and the physicalmore » vulnerability system are discussed. Methods for compounding damage from multiple weapons applied to one target are presented.« less

Nuclear Forensic Science: Analysis of Nuclear Material Out of Regulatory Control

DOE PAGES

Kristo, Michael J.; Gaffney, Amy M.; Marks, Naomi; ...

2016-05-11

Nuclear forensic science seeks to identify the origin of nuclear materials found outside regulatory control. It is increasingly recognized as an integral part of a robust nuclear security program. Our review highlights areas of active, evolving research in nuclear forensics, with a focus on analytical techniques commonly employed in Earth and planetary sciences. Applications of nuclear forensics to uranium ore concentrates (UOCs) are discussed first. UOCs have become an attractive target for nuclear forensic researchers because of the richness in impurities compared to materials produced later in the fuel cycle. Furthermore, the development of chronometric methods for age dating nuclearmore » materials is then discussed, with an emphasis on improvements in accuracy that have been gained from measurements of multiple radioisotopic systems. Finally, papers that report on casework are reviewed, to provide a window into current scientific practice.« less

A cell-targeted, size-photocontrollable, nuclear-uptake nanodrug delivery system for drug-resistant cancer therapy.

PubMed

Qiu, Liping; Chen, Tao; Öçsoy, Ismail; Yasun, Emir; Wu, Cuichen; Zhu, Guizhi; You, Mingxu; Han, Da; Jiang, Jianhui; Yu, Ruqin; Tan, Weihong

2015-01-14

The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell-membrane overexpression of P-glycoprotein (P-gp), which can actively efflux various anticancer drugs from the cell, is a major mechanism of MDR. Nuclear-uptake nanodrug delivery systems, which enable intranuclear release of anticancer drugs, are expected to address this challenge by bypassing P-gp. However, before entering the nucleus, the nanocarrier must pass through the cell membrane, necessitating coordination between intracellular and intranuclear delivery. To accommodate this requirement, we have used DNA self-assembly to develop a nuclear-uptake nanodrug system carried by a cell-targeted near-infrared (NIR)-responsive nanotruck for drug-resistant cancer therapy. Via DNA hybridization, small drug-loaded gold nanoparticles (termed nanodrugs) can self-assemble onto the side face of a silver-gold nanorod (NR, termed nanotruck) whose end faces were modified with a cell type-specific internalizing aptamer. By using this size-photocontrollable nanodrug delivery system, anticancer drugs can be efficiently accumulated in the nuclei to effectively kill the cancer cells.

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer.

PubMed

Garattini, Enrico; Bolis, Marco; Gianni', Maurizio; Paroni, Gabriela; Fratelli, Maddalena; Terao, Mineko

2016-07-05

Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells.

Comparison of taxon-specific versus general locus sets for targeted sequence capture in plant phylogenomics.

PubMed

Chau, John H; Rahfeldt, Wolfgang A; Olmstead, Richard G

2018-03-01

Targeted sequence capture can be used to efficiently gather sequence data for large numbers of loci, such as single-copy nuclear loci. Most published studies in plants have used taxon-specific locus sets developed individually for a clade using multiple genomic and transcriptomic resources. General locus sets can also be developed from loci that have been identified as single-copy and have orthologs in large clades of plants. We identify and compare a taxon-specific locus set and three general locus sets (conserved ortholog set [COSII], shared single-copy nuclear [APVO SSC] genes, and pentatricopeptide repeat [PPR] genes) for targeted sequence capture in Buddleja (Scrophulariaceae) and outgroups. We evaluate their performance in terms of assembly success, sequence variability, and resolution and support of inferred phylogenetic trees. The taxon-specific locus set had the most target loci. Assembly success was high for all locus sets in Buddleja samples. For outgroups, general locus sets had greater assembly success. Taxon-specific and PPR loci had the highest average variability. The taxon-specific data set produced the best-supported tree, but all data sets showed improved resolution over previous non-sequence capture data sets. General locus sets can be a useful source of sequence capture targets, especially if multiple genomic resources are not available for a taxon.

A Geant4-based Simulation to Evaluate the Feasibility of Using Nuclear Resonance Fluorescence (NRF) in Determining Atomic Compositions of Body Tissue in Cancer Diagnostics and Irradiation

NASA Astrophysics Data System (ADS)

Gilbo, Yekaterina; Wijesooriya, Krishni; Liyanage, Nilanga

2017-01-01

Customarily applied in homeland security for identifying concealed explosives and chemical weapons, NRF (Nuclear Resonance Fluorescence) may have high potential in determining atomic compositions of body tissue. High energy photons incident on a target excite the target nuclei causing characteristic re-emission of resonance photons. As the nuclei of each isotope have well-defined excitation energies, NRF uniquely indicates the isotopic content of the target. NRF radiation corresponding to nuclear isotopes present in the human body is emitted during radiotherapy based on Bremsstrahlung photons generated in a linear electron accelerator. We have developed a Geant4 simulation in order to help assess NRF capabilities in detecting, mapping, and characterizing tumors. We have imported a digital phantom into the simulation using anatomical data linked to known chemical compositions of various tissues. Work is ongoing to implement the University of Virginia's cancer center treatment setup and patient geometry, and to collect and analyze the simulation's physics quantities to evaluate the potential of NRF for medical imaging applications. Preliminary results will be presented.

Nanocarriers for nuclear imaging and radiotherapy of cancer.

PubMed

Mitra, Amitava; Nan, Anjan; Line, Bruce R; Ghandehari, Hamidreza

2006-01-01

Several nanoscale carriers (nanoparticles, liposomes, water-soluble polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resolution such as dual modality imaging with positron emission tomography/computed tomography (PET/CT) and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clinical applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clinical oncology. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclinical, clinical and long-term toxicity studies will be required to translate this technology to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.

Progress toward generating a ferret model of cystic fibrosis by somatic cell nuclear transfer

PubMed Central

Li, Ziyi; Engelhardt, John F

2003-01-01

Mammalian cloning by nuclear transfer from somatic cells has created new opportunities to generate animal models of genetic diseases in species other than mice. Although genetic mouse models play a critical role in basic and applied research for numerous diseases, often mouse models do not adequately reproduce the human disease phenotype. Cystic fibrosis (CF) is one such disease. Targeted ablation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in mice does not adequately replicate spontaneous bacterial infections observed in the human CF lung. Hence, several laboratories are pursuing alternative animal models of CF in larger species such as the pig, sheep, rabbits, and ferrets. Our laboratory has focused on developing the ferret as a CF animal model. Over the past few years, we have investigated several experimental parameters required for gene targeting and nuclear transfer (NT) cloning in the ferret using somatic cells. In this review, we will discuss our progress and the hurdles to NT cloning and gene-targeting that accompany efforts to generate animal models of genetic diseases in species such as the ferret. PMID:14613541

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

PubMed Central

Lapalombella, Rosa; Sun, Qingxiang; Williams, Katie; Tangeman, Larissa; Jha, Shruti; Zhong, Yiming; Goettl, Virginia; Mahoney, Emilia; Berglund, Caroline; Gupta, Sneha; Farmer, Alicia; Mani, Rajeswaran; Johnson, Amy J.; Lucas, David; Mo, Xiaokui; Daelemans, Dirk; Sandanayaka, Vincent; Shechter, Sharon; McCauley, Dilara; Shacham, Sharon; Kauffman, Michael

2012-01-01

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies. PMID:23034282

Revitalizing Nuclear Operations in the Joint Environment

DTIC Science & Technology

2014-02-01

height of the Cold War, US schol - ars and joint operational planners were working simultaneously on weapons development and operational art to employ...leadership’s large-target- category withholds thought necessary to maintain stability in a strategic crisis. The inclusion of nuclear effects and...escalation. The inclusion of these points in tomorrow’s doctrine as well as an intellec- tual discussion on the topic will inform Joint Staff planners

Overview of the data analysis and new micro-pattern gas detector development for the Active Target Time Projection Chamber (AT-TPC) project.

NASA Astrophysics Data System (ADS)

Ayyad, Yassid; Mittig, Wolfgang; Bazin, Daniel; Cortesi, Marco

2017-07-01

The Active Target Time Projection Chamber (AT-TPC) project at the NSCL (National Superconducting Cyclotron Laboratory, Michigan State University) is a novel active target detector tailored for low-energy nuclear reactions in inverse kinematics with radioactive ion beams. The AT-TPC allows for a full three dimensional reconstruction of the reaction and provides high luminosity without degradation of resolution by the thickness of the target. Since all the particles (and also the reaction vertex) are tracked inside the detector, the AT-TPC has full 4π efficiency. The AT-TPC can operate under a magnetic field (2 T) that improves the identification of the particles and the energy resolution through the measurement of the magnetic rigidity. Another important characteristic of the AT-TPC is the high-gain operation achieved by the hybrid thick Gas Electron Multipliers (THGEM)-Micromegas pad plane, that allow operation also in pure elemental gas. These two features make the AT-TPC a unique high resolution spectrometer with full acceptance for nuclear physics reactions. This work presents an overview of the project, focused on the data analysis and the development of new micro-pattern gas detectors.

The Defense Threat Reduction Agency's Technical Nuclear Forensics Research and Development Program

NASA Astrophysics Data System (ADS)

Franks, J.

2015-12-01

The Defense Threat Reduction Agency (DTRA) Technical Nuclear Forensics (TNF) Research and Development (R&D) Program's overarching goal is to design, develop, demonstrate, and transition advanced technologies and methodologies that improve the interagency operational capability to provide forensics conclusions after the detonation of a nuclear device. This goal is attained through the execution of three focus areas covering the span of the TNF process to enable strategic decision-making (attribution): Nuclear Forensic Materials Exploitation - Development of targeted technologies, methodologies and tools enabling the timely collection, analysis and interpretation of detonation materials.Prompt Nuclear Effects Exploitation - Improve ground-based capabilities to collect prompt nuclear device outputs and effects data for rapid, complementary and corroborative information.Nuclear Forensics Device Characterization - Development of a validated and verified capability to reverse model a nuclear device with high confidence from observables (e.g., prompt diagnostics, sample analysis, etc.) seen after an attack. This presentation will outline DTRA's TNF R&D strategy and current investments, with efforts focusing on: (1) introducing new technical data collection capabilities (e.g., ground-based prompt diagnostics sensor systems; innovative debris collection and analysis); (2) developing new TNF process paradigms and concepts of operations to decrease timelines and uncertainties, and increase results confidence; (3) enhanced validation and verification (V&V) of capabilities through technology evaluations and demonstrations; and (4) updated weapon output predictions to account for the modern threat environment. A key challenge to expanding these efforts to a global capability is the need for increased post-detonation TNF international cooperation, collaboration and peer reviews.

Synthesis of Actinide Materials for the Study of Basic Actinide Science and Rapid Separation of Fission Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dorhout, Jacquelyn Marie

This dissertation covers several distinct projects relating to the fields of nuclear forensics and basic actinide science. Post-detonation nuclear forensics, in particular, the study of fission products resulting from a nuclear device to determine device attributes and information, often depends on the comparison of fission products to a library of known ratios. The expansion of this library is imperative as technology advances. Rapid separation of fission products from a target material, without the need to dissolve the target, is an important technique to develop to improve the library and provide a means to develop samples and standards for testing separations.more » Several materials were studied as a proof-of-concept that fission products can be extracted from a solid target, including microparticulate (< 10 μm diameter) dUO 2, porous metal organic frameworks (MOFs) synthesized from depleted uranium (dU), and other organicbased frameworks containing dU. The targets were irradiated with fast neutrons from one of two different neutron sources, contacted with dilute acids to facilitate the separation of fission products, and analyzed via gamma spectroscopy for separation yields. The results indicate that smaller particle sizes of dUO 2 in contact with the secondary matrix KBr yield higher separation yields than particles without a secondary matrix. It was also discovered that using 0.1 M HNO 3 as a contact acid leads to the dissolution of the target material. Lower concentrations of acid were used for future experiments. In the case of the MOFs, a larger pore size in the framework leads to higher separation yields when contacted with 0.01 M HNO 3. Different types of frameworks also yield different results.« less

Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin.

PubMed

Chaya, D; Hayamizu, T; Bustin, M; Zaret, K S

2001-11-30

Nucleosome-like particles and acetylated histones occur near active promoters and enhancers, and certain transcription factors can recognize their target sites on the surface of a nucleosome in vitro; yet it has been unclear whether transcription factors can occupy target sites on nucleosomes in native chromatin. We developed a method for sequential chromatin immunoprecipitation of distinct nuclear proteins that are simultaneously cross-linked to nucleosome-sized genomic DNA segments. We find that core histone H2A co-occupies, along with the FoxA (hepatocyte nuclear factor-3) transcription factor, DNA for the albumin transcriptional enhancer in native liver chromatin, where the enhancer is active. Because histone H2A on nuclear DNA is only known to exist in nucleosomes, we conclude that transcription factors can form a stable complex on nucleosomes at an active enhancer element in vivo.

Goat red blood cells as precursor for iron oxide nanocrystal synthesis to develop nuclear targeted lung cancer therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sreevani, Vellingiri; Shanthi, Krishnamurthy; Kannan, Soundarapandian, E-mail: sk_protein@buc.edu.in

Graphical abstract: - Highlights: • Molecular approach of synthesis of Fe{sub 2}O{sub 3}-NC using goat blood as a bio-precursor. • The method is simple, efficient and environment friendly. • Synthesized nanocrystals were characterized by UV–vis spectroscopy, XRD, SEM, TEM, DLS and EDS. • Nanocrystals exhibited potent cytotoxicity against A549 cancer cell. • Nuclear targeting with expression of caspase-3, caspase-7 and Bcl-2 in A549 cancer cells. - Abstract: In this study, we synthesised iron oxide nanocrystals (Fe{sub 2}O{sub 3}-NC) from goat blood (bio-precursor) using red blood cells (RBC) lysis method (a molecular level approach) for the first time. The formation ofmore » Fe{sub 2}O{sub 3}-NC was achieved through a single-phase chemical reduction method. The size distribution of Fe{sub 2}O{sub 3}-NC falls between 20–30 nm for pellet and 100–200 nm for lysate and were found to be crystalline. Fe{sub 2}O{sub 3}-NC demonstrated significant cytotoxicity on A549. We report the direct visualization of interactions between Fe{sub 2}O{sub 3}-NC and the cancer cell nucleus. The active transport of Fe{sub 2}O{sub 3}-NC to the nucleus induces major changes to nuclear phenotype via nuclear envelope invaginations. We further examined the root cause for the involvement of Fe{sub 2}O{sub 3}-NC on the expression of caspase-3, caspase-7 and Bcl-2 in A549 cancer cells. This functional proteomic analysis clearly implies that the lung cancer cell proliferation is perfectly targeted by the biosynthesised Fe{sub 2}O{sub 3}-NC which could provide new insight for nuclear-targeted cancer therapy.« less

Spallation neutron production and the current intra-nuclear cascade and transport codes

NASA Astrophysics Data System (ADS)

Filges, D.; Goldenbaum, F.; Enke, M.; Galin, J.; Herbach, C.-M.; Hilscher, D.; Jahnke, U.; Letourneau, A.; Lott, B.; Neef, R.-D.; Nünighoff, K.; Paul, N.; Péghaire, A.; Pienkowski, L.; Schaal, H.; Schröder, U.; Sterzenbach, G.; Tietze, A.; Tishchenko, V.; Toke, J.; Wohlmuther, M.

A recent renascent interest in energetic proton-induced production of neutrons originates largely from the inception of projects for target stations of intense spallation neutron sources, like the planned European Spallation Source (ESS), accelerator-driven nuclear reactors, nuclear waste transmutation, and also from the application for radioactive beams. In the framework of such a neutron production, of major importance is the search for ways for the most efficient conversion of the primary beam energy into neutron production. Although the issue has been quite successfully addressed experimentally by varying the incident proton energy for various target materials and by covering a huge collection of different target geometries --providing an exhaustive matrix of benchmark data-- the ultimate challenge is to increase the predictive power of transport codes currently on the market. To scrutinize these codes, calculations of reaction cross-sections, hadronic interaction lengths, average neutron multiplicities, neutron multiplicity and energy distributions, and the development of hadronic showers are confronted with recent experimental data of the NESSI collaboration. Program packages like HERMES, LCS or MCNPX master the prevision of reaction cross-sections, hadronic interaction lengths, averaged neutron multiplicities and neutron multiplicity distributions in thick and thin targets for a wide spectrum of incident proton energies, geometrical shapes and materials of the target generally within less than 10% deviation, while production cross-section measurements for light charged particles on thin targets point out that appreciable distinctions exist within these models.

Non-Strategic Nuclear Targeting in a Non-Nuclear Army

DTIC Science & Technology

1994-06-03

their needs. After all, the nucler planners and target analysts at corps level must surely consider their preparedness an important issue. Also...controlled escalation (the nuclear signal) and its ability to apply nuclear power in a decisive manner. A hedge against the emergence of an overwhelming...manuals envision NSNF as powerful yet flexible alternatives to the more destabilizing strategic nuclear weapons. NSNF could be used as a show of

Nuclear transport in Entamoeba histolytica: knowledge gap and therapeutic potential.

PubMed

Gwairgi, Marina A; Ghildyal, Reena

2018-03-22

Entamoeba histolytica is the protozoan parasite that causes human amoebiasis. It is one of the leading parasitic disease burdens in tropical regions and developing countries, with spread to developed countries through migrants from and travellers to endemic regions. Understanding E. histolytica's invasion mechanisms requires an understanding of how it interacts with external cell components and how it engulfs and kills cells (phagocytosis). Recent research suggests that optimal phagocytosis requires signalling events from the cell surface to the nucleus via the cytoplasm, and the induction of several factors that are transported to the plasma membrane. Current research in other protozoans suggests the presence of proteins with nuclear localization signals, nuclear export signals and Ran proteins; however, there is limited literature on their functionality and their functional similarity to higher eukaryotes. Based on learnings from the development of antivirals, nuclear transport elements in E. histolytica may present viable, specific, therapeutic targets. In this review, we aim to summarize our limited knowledge of the eukaryotic nuclear transport mechanisms that are conserved and may function in E. histolytica.

Overview on the target fabrication facilities at ELI-NP and ongoing strategies

NASA Astrophysics Data System (ADS)

Gheorghiu, C. C.; Leca, V.; Popa, D.; Cernaianu, M. O.; Stutman, D.

2016-10-01

Along with the development of petawatt class laser systems, the interaction between high power lasers and matter flourished an extensive research, with high-interest applications like: laser nuclear physics, proton radiography or cancer therapy. The new ELI-NP (Extreme Light Infrastructure - Nuclear Physics) petawatt laser facility, with 10PW and ~ 1023W/cm2 beam intensity, is one of the innovative projects that will provide novel research of fundamental processes during light-matter interaction. As part of the ELI-NP facility, Targets Laboratory will provide the means for in-house manufacturing and characterization of the required targets (mainly solid ones) for the experiments, in addition to the research activity carried out in order to develop novel target designs with improved performances. A description of the Targets Laboratory with the main pieces of equipment and their specifications are presented. Moreover, in view of the latest progress in the target design, one of the proposed strategies for the forthcoming experiments at ELI-NP is also described, namely: ultra-thin patterned foil of diamond-like carbon (DLC) coated with a carbon-based ultra-low density layer. The carbon foam which behaves as a near-critical density plasma, will allow the controlled-shaping of the laser pulse before the main interaction with the solid foil. Particular emphasis will be directed towards the target's design optimization, by simulation tests and tuning the key-properties (thickness/length, spacing, density foam, depth, periodicity etc.) which are expected to have a crucial effect on the laser-matter interaction process.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 Institutemore » (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 development of the relevant teaching materials for the course have largely been completed, tailoring the course for targeted audiences becomes a relatively easy task, requiring less effort and providing more flexibility for both the lecturers and future participants. One-day or two-day courses with focus specifically on the U.S. transport security requirements can be delivered, at locations away from Argonne, by one or two principal lecturers to targeted audiences such as regulators, shippers, carriers, state and local law enforcement personnel, and emergency responders. This paper will highlight the lessons learned in hosting previous one-week courses and discuss the development of options for detailed and/or customized courses/workshops for targeted key audiences.« less

Systems and methods for processing irradiation targets through a nuclear reactor

DOEpatents

Dayal, Yogeshwar; Saito, Earl F.; Berger, John F.; Brittingham, Martin W.; Morales, Stephen K.; Hare, Jeffrey M.

2016-05-03

Apparatuses and methods produce radioisotopes in instrumentation tubes of operating commercial nuclear reactors. Irradiation targets may be inserted and removed from instrumentation tubes during operation and converted to radioisotopes otherwise unavailable during operation of commercial nuclear reactors. Example apparatuses may continuously insert, remove, and store irradiation targets to be converted to useable radioisotopes or other desired materials at several different origin and termination points accessible outside an access barrier such as a containment building, drywell wall, or other access restriction preventing access to instrumentation tubes during operation of the nuclear plant.

DEAE-Dextran coated paclitaxel nanoparticles act as multifunctional nano system for intranuclear delivery to triple negative breast cancer through VEGF and NOTCH1 inhibition.

PubMed

Bakrania, Anita K; Variya, Bhavesh C; Rathod, Lalaji V; Patel, Snehal S

2018-01-01

Triple negative breast cancer revolution has identified a plethora of therapeutic targets making it apparent that a single target for its treatment could be rare hence creating an urge to develop robust technologies for combination drug therapy. Paclitaxel, hailed as the most significant advancement in chemotherapy faces several underpinnings due to its low solubility and permeability. Advancing research has demonstrated the role of interferons in cancer. DEAE-Dextran, an emerging molecule with evidence of interferon induction was utilized in the present study to develop a nanoformulation in conjugation with paclitaxel to target multiple therapeutic pathways, with diminution of paclitaxel adverse effects and develop a specific targeted nano system. Evidently, it was demonstrated that DEAE-Dextran coated nanoformulation portrays significant synergistic cytotoxicity in the various cell lines. Moreover, overcoming the activation of ROS by paclitaxel, the combination drug therapy more effectively inhibited ROS through β-interferon induction. The nanoformulation was further conjugated to FITC for internalization studies which subsequently indicated maximum cellular uptake at 60min post treatment demonstrated by green fluorescence from FITC lighting up the nuclear membrane. Precisely, the mechanistic approach of nuclear-targeted nanoformulation was evaluated by in vivo xenograft studies which showed a synergistic release of β-interferon at the target organ. Moreover, the combination nanoformulation inculcated multiple mechanistic approaches through VEGF and NOTCH1 inhibition along with dual β and γ-interferon overexpression. Overall, the combination therapy may be a promising multifunctional nanomaterial for intranuclear drug delivery in TNBC. Copyright © 2017 Elsevier B.V. All rights reserved.

The radioisotope complex project “RIC-80” at the Petersburg Nuclear Physics Institute

DOE Office of Scientific and Technical Information (OSTI.GOV)

Panteleev, V. N., E-mail: vnp@pnpi.spb.ru; Barzakh, A. E.; Batist, L. Kh.

2015-12-15

The high current cyclotron C-80 capable of producing 40-80 MeV proton beams with a current of up to 200 μA has been constructed at Petersburg Nuclear Physics Institute. One of the main goals of the C-80 is the production of a wide spectrum of medical radionuclides for diagnostics and therapy. The project development of the radioisotope complex RIC-80 (radioisotopes at the cyclotron C-80) at the beam of C-80 has been completed. The RIC-80 complex is briefly discussed in this paper. The combination of the mass-separator with the target-ion source device, available at one of the new target stations for on-linemore » or semi on-line production of a high purity separated radioisotopes, is explored in greater detail. The results of target and ion source tests for a mass-separator method for the production of high purity radioisotopes {sup 82}Sr and {sup 223,224}Ra are also presented.« less

The radioisotope complex project "RIC-80" at the Petersburg Nuclear Physics Institute.

PubMed

Panteleev, V N; Barzakh, A E; Batist, L Kh; Fedorov, D V; Ivanov, V S; Moroz, F V; Molkanov, P L; Orlov, S Yu; Volkov, Yu M

2015-12-01

The high current cyclotron C-80 capable of producing 40-80 MeV proton beams with a current of up to 200 μA has been constructed at Petersburg Nuclear Physics Institute. One of the main goals of the C-80 is the production of a wide spectrum of medical radionuclides for diagnostics and therapy. The project development of the radioisotope complex RIC-80 (radioisotopes at the cyclotron C-80) at the beam of C-80 has been completed. The RIC-80 complex is briefly discussed in this paper. The combination of the mass-separator with the target-ion source device, available at one of the new target stations for on-line or semi on-line production of a high purity separated radioisotopes, is explored in greater detail. The results of target and ion source tests for a mass-separator method for the production of high purity radioisotopes (82)Sr and (223,224)Ra are also presented.

Development of methods for calculating basic features of the nuclear contribution to single event upsets under the effect of protons of moderately high energy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chechenin, N. G., E-mail: chechenin@sinp.msu.ru; Chuvilskaya, T. V.; Shirokova, A. A.

2015-10-15

As a continuation and a development of previous studies of our group that were devoted to the investigation of nuclear reactions induced by protons of moderately high energy (between 10 and 400 MeV) in silicon, aluminum, and tungsten atoms, the results obtained by exploring nuclear reactions on atoms of copper, which is among the most important components in materials for contact pads and pathways in modern and future ultralarge-scale integration circuits, especially in three-dimensional topology, are reported in the present article. The nuclear reactions in question lead to the formation of the mass and charge spectra of recoil nuclei rangingmore » fromheavy target nuclei down to helium and hydrogen. The kineticenergy spectra of reaction products are calculated. The results of the calculations based on the procedure developed by our group are compared with the results of calculations and experiments performed by other authors.« less

Method for non-intrusively identifying a contained material utilizing uncollided nuclear transmission measurements

DOEpatents

Morrison, John L.; Stephens, Alan G.; Grover, S. Blaine

2001-11-20

An improved nuclear diagnostic method identifies a contained target material by measuring on-axis, mono-energetic uncollided particle radiation transmitted through a target material for two penetrating radiation beam energies, and applying specially developed algorithms to estimate a ratio of macroscopic neutron cross-sections for the uncollided particle radiation at the two energies, where the penetrating radiation is a neutron beam, or a ratio of linear attenuation coefficients for the uncollided particle radiation at the two energies, where the penetrating radiation is a gamma-ray beam. Alternatively, the measurements are used to derive a minimization formula based on the macroscopic neutron cross-sections for the uncollided particle radiation at the two neutron beam energies, or the linear attenuation coefficients for the uncollided particle radiation at the two gamma-ray beam energies. A candidate target material database, including known macroscopic neutron cross-sections or linear attenuation coefficients for target materials at the selected neutron or gamma-ray beam energies, is used to approximate the estimated ratio or to solve the minimization formula, such that the identity of the contained target material is discovered.

Precision measurement of the n-3He incoherent scattering length using neutron interferometry.

PubMed

Huber, M G; Arif, M; Black, T C; Chen, W C; Gentile, T R; Hussey, D S; Pushin, D A; Wietfeldt, F E; Yang, L

2009-05-22

We report the first measurement of the low-energy neutron-(3)He incoherent scattering length using neutron interferometry: b_{i};{'} = (-2.512 +/- 0.012 stat +/- 0.014 syst) fm. This is in good agreement with a recent calculation using the AV18 + 3N potential. The neutron-(3)He scattering lengths are important for testing and developing nuclear potential models that include three-nucleon forces, effective field theories for few-body nuclear systems, and neutron scattering measurements of quantum excitations in liquid helium. This work demonstrates the first use of a polarized nuclear target in a neutron interferometer.

TLX: A master regulator for neural stem cell maintenance and neurogenesis.

PubMed

Islam, Mohammed M; Zhang, Chun-Li

2015-02-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development. Copyright © 2014 Elsevier B.V. All rights reserved.

Development of an advanced antineutrino detector for reactor monitoring

DOE PAGES

Classen, T.; Bernstein, A.; Bowden, N. S.; ...

2014-11-05

We present the development of a compact antineutrino detector for the purpose of nuclear reactor monitoring, improving upon a previously successful design. Our paper will describe the design improvements of the detector which increases the antineutrino detection efficiency threefold over the previous effort. There are two main design improvements over previous generations of detectors for nuclear reactor monitoring: dual-ended optical readout and single volume detection mass. The dual-ended optical readout eliminates the need for fiducialization and increases the uniformity of the detector's optical response. The containment of the detection mass in a single active volume provides more target mass permore » detector footprint, a key design criteria for operating within a nuclear power plant. This technology could allow for real-time monitoring of the evolution of a nuclear reactor core, independent of reactor operator declarations of fuel inventories, and may be of interest to the safeguards community.« less

Interference Effects of Radiation Emitted from Nuclear Excitons

NASA Astrophysics Data System (ADS)

Potzel, W.; van Bürck, U.; Schindelmann, P.; Hagn, H.; Smirnov, G. V.; Popov, S. L.; Gerdau, E.; Shvyd'Ko, Yu. V.; Jäschke, J.; Rüter, H. D.; Chumakov, A. I.; Rüffer, R.

2003-12-01

Interference effects in nuclear forward scattering of synchrotron radiation (NFSSR) from two spatially separated stainless-steel foils A and B mounted downstream behind each other have been investigated. Target A can be sinusoidally vibrated by high-frequency (MHz) ultrasound (US), target B is moved at a constant Doppler velocity which is large compared to the natural width of the nuclear transition. Due to this large Doppler shift radiative coupling between both targets is disrupted and the nuclear excitons in A and B develop independently in space and time after the SR pulse. As a consequence, the emission from the whole system (A&B) is dominated by the interference of the emissions from A and B. The application of US to target A is a powerful method to change the relative phasing of the emissions and thus to investigate interference effects originating from the two nuclear excitons in detail. Four distinct cases were studied: (a) If target A is kept stationary and only B is moved at large constant velocity v, the interference pattern exhibits a Quantum Beat (QB) whose period is determined by v. (b) If, in addition, target A is sinusoidally vibrated in a piston-like motion by US and the initial US phase Φ0 is locked to the SR pulse, the QB is frequency modulated by the US. The variation of the QB frequency increases with the US modulation index m. (c) In the case that Φ0 is not synchronized to the SR pulse (phase averaging over Φ0) drastic changes of the amplitude and phase reversals of the QB pattern occur in the time regions around odd multiples of half of the US period. (d) If Φ0 is not synchronized to the SR pulse and the US motion is no longer pistonlike, the NFSSR intensity has to be averaged over both Φ0 and m (amplitude) of the US motion. Surprisingly the QB interference pattern does not vanish completely but a short QB signal remains at times of the full US period even at high values of m. All NFSSR patterns investigated are interpreted and quantitatively described by the dynamical theory.

APPARATUS FOR MEASURING NEUTRON CROSS SECTIONS

DOEpatents

Cranberg, L.

1959-07-14

An apparatus is described for analyzing the nuclear reaction products resulting from impingement of nuclear particles against a selected target material and automatically recording the number of reaction prcducts in selected energy levels. The target is bombarded by ions from a particle accelerator and the target potential is cyclicly varied over a particular energy range by a modulator. A nuclear reaction detector is lccated adjacent the target to produce pulses for each reaction product. The output from the detector and the modulator are coupled to a function sampler, for generating a pulse in respcnse to each detected event having an amplitude proportional to the amplitude of the instantaneous target potential. The later pulses are coupled to a multichannel analyzer, whereby nuclear reactions are recorded in appropriate channels of the analyzer in correspcndence with the magnitude of the energy of the impinging ions.

The Daya Bay antineutrino detector filling system and liquid mass measurement

NASA Astrophysics Data System (ADS)

Band, H. R.; Cherwinka, J. J.; Draeger, E.; Heeger, K. M.; Hinrichs, P.; Lewis, C. A.; Mattison, H.; McFarlane, M. C.; Webber, D. M.; Wenman, D.; Wang, W.; Wise, T.; Xiao, Q.

2013-09-01

The Daya Bay Reactor Neutrino Experiment has measured the neutrino mixing angle θ13 to world-leading precision. The experiment uses eight antineutrino detectors filled with 20-tons of gadolinium-doped liquid scintillator to detect antineutrinos emitted from the Daya Bay nuclear power plant through the inverse beta decay reaction. The precision measurement of sin22θ13 relies on the relative antineutrino interaction rates between detectors at near (400 m) and far (roughly 1.8 km) distances from the nuclear reactors. The measured interaction rate in each detector is directly proportional to the number of protons in the liquid scintillator target. A precision detector filling system was developed to simultaneously fill the three liquid zones of the antineutrino detectors and measure the relative target mass between detectors to < 0.02%. This paper describes the design, operation, and performance of the system and the resulting precision measurement of the detectors' target liquid masses.

Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics

PubMed Central

Huang, Pengxiang; Chandra, Vikas; Rastinejad, Fraydoon

2013-01-01

As ligand-regulated transcription factors, the nuclear hormone receptors are nearly ideal drug targets, with internal pockets that bind to hydrophobic, drug-like molecules and well-characterized ligand-induced conformational changes that recruit transcriptional coregulators to promoter elements. Yet, due to the multitude of genes under the control of a single receptor, the major challenge has been the identification of ligands with gene-selective actions, impacting disease outcomes through a narrow subset of target genes and not across their entire gene-regulatory repertoire. Here, we summarize the concepts and work to date underlying the development of steroidal and nonsteroidal receptor ligands, including the use of crystal structures, high-throughput screens, and rational design approaches for finding useful therapeutic molecules. Difficulties in finding selective receptor modulators require a more complete understanding of receptor interdomain communications, posttranslational modifications, and receptor-protein interactions that could be exploited for target gene selectivity. PMID:20148675

Target of Rapamycin Regulates Development and Ribosomal RNA Expression through Kinase Domain in Arabidopsis1[W][OA

PubMed Central

Ren, Maozhi; Qiu, Shuqing; Venglat, Prakash; Xiang, Daoquan; Feng, Li; Selvaraj, Gopalan; Datla, Raju

2011-01-01

Target of rapamycin (TOR) is a central regulator of cell growth, cell death, nutrition, starvation, hormone, and stress responses in diverse eukaryotes. However, very little is known about TOR signaling and the associated functional domains in plants. We have taken a genetic approach to dissect TOR functions in Arabidopsis (Arabidopsis thaliana) and report here that the kinase domain is essential for the role of TOR in embryogenesis and 45S rRNA expression. Twelve new T-DNA insertion mutants, spanning 14.2 kb of TOR-encoding genomic region, have been characterized. Nine of these share expression of defective kinase domain and embryo arrest at 16 to 32 cell stage. However, three T-DNA insertion lines affecting FATC domain displayed normal embryo development, indicating that FATC domain was dispensable in Arabidopsis. Genetic complementation showed that the TOR kinase domain alone in tor-10/tor-10 mutant background can rescue early embryo lethality and restore normal development. Overexpression of full-length TOR or kinase domain in Arabidopsis displayed developmental abnormalities in meristem, leaf, root, stem, flowering time, and senescence. We further show that TOR, especially the kinase domain, plays a role in ribosome biogenesis by activating 45S rRNA production. Of the six putative nuclear localization sequences in the kinase domain, nuclear localization sequence 6 was identified to confer TOR nuclear targeting in transient expression assays. Chromatin immunoprecipitation studies revealed that the HEAT repeat domain binds to 45S rRNA promoter and the 5′ external transcribed spacer elements motif. Together, these results show that TOR controls the embryogenesis, postembryonic development, and 45S rRNA production through its kinase domain in Arabidopsis. PMID:21266656

Development of activity pencil beam algorithm using measured distribution data of positron emitter nuclei generated by proton irradiation of targets containing (12)C, (16)O, and (40)Ca nuclei in preparation of clinical application.

PubMed

Miyatake, Aya; Nishio, Teiji; Ogino, Takashi

2011-10-01

The purpose of this study is to develop a new calculation algorithm that is satisfactory in terms of the requirements for both accuracy and calculation time for a simulation of imaging of the proton-irradiated volume in a patient body in clinical proton therapy. The activity pencil beam algorithm (APB algorithm), which is a new technique to apply the pencil beam algorithm generally used for proton dose calculations in proton therapy to the calculation of activity distributions, was developed as a calculation algorithm of the activity distributions formed by positron emitter nuclei generated from target nuclear fragment reactions. In the APB algorithm, activity distributions are calculated using an activity pencil beam kernel. In addition, the activity pencil beam kernel is constructed using measured activity distributions in the depth direction and calculations in the lateral direction. (12)C, (16)O, and (40)Ca nuclei were determined as the major target nuclei that constitute a human body that are of relevance for calculation of activity distributions. In this study, "virtual positron emitter nuclei" was defined as the integral yield of various positron emitter nuclei generated from each target nucleus by target nuclear fragment reactions with irradiated proton beam. Compounds, namely, polyethylene, water (including some gelatin) and calcium oxide, which contain plenty of the target nuclei, were irradiated using a proton beam. In addition, depth activity distributions of virtual positron emitter nuclei generated in each compound from target nuclear fragment reactions were measured using a beam ON-LINE PET system mounted a rotating gantry port (BOLPs-RGp). The measured activity distributions depend on depth or, in other words, energy. The irradiated proton beam energies were 138, 179, and 223 MeV, and measurement time was about 5 h until the measured activity reached the background level. Furthermore, the activity pencil beam data were made using the activity pencil beam kernel, which was composed of the measured depth data and the lateral data including multiple Coulomb scattering approximated by the Gaussian function, and were used for calculating activity distributions. The data of measured depth activity distributions for every target nucleus by proton beam energy were obtained using BOLPs-RGp. The form of the depth activity distribution was verified, and the data were made in consideration of the time-dependent change of the form. Time dependence of an activity distribution form could be represented by two half-lives. Gaussian form of the lateral distribution of the activity pencil beam kernel was decided by the effect of multiple Coulomb scattering. Thus, the data of activity pencil beam involving time dependence could be obtained in this study. The simulation of imaging of the proton-irradiated volume in a patient body using target nuclear fragment reactions was feasible with the developed APB algorithm taking time dependence into account. With the use of the APB algorithm, it was suggested that a system of simulation of activity distributions that has levels of both accuracy and calculation time appropriate for clinical use can be constructed.

The Homothorax homeoprotein activates the nuclear localization of another homeoprotein, Extradenticle, and suppresses eye development in Drosophila

PubMed Central

Pai, Chi-Yun; Kuo, Tung-Sheng; Jaw, Thomas J.; Kurant, Estee; Chen, Cheng-Tse; Bessarab, Dmitri A.; Salzberg, Adi; Sun, Y. Henry

1998-01-01

The Extradenticle (Exd) protein in Drosophila acts as a cofactor to homeotic proteins. Its nuclear localization is regulated. We report the cloning of the Drosophila homothorax (hth) gene, a homolog of the mouse Meis1 proto-oncogene that has a homeobox related to that of exd. Comparison with Meis1 finds two regions of high homology: a novel MH domain and the homeodomain. In imaginal discs, hth expression coincides with nuclear Exd. hth and exd also have virtually identical, mutant clonal phenotypes in adults. These results suggest that hth and exd function in the same pathway. We show that hth acts upstream of exd and is required and sufficient for Exd protein nuclear localization. We also show that hth and exd are both negative regulators of eye development; their mutant clones caused ectopic eye formation. Targeted expression of hth, but not of exd, in the eye disc abolished eye development completely. We suggest that hth acts with exd to delimit the eye field and prevent inappropriate eye development. PMID:9450936

A Novel Antiviral Target Structure Involved in the RNA Binding, Dimerization, and Nuclear Export Functions of the Influenza A Virus Nucleoprotein

PubMed Central

Yamada, Kazunori; Kondoh, Yasumitsu; Hikono, Hirokazu; Osada, Hiroyuki; Tomii, Kentaro; Saito, Takehiko; Aida, Yoko

2015-01-01

Developing antiviral therapies for influenza A virus (IAV) infection is an ongoing process because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. The ideal strategy is to develop drugs that target well-conserved, functionally restricted, and unique surface structures without affecting host cell function. We recently identified the antiviral compound, RK424, by screening a library of 50,000 compounds using cell-based infection assays. RK424 showed potent antiviral activity against many different subtypes of IAV in vitro and partially protected mice from a lethal dose of A/WSN/1933 (H1N1) virus in vivo. Here, we show that RK424 inhibits viral ribonucleoprotein complex (vRNP) activity, causing the viral nucleoprotein (NP) to accumulate in the cell nucleus. In silico docking analysis revealed that RK424 bound to a small pocket in the viral NP. This pocket was surrounded by three functionally important domains: the RNA binding groove, the NP dimer interface, and nuclear export signal (NES) 3, indicating that it may be involved in the RNA binding, oligomerization, and nuclear export functions of NP. The accuracy of this binding model was confirmed in a NP-RK424 binding assay incorporating photo-cross-linked RK424 affinity beads and in a plaque assay evaluating the structure-activity relationship of RK424. Surface plasmon resonance (SPR) and pull-down assays showed that RK424 inhibited both the NP-RNA and NP-NP interactions, whereas size exclusion chromatography showed that RK424 disrupted viral RNA-induced NP oligomerization. In addition, in vitro nuclear export assays confirmed that RK424 inhibited nuclear export of NP. The amino acid residues comprising the NP pocket play a crucial role in viral replication and are highly conserved in more than 7,000 NP sequences from avian, human, and swine influenza viruses. Furthermore, we found that the NP pocket has a surface structure different from that of the pocket in host molecules. Taken together, these results describe a promising new approach to developing influenza virus drugs that target a novel pocket structure within NP. PMID:26222066

The Gpn3 Q279* cancer-associated mutant inhibits Gpn1 nuclear export and is deficient in RNA polymerase II nuclear targeting.

PubMed

Barbosa-Camacho, Angel A; Méndez-Hernández, Lucía E; Lara-Chacón, Bárbara; Peña-Gómez, Sonia G; Romero, Violeta; González-González, Rogelio; Guerra-Moreno, José A; Robledo-Rivera, Angélica Y; Sánchez-Olea, Roberto; Calera, Mónica R

2017-11-01

Gpn3 is required for RNA polymerase II (RNAPII) nuclear targeting. Here, we investigated the effect of a cancer-associated Q279* nonsense mutation in Gpn3 cellular function. Employing RNAi, we replaced endogenous Gpn3 by wt or Q279* RNAi-resistant Gpn3R in epithelial model cells. RNAPII nuclear accumulation and transcriptional activity were markedly decreased in cells expressing only Gpn3R Q279*. Wild-type Gpn3R localized to the cytoplasm but a fraction of Gpn3R Q279* entered the cell nucleus and inhibited Gpn1-EYFP nuclear export. This property and the transcriptional deficit in Gpn3R Q279*-expressing cells required a PDZ-binding motif generated by the Q279* mutation. We conclude that an acquired PDZ-binding motif in Gpn3 Q279* caused Gpn3 nuclear entry, and inhibited Gpn1 nuclear export and Gpn3-mediated RNAPII nuclear targeting. © 2017 Federation of European Biochemical Societies.

Overview of the ISOL facility for the RISP

NASA Astrophysics Data System (ADS)

Woo, H. J.; Kang, B. H.; Tshoo, K.; Seo, C. S.; Hwang, W.; Park, Y.-H.; Yoon, J. W.; Yoo, S. H.; Kim, Y. K.; Jang, D. Y.

2015-02-01

The key feature of the Isotope Separation On-Line (ISOL) facility is its ability to provide high-intensity and high-quality beams of neutron-rich isotopes with masses in the range of 80-160 by means of a 70-MeV proton beam directly impinging on uranium-carbide thin-disc targets to perform forefront research in nuclear structure, nuclear astrophysics, reaction dynamics and interdisciplinary fields like medical, biological and material sciences. The technical design of the 10-kW and the 35-kW direct fission targets with in-target fission rates of up to 1014 fissions/s has been finished, and for the development of the ISOL fission-target chemistry an initial effort has been made to produce porous lanthanum-carbide (LaCx) discs as a benchmark for the final production of porous UCx discs. For the production of various beams, three classes of ion sources are under development at RISP (Rare Isotope Science Project), the surface ion source, the plasma ion source (FEBIAD), the laser ion source, and the engineering design of the FEBIAD is in progress for prototype fabrication. The engineering design of the ISOL target/ion source front-end system is also in progress, and a prototype will be used for an off-line test facility in front of the pre-separator. The technical designs of other basic elements at the ISOL facility, such as the RF-cooler, the high-resolution mass separator, and the A/q separator, have been finished, and the results, along with the future plans, are introduced.

Study of nuclear matter in hard proton-nuclei and nuclei-nuclei collisions at the U70 accelerator (FLUKTON project proposal)

NASA Astrophysics Data System (ADS)

Antonov, N. N.; Baldin, A. A.; Viktorov, V. A.; Gapienko, V. A.; Gapienko, G. S.; Gres, V. N.; Ilyushin, M. A.; Korotkov, V. A.; Mysnik, A. I.; Prudkoglyad, A. F.; Pryanikov, D. S.; Semak, A. A.; Stavinsky, A. V.; Terekhov, V. I.; Uglekov, V. Ya.; Ukhanov, M. N.; Chuiko, B. V.; Shimansky, S. S.

2017-11-01

A two-arm spectrometer FLUKTON for investigations in the field of relativistic nuclear physics at U70 energies is proposed to be constructed on base of the existing detector SPIN (IHEP, Protvino). The main objective is to obtain new data on clusters of cold superdense nuclear matter. Interaction of a high intensity proton beam with nuclear targets and an ion beam with liquid hydrogen and nuclear targets will be studied.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirkpatrick, R. C.

Nuclear fusion was discovered experimentally in 1933-34 and other charged particle nuclear reactions were documented shortly thereafter. Work in earnest on the fusion ignition problem began with Edward Teller's group at Los Alamos during the war years. His group quantified all the important basic atomic and nuclear processes and summarized their interactions. A few years later, the success of the early theory developed at Los Alamos led to very successful thermonuclear weapons, but also to decades of unsuccessful attempts to harness fusion as an energy source of the future. The reasons for this history are many, but it seems appropriatemore » to review some of the basics with the objective of identifying what is essential for success and what is not. This tutorial discusses only the conditions required for ignition in small fusion targets and how the target design impacts driver requirements. Generally speaking, the driver must meet the energy, power and power density requirements needed by the fusion target. The most relevant parameters for ignition of the fusion fuel are the minimum temperature and areal density (rhoR), but these parameters set secondary conditions that must be achieved, namely an implosion velocity, target size and pressure, which are interrelated. Despite the apparent simplicity of inertial fusion targets, there is not a single mode of fusion ignition, and the necessary combination of minimum temperature and areal density depends on the mode of ignition. However, by providing a magnetic field of sufficient strength, the conditions needed for fusion ignition can be drastically altered. Magnetized target fusion potentially opens up a vast parameter space between the extremes of magnetic and inertial fusion.« less

Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.

PubMed

Hagiwara, Kyoji; Ishii, Hideki; Murakami, Tomoyuki; Takeshima, Shin-nosuke; Chutiwitoonchai, Nopporn; Kodama, Eiichi N; Kawaji, Kumi; Kondoh, Yasumitsu; Honda, Kaori; Osada, Hiroyuki; Tsunetsugu-Yokota, Yasuko; Suzuki, Masaaki; Aida, Yoko

2015-01-01

The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.

Development, Application, and Implementation of RAMCAP to Characterize Nuclear Power Plant Risk From Terrorism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaertner, John P.; Teagarden, Grant A.

2006-07-01

In response to increased interest in risk-informed decision making regarding terrorism, EPRI and ERIN Engineering were selected by U.S. DHS and ASME to develop and demonstrate the RAMCAP method for nuclear power plant (NPP) risk assessment. The objective is to characterize plant-specific NPP risk for risk management opportunities and to provide consistent information for DHS decision making. This paper is an update of this project presented at the American Nuclear Society (ANS) International Topical Meeting on Probabilistic Safety Analysis (PSA05) in September, 2005. The method uses a characterization of risk as a function of Consequence, Vulnerability, and Threat. For eachmore » site, worst case scenarios are developed for each of sixteen benchmark threats. Nuclear RAMCAP hypothesizes that the intent of the perpetrator is to cause offsite radiological consequences. Specific targets are the reactor core, the spent fuel pool, and nuclear spent fuel in a dry storage facility (ISFSI). Results for each scenario are presented as conditional risk for financial loss, early fatalities and early injuries. Expected consequences for each scenario are quantified, while vulnerability is estimated on a relative likelihood scale. Insights for other societal risks are provided. Although threat frequencies are not provided, target attractiveness and threat deterrence are estimated. To assure efficiency, completeness, and consistency; results are documented using standard RAMCAP Evaluator software. Trial applications were successfully performed at four plant sites. Implementation at all other U.S. commercial sites is underway, supported by the Nuclear Sector Coordinating Council (NSCC). Insights from RAMCAP results at 23 U.S. plants completed to date have been compiled and presented to the NSCC. Results are site-specific. Physical security barriers, an armed security force, preparedness for design-basis threats, rugged design against natural hazards, multiple barriers between fuel and environment, accident mitigation capability, severe accident management procedures, and offsite emergency plans are risk-beneficial against all threat types. (authors)« less

Molecular Determinants of Magnolol Targeting Both RXRα and PPARγ

PubMed Central

Chen, Lili; Chen, Jing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

2011-01-01

Nuclear receptors retinoic X receptor α (RXRα) and peroxisome proliferator activated receptor γ (PPARγ) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRα and PPARγ is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRα and PPARγ. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXRα:PPARγ heterodimer, instead of RXR-response element (RXRE) mediated by RXRα:RXRα homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRα and PPARγ ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXRα L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARγ Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRα and PPARγ are determined. As the first report on the dual agonist targeting RXRα and PPARγ with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design. PMID:22140563

Roles of the nuclear lamina in stable nuclear association and assembly of a herpesviral transactivator complex on viral immediate-early genes.

PubMed

Silva, Lindsey; Oh, Hyung Suk; Chang, Lynne; Yan, Zhipeng; Triezenberg, Steven J; Knipe, David M

2012-01-01

Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin. In contrast, we found that early herpes simplex virus (HSV) genome complexes localize near the nuclear lamina and that this localization is associated with reduced heterochromatin on the viral genome and increased viral immediate-early (IE) gene transcription. In this study, we examined the mechanism of this effect and found that input virion transactivator protein, virion protein 16 (VP16), targets sites adjacent to the nuclear lamina and is required for targeting of the HSV genome to the nuclear lamina, exclusion of heterochromatin from viral replication compartments, and reduction of heterochromatin on the viral genome. Because cells infected with the VP16 mutant virus in1814 showed a phenotype similar to that of lamin A/C(-/-) cells infected with wild-type virus, we hypothesized that the nuclear lamina is required for VP16 activator complex formation. In lamin A/C(-/-) mouse embryo fibroblasts, VP16 and Oct-1 showed reduced association with the viral IE gene promoters, the levels of VP16 and HCF-1 stably associated with the nucleus were lower than in wild-type cells, and the association of VP16 with HCF-1 was also greatly reduced. These results show that the nuclear lamina is required for stable nuclear localization and formation of the VP16 activator complex and provide evidence for the nuclear lamina being the site of assembly of the VP16 activator complex. The targeting of chromosomes in the cell nucleus is thought to be important in the regulation of expression of genes on the chromosomes. The major documented effect of intranuclear targeting has been silencing of chromosomes at sites near the nuclear periphery. In this study, we show that targeting of the herpes simplex virus DNA genome to the nuclear periphery promotes formation of transcriptional activator complexes on the viral genome, demonstrating that the nuclear periphery also has sites for activation of transcription. These results highlight the importance of the nuclear lamina, the structure that lines the inner nuclear membrane, in both transcriptional activation and repression. Future studies defining the molecular structures of these two types of nuclear sites should define new levels of gene regulation.

Identifying MicroRNAs and Transcript Targets in Jatropha Seeds

PubMed Central

Galli, Vanessa; Guzman, Frank; de Oliveira, Luiz F. V.; Loss-Morais, Guilherme; Körbes, Ana P.; Silva, Sérgio D. A.; Margis-Pinheiro, Márcia M. A. N.; Margis, Rogério

2014-01-01

MicroRNAs, or miRNAs, are endogenously encoded small RNAs that play a key role in diverse plant biological processes. Jatropha curcas L. has received significant attention as a potential oilseed crop for the production of renewable oil. Here, a sRNA library of mature seeds and three mRNA libraries from three different seed development stages were generated by deep sequencing to identify and characterize the miRNAs and pre-miRNAs of J. curcas. Computational analysis was used for the identification of 180 conserved miRNAs and 41 precursors (pre-miRNAs) as well as 16 novel pre-miRNAs. The predicted miRNA target genes are involved in a broad range of physiological functions, including cellular structure, nuclear function, translation, transport, hormone synthesis, defense, and lipid metabolism. Some pre-miRNA and miRNA targets vary in abundance between the three stages of seed development. A search for sequences that produce siRNA was performed, and the results indicated that J. curcas siRNAs play a role in nuclear functions, transport, catalytic processes and disease resistance. This study presents the first large scale identification of J. curcas miRNAs and their targets in mature seeds based on deep sequencing, and it contributes to a functional understanding of these miRNAs. PMID:24551031

Deploying Solid Targets in Dense Plasma Focus Devices for Improved Neutron Yields

NASA Astrophysics Data System (ADS)

Podpaly, Y. A.; Chapman, S.; Povilus, A.; Falabella, S.; Link, A.; Shaw, B. H.; Cooper, C. M.; Higginson, D.; Holod, I.; Sipe, N.; Gall, B.; Schmidt, A. E.

2017-10-01

We report on recent progress in using solid targets in dense plasma focus (DPF) devices. DPFs have been observed to generate energetic ion beams during the pinch phase; these beams interact with the dense plasma in the pinch region as well as the background gas and are believed to be the primary neutron generation mechanism for a D2 gas fill. Targets can be placed in the beam path to enhance neutron yield and to shorten the neutron pulse if desired. In this work, we measure yields from placing titanium deuteride foils, deuterated polyethylene, and non-deuterated control targets in deuterium filled DPFs at both megajoule and kilojoule scales. Furthermore, we have deployed beryllium targets in a helium gas-filled, kilojoule scale DPF for use as a potential AmBe radiological source replacement. Neutron yield, neutron time of flight, and optical images are used to diagnose the effectiveness of target deployments relative to particle-in-cell simulation predictions. A discussion of target holder engineering for material compatibility and damage control will be shown as well. Prepared by LLNL under Contract DE-AC52-07NA27344. Supported by the Office of Defense Nuclear Nonproliferation Research and Development within U.S. DOE's National Nuclear Security Administration and the LLNL Institutional Computing Grand Challenge program.

Graphical Environment Tools for Application to Gamma-Ray Energy Tracking Arrays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Todd, Richard A.; Radford, David C.

2013-12-30

Highly segmented, position-sensitive germanium detector systems are being developed for nuclear physics research where traditional electronic signal processing with mixed analog and digital function blocks would be enormously complex and costly. Future systems will be constructed using pipelined processing of high-speed digitized signals as is done in the telecommunications industry. Techniques which provide rapid algorithm and system development for future systems are desirable. This project has used digital signal processing concepts and existing graphical system design tools to develop a set of re-usable modular functions and libraries targeted for the nuclear physics community. Researchers working with complex nuclear detector arraysmore » such as the Gamma-Ray Energy Tracking Array (GRETA) have been able to construct advanced data processing algorithms for implementation in field programmable gate arrays (FPGAs) through application of these library functions using intuitive graphical interfaces.« less

Nuclear science and society: social inclusion through scientific education

NASA Astrophysics Data System (ADS)

Levy, Denise S.

2017-11-01

This article presents a web-based educational project focused on the potential value of Information and Communication Technology to enhance communication and education on nuclear science throughout Brazil. The project is designed to provide trustworthy information about the beneficial uses of nuclear technology, educating children and teenagers, as well as their parents and teachers, demystifying paradigms and combating misinformation. Making use of a range of interactive activities, the website presents short courses and curiosities, with different themes that comprise the several aspects of the beneficial applications of nuclear science. The intention of the many interactive activities is to encourage research and to enhance learning opportunities through a self-learning universe where the target public is introduced to the basic concepts of nuclear physics, such as nuclides and isotopes, atomic interactions, radioactive decay, biological effects of radiation, nuclear fusion, nuclear fission, nuclear reactors, nuclear medicine, radioactive dating methods and natural occurring radiation, among other ideas and concepts in nuclear physics. Democratization of scientific education can inspire new thoughts, stimulate development and encourage scientific and technological researches.

Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators.

PubMed

Kremoser, Claus; Albers, Michael; Burris, Thomas P; Deuschle, Ulrich; Koegl, Manfred

2007-10-01

Drugs that target nuclear receptors are clinically, as well as commercially, successful. Their widespread use, however, is limited by an inherent propensity of nuclear receptors to trigger beneficial, as well as adverse, pharmacological effects upon drug activation. Hence, selective drugs that display reduced adverse effects, such as the selective estrogen receptor modulator (SERM) Raloxifene, have been developed by guidance through classical cell culture assays and animal trials. Full agonist and selective modulator nuclear receptor drugs, in general, differ by their ability to recruit certain cofactors to the receptor protein. Hence, systematic cofactor profiling is advancing into an approach for the rationally guided identification of selective NR modulators (SNuRMs) with improved therapeutic ratio.

PPKs mediate direct signal transfer from pytochrome photreceptors to transdcription factor PIF3

USDA-ARS?s Scientific Manuscript database

Upon light-induced nuclear translocation, phytochrome (phy) sensory photoreceptors interact with, and induce rapid phosphorylation and consequent ubiquitin-mediated degradation of, transcription factors, called PIFs, thereby regulating target gene expression and plant development. Nevertheless, the ...

Prolonged, brain-wide expression of nuclear-localized GCaMP3 for functional circuit mapping

PubMed Central

Kim, Christina K.; Miri, Andrew; Leung, Louis C.; Berndt, Andre; Mourrain, Philippe; Tank, David W.; Burdine, Rebecca D.

2014-01-01

Larval zebrafish offer the potential for large-scale optical imaging of neural activity throughout the central nervous system; however, several barriers challenge their utility. First, ~panneuronal probe expression has to date only been demonstrated at early larval stages up to 7 days post-fertilization (dpf), precluding imaging at later time points when circuits are more mature. Second, nuclear exclusion of genetically-encoded calcium indicators (GECIs) limits the resolution of functional fluorescence signals collected during imaging. Here, we report the creation of transgenic zebrafish strains exhibiting robust, nuclearly targeted expression of GCaMP3 across the brain up to at least 14 dpf utilizing a previously described optimized Gal4-UAS system. We confirmed both nuclear targeting and functionality of the modified probe in vitro and measured its kinetics in response to action potentials (APs). We then demonstrated in vivo functionality of nuclear-localized GCaMP3 in transgenic zebrafish strains by identifying eye position-sensitive fluorescence fluctuations in caudal hindbrain neurons during spontaneous eye movements. Our methodological approach will facilitate studies of larval zebrafish circuitry by both improving resolution of functional Ca2+ signals and by allowing brain-wide expression of improved GECIs, or potentially any probe, further into development. PMID:25505384

Heterodimers of Retinoic Acid Receptors and Thyroid Hormone Receptors Display Unique Combinatorial Regulatory Properties

PubMed Central

Lee, Sangho; Privalsky, Martin L.

2009-01-01

Nuclear receptors are ligand-regulated transcription factors that regulate key aspects of metazoan development, differentiation, and homeostasis. Nuclear receptors recognize target genes by binding to specific DNA recognition sequences, denoted hormone response elements (HREs). Many nuclear receptors can recognize HREs as either homodimers or heterodimers. Retinoid X receptors (RXRs), in particular, serve as important heterodimer partners for many other nuclear receptors, including thyroid hormone receptors (TRs), and RXR/TR heterodimers have been proposed to be the primary mediators of target gene regulation by T3 hormone. Here, we report that the retinoic acid receptors (RARs), a distinct class of nuclear receptors, are also efficient heterodimer partners for TRs. These RAR/TR heterodimers form with similar affinities as RXR/TR heterodimers on an assortment of consensus and natural HREs, and preferentially assemble with the RAR partner 5′ of the TR moiety. The corepressor and coactivator recruitment properties of these RAR/TR heterodimers and their transcriptional activities in vivo are distinct from those observed with the corresponding RXR heterodimers. Our studies indicate that RXRs are not unique in their ability to partner with TRs, and that RARs can also serve as robust heterodimer partners and combinatorial regulators of T3-modulated gene expression. PMID:15650024

The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86Y and 90Y

PubMed Central

Rösch, Frank; Herzog, Hans; Qaim, Syed M.

2017-01-01

In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the “best one” for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair 86Y/90Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide 90Y (t½ = 2.7 d) had been available for a long time via the 90Sr/90Y generator system, the β+ emitter 86Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of 86Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90Y-labelled compound in terms of mGy or mSv per MBq 90Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed. PMID:28632200

Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis.

PubMed

O'Léime, Ciarán S; Cryan, John F; Nolan, Yvonne M

2017-11-01

Hippocampal neurogenesis, the process by which new neurons are born and develop into the host circuitry, begins during embryonic development and persists throughout adulthood. Over the last decade considerable insights have been made into the role of hippocampal neurogenesis in cognitive function and the cellular mechanisms behind this process. Additionally, an increasing amount of evidence exists on the impact of environmental factors, such as stress and neuroinflammation on hippocampal neurogenesis and subsequent impairments in cognition. Elevated expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus is established as a significant contributor to the neuronal demise evident in many neurological and psychiatric disorders and is now known to negatively regulate hippocampal neurogenesis. In order to prevent the deleterious effects of IL-1β on neurogenesis it is necessary to identify signalling pathways and regulators of neurogenesis within neural progenitor cells that can interact with IL-1β. Nuclear receptors are ligand regulated transcription factors that are involved in modulating a large number of cellular processes including neurogenesis. In this review we focus on the signalling mechanisms of specific nuclear receptors involved in regulating neurogenesis (glucocorticoid receptors, peroxisome proliferator activated receptors, estrogen receptors, and nuclear receptor subfamily 2 group E member 1 (NR2E1 or TLX)). We propose that these nuclear receptors could be targeted to inhibit neuroinflammatory signalling pathways associated with IL-1β. We discuss their potential to be therapeutic targets for neuroinflammatory disorders affecting hippocampal neurogenesis and associated cognitive function. Copyright © 2017 Elsevier Inc. All rights reserved.

Calcium-regulated nuclear enzymes: potential mediators of phytochrome-induced changes in nuclear metabolism?

NASA Technical Reports Server (NTRS)

Roux, S. J.

1992-01-01

Calcium ions have been proposed to serve as important regulatory elements in stimulus-response coupling for phytochrome responses. An important test of this hypothesis will be to identify specific targets of calcium action that are required for some growth or development process induced by the photoactivated form of phytochrome (Pfr). Initial studies have revealed that there are at least two enzymes in pea nuclei that are stimulated by Pfr in a Ca(2+)-dependent fashion, a calmodulin-regulated nucleoside triphosphatase and a calmodulin-independent but Ca(2+)-dependent protein kinase. The nucleoside triphosphatase appears to be associated with the nuclear envelope, while the protein kinase co-purifies with a nuclear fraction highly enriched for chromatin. This short review summarizes the latest findings on these enzymes and relates them to what is known about Pfr-regulated nuclear metabolism.

Nuclear forensic analysis of a non-traditional actinide sample

DOE PAGES

Doyle, Jamie L.; Kuhn, Kevin John; Byerly, Benjamin; ...

2016-06-15

Nuclear forensic publications, performance tests, and research and development efforts typically target the bulk global inventory of intentionally safeguarded materials, such as plutonium (Pu) and uranium (U). Other materials, such as neptunium (Np), pose a nuclear security risk as well. Trafficking leading to recovery of an interdicted Np sample is a realistic concern especially for materials originating in countries that reprocesses fuel. Using complementary forensic methods, potential signatures for an unknown Np oxide sample were investigated. Measurement results were assessed against published Np processes to present hypotheses as to the original intended use, method of production, and origin for thismore » Np oxide.« less

Nuclear forensic analysis of a non-traditional actinide sample.

PubMed

Doyle, Jamie L; Kuhn, Kevin; Byerly, Benjamin; Colletti, Lisa; Fulwyler, James; Garduno, Katherine; Keller, Russell; Lujan, Elmer; Martinez, Alexander; Myers, Steve; Porterfield, Donivan; Spencer, Khalil; Stanley, Floyd; Townsend, Lisa; Thomas, Mariam; Walker, Laurie; Xu, Ning; Tandon, Lav

2016-10-01

Nuclear forensic publications, performance tests, and research and development efforts typically target the bulk global inventory of intentionally safeguarded materials, such as plutonium (Pu) and uranium (U). Other materials, such as neptunium (Np), pose a nuclear security risk as well. Trafficking leading to recovery of an interdicted Np sample is a realistic concern especially for materials originating in countries that reprocesses fuel. Using complementary forensic methods, potential signatures for an unknown Np oxide sample were investigated. Measurement results were assessed against published Np processes to present hypotheses as to the original intended use, method of production, and origin for this Np oxide. Published by Elsevier B.V.

Student research with 400keV beams: {sup 13}N radioisotope production target development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fru, L. Che; Clymer, J.; Compton, N.

2013-04-19

The AN400 Van de Graaff accelerator at the Minnesota State University, Mankato, Applied Nuclear Science Lab has demonstrated utility as an accessible and versatile platform for student research. Despite the limits of low energy, the research team successfully developed projects with applications to the wider radioisotope production community. A target system has been developed for producing and extracting {sup 13}N by the {sup 12}C(d,n){sup 13}N reaction below 400keV. The system is both reusable and robust, with future applications to higher energy machines producing this important radioisotope for physiological imaging studies with Positron Emission Tomography. Up to 36({+-}1)% of the {supmore » 13}N was extracted from the graphite matrix when 35 A current was externally applied to the graphite target while simultaneously flushing the target chamber with CO{sub 2} gas.« less

Recent Progress in the Design and Discovery of RXR Modulators Targeting Alternate Binding Sites of the Receptor.

PubMed

Su, Ying; Zeng, Zhiping; Chen, Ziwen; Xu, Dan; Zhang, Weidong; Zhang, Xiao-Kun

2017-01-01

Retinoid X receptors (RXRs) occupy a central position within the nuclear receptor superfamily. They not only function as important transcriptional factors but also exhibit diverse nongenomic biological activities. The pleiotropic actions of RXRs under both physiological and pathophysiological conditions confer RXRs important drug targets for the treatment of cancer, and metabolic and neurodegenerative diseases. RXR modulators have been studied for the purpose of developing both drug molecules and chemical tools for biological investigation of RXR. Development of RXR modulators has focused on small molecules targeting the canonical ligand-binding pocket. However, accumulating results have demonstrated that there are other binding mechanisms by which small molecules interact with RXR to act as RXR modulators. This review discusses the recent development in the design and discovery of RXR modulators with a focus on those targeting novel binding sites on RXR.

Probing nuclear effects using single-transverse kinematic imbalance with MINERvA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, X. -G.; Betancourt, M.

2016-08-15

Kinematic imbalance of the final-state particles in the plane transverse to the neutrino direction provides a sensitive probe of nuclear effects. In this contribution, we report the MINERvA measurement of the single-transverse kinematic imbalance in neutrino charged-current quasielastic-like events on CH targets. To improve the momentum measurements of the final-state particles, we develop a method to select elastically scattering contained (ESC) protons and a general procedure to correct the transverse momentum scales.

Targets for the production of radioisotopes and method of assembly

DOEpatents

Quinby, Thomas C.

1976-01-01

A target for preparation of radioisotopes by nuclear bombardment, and a method for its assembly are provided. A metallic sample to be bombarded is enclosed within a metallic support structure and the resulting target subjected to heat and pressure to effect diffusion bonds therebetween. The bonded target is capable of withstanding prolonged exposure to nuclear bombardment without thermal damage to the sample.

Temperature Stabilization of the NIFFTE Time Projection Chamber

NASA Astrophysics Data System (ADS)

Hicks, Caleb

2017-09-01

The Neutron Induced Fission Fragment Tracking Experiment (NIFFTE) is a collaboration measuring nuclear fission cross sections for use in advanced nuclear reactors. A neutron beam incident on targets of Uranium-235, Uranium-238, and Plutonium-239 is used to measure the neutron induced fission cross sections for these isotopes. A Time Projection Chamber (TPC) is used to record these reactions. Significant heat is generated by the readout cards mounted on the TPC, which are cooled by fans. One proposed measurement of the experiment is to compare the cross sections of the target to a proton target of gaseous hydrogen. A constant temperature inside the TPC's pressure vessel is desirable to maintain a constant number of hydrogen target atoms. In addition, a constant temperature minimizes the strain and wrinkles on an amplifying mesh inside the TPC. This poster describes the successful work to develop, build, and install a fan controller using a Raspberry Pi, an Arduino, and a custom circuit board to implement an algorithm called Proportional-Integral-Derivative control. This research was supported by US DOE MENP Grant DE-FG02-03ER41243.

Targeting Quiescence in Prostate Cancer

DTIC Science & Technology

2017-10-01

CRISPR /Cas9 to generate cell lines where the reporters are integrated endogenously into 5 essential cell cycle genes to avoid epigenetic silencing. In...Developed and began an improved CRISPR /Cas9-based strategy to target reporters to endogenous gene loci in PC3 and C4-2B cells to prevent silencing...serum. An improved CRISPR /Cas9-based strategy to avoid cell cycle reporter silencing and incorporate a constitutive nuclear marker As described

Pion Production for Neutrino Factory-challenges

DOE Office of Scientific and Technical Information (OSTI.GOV)

Breton, Florian; Le Couedic, Clement; Soler, F. J. P.

2011-10-06

One of the key issues in the design of a Neutrino Factory target station is the determination of the optimum kinetic energy of the proton beam due to the large uncertainties in simulations of protons impinging on nuclear targets. In this paper we have developed a procedure to correct GEANT4 simulations for the HARP data, and we have determined the yield of muons expected at the front-end of a Neutrino Factory as a function of target material (Be, C, Al, Ta and Pb) and energy (3-12 GeV).The maximum muon yield is found between 5 and 8 GeV for high Zmore » targets and 3 GeV for low Z targets.« less

Start, Stop, Restart: The Recent History of Federal Funding for Radiochemistry Education

NASA Astrophysics Data System (ADS)

Williamson, R. Craig

2009-08-01

Over the course of the 2009, Federal Fiscal Year the U.S. Departments of Homeland Security and Defense will introduce university programs designed to provide the U.S. national laboratories with a highly qualified workforce in nuclear forensics. These programs are designed to recruit the best and brightest students, develop universities research and education activities, and to enhance university/laboratory(s) interactions nuclear forensics. The approach will be comprehensive in that it will target undergraduate and graduate students, faculty members and institutions. This will include an undergraduate research program designed to encourage emerging seniors to perform research at designated national laboratories throughout the United States. In addition to the undergraduate program, a nationally competitive graduate fellowship program in nuclear forensics was established in 2008. This program provides a four-year appointment with a monthly stipend, full payment of tuition and fees, the establishment of participating universities, and required post-graduate positions in nuclear forensics. A Nuclear Forensics Education Award program will also be introduced. This broad-based program will have an impact on university programs interested in developing nuclear forensics capabilities. This will include funds for instrumentation and equipment, faculty members, students, and curriculum.

Cross section measurements for production of positron emitters for PET imaging in carbon therapy

NASA Astrophysics Data System (ADS)

Salvador, S.; Colin, J.; Cussol, D.; Divay, C.; Fontbonne, J.-M.; Labalme, M.

2017-04-01

In light ion beam therapy, positron (β+) emitters are produced by the tissue nuclei through nuclear interactions with the beam ions. They can be used for the verification of the delivered dose using positron emission tomography by comparing the spatial distribution of the β+ emitters activity to a computer simulation taking into account the patient morphology and the treatment plan. However, the accuracy of the simulation greatly depends on the method used to generate the nuclear interactions producing these emitters. In the case of Monte Carlo (MC) simulations, the nuclear interaction models still lack the required accuracy due to insufficient experimental cross section data. This is particularly true for carbon therapy where literature data on fragmentation cross sections of a carbon beam with targets of medical interest are very scarce. Therefore, we performed at GANIL in July 2016 measurements on β+ emitter production cross sections with a carbon beam at 25, 50, and 95 MeV/nucleon on thin targets (C, N, O, and PMMA). We extracted the production cross section of C,1110, 13N, and O,1514 that are essential to constrain or develop MC nuclear fragmentation models.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong

Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None ofmore » the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.« less

Low carbon and clean energy scenarios for India: Analysis of targets approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shukla, Priyadarshi R.; Chaturvedi, Vaibhav

2012-12-01

Low carbon energy technologies are gaining increasing importance in India for reducing emissions as well as diversifying its energy supply mix. The present paper presents and analyses a targeted approach for pushing solar, wind and nuclear technologies in the Indian energy market. Targets for these technologies have been constructed on the basis of Indian government documents, policy announcements and expert opinion. Different targets have been set for the reference scenario and the carbon price scenario. In the reference scenario it is found that in the long run all solar, wind and nuclear will achieve their targets without any subsidy push.more » In the short run however, nuclear and solar energy require significant subsidy push. Nuclear energy requires a much higher subsidy allocation as compared to solar because the targets assumed are also higher for nuclear energy. Under a carbon price scenario, the carbon price drives the penetration of these technologies significantly. Still subsidy is required especially in the short run when the carbon price is low. It is also found that pushing solar, wind and nuclear technologies might lead to decrease in share of CCS under the price scenario and biomass under both BAU and price scenario, which implies that one set of low carbon technologies is substituted by other set of low carbon technologies. Thus the objective of emission mitigation might not be achieved due to this substitution. Moreover sensitivity on nuclear energy cost was done to represent risk mitigation for this technology and it was found that higher cost can significantly decrease the share of this technology under both the BAU and carbon price scenario.« less

Paramecium tetraurelia chromatin assembly factor-1-like protein PtCAF-1 is involved in RNA-mediated control of DNA elimination.

PubMed

Ignarski, Michael; Singh, Aditi; Swart, Estienne C; Arambasic, Miroslav; Sandoval, Pamela Y; Nowacki, Mariusz

2014-10-29

Genome-wide DNA remodelling in the ciliate Paramecium is ensured by RNA-mediated trans-nuclear crosstalk between the germline and the somatic genomes during sexual development. The rearrangements include elimination of transposable elements, minisatellites and tens of thousands non-coding elements called internally eliminated sequences (IESs). The trans-nuclear genome comparison process employs a distinct class of germline small RNAs (scnRNAs) that are compared against the parental somatic genome to select the germline-specific subset of scnRNAs that subsequently target DNA elimination in the progeny genome. Only a handful of proteins involved in this process have been identified so far and the mechanism of DNA targeting is unknown. Here we describe chromatin assembly factor-1-like protein (PtCAF-1), which we show is required for the survival of sexual progeny and localizes first in the parental and later in the newly developing macronucleus. Gene silencing shows that PtCAF-1 is required for the elimination of transposable elements and a subset of IESs. PTCAF-1 depletion also impairs the selection of germline-specific scnRNAs during development. We identify specific histone modifications appearing during Paramecium development which are strongly reduced in PTCAF-1 depleted cells. Our results demonstrate the importance of PtCAF-1 for the epigenetic trans-nuclear cross-talk mechanism. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action

PubMed Central

Martinez-Arguelles, Daniel B.; Papadopoulos, Vassilios

2010-01-01

Steroid hormones participate in organ development, reproduction, body homeostasis, and stress responses. The steroid machinery is expressed in a development- and tissue-specific manner, with the expression of these factors being tightly regulated by an array of transcription factors (TFs). Epigenetics provides an additional layer of gene regulation through DNA methylation and histone tail modifications. Evidence of epigenetic regulation of key steroidogenic enzymes is increasing, though this does not seem to be a predominant regulatory pathway. Steroid hormones exert their action in target tissues through steroid nuclear receptors belonging to the NR3A and NR3C families. Nuclear receptor expression levels and post-translational modifications regulate their function and dictate their sensitivity to steroid ligands. Nuclear receptors and TFs are more likely to be epigenetically regulated than proteins involved in steroidogenesis and have secondary impact on the expression of these steroidogenic enzymes. Here we review evidence for epigenetic regulation of enzymes, transcription factors, and nuclear receptors related to steroid biogenesis and action. PMID:20156469

Plant nuclear hormone receptors: a role for small molecules in protein-protein interactions.

PubMed

Lumba, Shelley; Cutler, Sean; McCourt, Peter

2010-01-01

Plant hormones are a group of chemically diverse small molecules that direct processes ranging from growth and development to biotic and abiotic stress responses. Surprisingly, genome analyses suggest that classic animal nuclear hormone receptor homologs do not exist in plants. It now appears that plants have co-opted several protein families to perceive hormones within the nucleus. In one solution to the problem, the hormones auxin and jasmonate (JA) act as “molecular glue” that promotes protein-protein interactions between receptor F-boxes and downstream corepressor targets. In another solution, gibberellins (GAs) bind and elicit a conformational change in a novel soluble receptor family related to hormone-sensitive lipases. Abscisic acid (ABA), like GA, also acts through an allosteric mechanism involving a START-domain protein. The molecular identification of plant nuclear hormone receptors will allow comparisons with animal nuclear receptors and testing of fundamental questions about hormone function in plant development and evolution.

A Nuclear Waste Management Cost Model for Policy Analysis

NASA Astrophysics Data System (ADS)

Barron, R. W.; Hill, M. C.

2017-12-01

Although integrated assessments of climate change policy have frequently identified nuclear energy as a promising alternative to fossil fuels, these studies have often treated nuclear waste disposal very simply. Simple assumptions about nuclear waste are problematic because they may not be adequate to capture relevant costs and uncertainties, which could result in suboptimal policy choices. Modeling nuclear waste management costs is a cross-disciplinary, multi-scale problem that involves economic, geologic and environmental processes that operate at vastly different temporal scales. Similarly, the climate-related costs and benefits of nuclear energy are dependent on environmental sensitivity to CO2 emissions and radiation, nuclear energy's ability to offset carbon emissions, and the risk of nuclear accidents, factors which are all deeply uncertain. Alternative value systems further complicate the problem by suggesting different approaches to valuing intergenerational impacts. Effective policy assessment of nuclear energy requires an integrated approach to modeling nuclear waste management that (1) bridges disciplinary and temporal gaps, (2) supports an iterative, adaptive process that responds to evolving understandings of uncertainties, and (3) supports a broad range of value systems. This work develops the Nuclear Waste Management Cost Model (NWMCM). NWMCM provides a flexible framework for evaluating the cost of nuclear waste management across a range of technology pathways and value systems. We illustrate how NWMCM can support policy analysis by estimating how different nuclear waste disposal scenarios developed using the NWMCM framework affect the results of a recent integrated assessment study of alternative energy futures and their effects on the cost of achieving carbon abatement targets. Results suggest that the optimism reflected in previous works is fragile: Plausible nuclear waste management costs and discount rates appropriate for intergenerational cost-benefit analysis produce many scenarios where nuclear energy is economically unattractive.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Zhen; Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058; Xiang, Wenqing

Highlights: {yields} LNA-modified oligonucleotides can pass through the plasma membrane of cultured cells even without using transfection machinery. {yields} LNA-modified oligonucleotides passed efficiently across the cell membrane, and lipid-coating facilitated translocation from the cytoplasm to the nucleus. {yields} LNA-oligonucleotide designed to target nuclear HBV DNA efficiently suppresses HBV replication and transcription in cultured hepatic cells. -- Abstract: Silencing target genes with small regulatory RNAs is widely used to investigate gene function and therapeutic drug development. Recently, triplex-based approaches have provided another attractive means to achieve targeted gene regulation and gene manipulation at the molecular and cellular levels. Nuclear entry ofmore » oligonucleotides and enhancement of their affinity to the DNA targets are key points of such approaches. In this study, we developed lipid-based transport of a locked-nucleic-acid (LNA)-modified oligonucleotide for hepatitis B virus (HBV) DNA interference in human hepatocytes expressing HBV genomic DNA. In these cells, the LNA-modified oligonucleotides passed efficiently across the cell membrane, and lipid-coating facilitated translocation from the cytoplasm to the nucleus. The oligonucleotide specifically targeting HBV DNA clearly interfered with HBV DNA transcription as shown by a block in pregenomic RNA (pgRNA) production. The HBV DNA-targeted oligonucleotide suppressed HBV DNA replication and HBV protein production more efficiently than small interfering RNAs directed to the pgRNA. These results demonstrate that fusion with lipid can carry LNA-modified oligonucleotides to the nucleus where they regulate gene expression. Interfering with HBV DNA transcription by LNA-modified oligonucleotides has strong potential as a new strategy for HBV inhibition.« less

[Nuclear transfer of goat somatic cells transgenic for human lactoferrin].

PubMed

Li, Lan; Shen, Wei; Pan, Qing-Yu; Min, Ling-Jiang; Sun, Yu-Jiang; Fang, Yong-Wei; Deng, Ji-Xian; Pan, Qing-Jie

2006-12-01

Transgenic animal mammary gland bioreactors are being used to produce recombinant proteins with appropriate post-translational modifications, and nuclear transfer of transgenic somatic cells is a more powerful method to produce mammary gland bioreactor. Here we describe efficient gene transfer and nuclear transfer in goat somatic cells. Gene targeting vector pGBC2LF was constructed by cloning human lactoferrin (LF) gene cDNA into exon 2 of the milk goat beta-casein gene, and the endogenous start condon was replaced by that of human LF gene. Goat fetal fibroblasts were transfected with linearized pGBC2LF and 14 cell lines were positive according to PCR and Southern blot. The transgenic cells were used as donor cells of nuclear transfer, and some of reconstructed embryos could develop to blastocyst in vitro.

Advanced Borobond™ Shields for Nuclear Materials Containment and Borobond™ Immobilization of Volatile Fission Products - Final CRADA Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagh, Arun S.

2016-05-19

Borobond is a company-proprietary material developed by the CRADA partner in collaboration with Argonne, and is based on Argonne's Ceramicrete technology. It is being used by DOE for nuclear materials safe storage, and Boron Products, LLC is the manufacturer and supplier of Borobond. The major objective of this project was to produce a more versatile composition of this material and find new applications. Major target applications were use for nuclear radiation shields, such as in dry storage casks; use in immobilization of most difficult waste streams, such as Hanford K-Basin waste; use for soluble and volatile fission products, such asmore » Cs, Tc, Sr, and I; and use for corrosion and fire protection applications in nuclear facilities.« less

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Providing security assurance in line with national DBT assumptions

NASA Astrophysics Data System (ADS)

Bajramovic, Edita; Gupta, Deeksha

2017-01-01

As worldwide energy requirements are increasing simultaneously with climate change and energy security considerations, States are thinking about building nuclear power to fulfill their electricity requirements and decrease their dependence on carbon fuels. New nuclear power plants (NPPs) must have comprehensive cybersecurity measures integrated into their design, structure, and processes. In the absence of effective cybersecurity measures, the impact of nuclear security incidents can be severe. Some of the current nuclear facilities were not specifically designed and constructed to deal with the new threats, including targeted cyberattacks. Thus, newcomer countries must consider the Design Basis Threat (DBT) as one of the security fundamentals during design of physical and cyber protection systems of nuclear facilities. IAEA NSS 10 describes the DBT as "comprehensive description of the motivation, intentions and capabilities of potential adversaries against which protection systems are designed and evaluated". Nowadays, many threat actors, including hacktivists, insider threat, cyber criminals, state and non-state groups (terrorists) pose security risks to nuclear facilities. Threat assumptions are made on a national level. Consequently, threat assessment closely affects the design structures of nuclear facilities. Some of the recent security incidents e.g. Stuxnet worm (Advanced Persistent Threat) and theft of sensitive information in South Korea Nuclear Power Plant (Insider Threat) have shown that these attacks should be considered as the top threat to nuclear facilities. Therefore, the cybersecurity context is essential for secure and safe use of nuclear power. In addition, States should include multiple DBT scenarios in order to protect various target materials, types of facilities, and adversary objectives. Development of a comprehensive DBT is a precondition for the establishment and further improvement of domestic state nuclear-related regulations in the field of physical and cyber protection. These national regulations have to be met later on by I&C platform suppliers, electrical systems suppliers, system integrators and turn-key providers.

2017 Report for New LANL Physical Vapor Deposition Capability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roman, Audrey Rae; Zhao, Xinxin; Bond, Evelyn M.

There is an urgent need at LANL to achieve uniform, thin film actinide targets that are essential for nuclear physics experiments. The target preparation work is currently performed externally by Professor Walter Loveland at Oregon State University, who has made various evaporated actinide targets such as Th and U for use on several nuclear physics measurements at LANSCE. We are developing a vapor deposition capability, with the goal of evaporating Th and U in the Actinide Research Facility (ARF) at TA-48. In the future we plan to expand this work to evaporating transuranic elements, such as Pu. The ARF ismore » the optimal location for evaporating actinides because this lab is specifically dedicated to actinide research. There are numerous instruments in the ARF that can be used to provide detailed characterization of the evaporated thin films such as: Table top Scanning Electron Microscope, In-situ X-Ray Diffraction, and 3D Raman spectroscopy. These techniques have the ability to determine the uniformity, surface characterization, and composition of the deposits.« less

A domain unique to plant RanGAP is responsible for its targeting to the plant nuclear rim

PubMed Central

Rose, Annkatrin; Meier, Iris

2001-01-01

Ran is a small signaling GTPase that is involved in nucleocytoplasmic transport. Two additional functions of animal Ran in the formation of spindle asters and the reassembly of the nuclear envelope in mitotic cells have been recently reported. In contrast to Ras or Rho, Ran is not associated with membranes. Instead, the spatial sequestering of its accessory proteins, the Ran GTPase-activating protein RanGAP and the nucleotide exchange factor RCC1, appears to define the local concentration of RanGTP vs. RanGDP involved in signaling. Mammalian RanGAP is bound to the nuclear pore by a mechanism involving the attachment of small ubiquitin-related modifier protein (SUMO) to its C terminus and the subsequent binding of the SUMOylated domain to the nucleoporin Nup358. Here we show that plant RanGAP utilizes a different mechanism for nuclear envelope association, involving a novel targeting domain that appears to be unique to plants. The N-terminal WPP domain is highly conserved among plant RanGAPs and the small, plant-specific nuclear envelope-associated protein MAF1, but not present in yeast or animal RanGAP. Confocal laser scanning microscopy of green fluorescent protein (GFP) fusion proteins showed that it is necessary for RanGAP targeting and sufficient to target the heterologous protein GFP to the plant nuclear rim. The highly conserved tryptophan and proline residues of the WPP motif are necessary for its function. The 110-aa WPP domain is the first nuclear-envelope targeting domain identified in plants. Its fundamental difference to its mammalian counterpart implies that different mechanisms have evolved in plants and animals to anchor RanGAP at the nuclear surface. PMID:11752475

A critical assessment of boron target compounds for boron neutron capture therapy.

PubMed

Hawthorne, M Frederick; Lee, Mark W

2003-01-01

Boron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.

Advances in Monte-Carlo code TRIPOLI-4®'s treatment of the electromagnetic cascade

NASA Astrophysics Data System (ADS)

Mancusi, Davide; Bonin, Alice; Hugot, François-Xavier; Malouch, Fadhel

2018-01-01

TRIPOLI-4® is a Monte-Carlo particle-transport code developed at CEA-Saclay (France) that is employed in the domains of nuclear-reactor physics, criticality-safety, shielding/radiation protection and nuclear instrumentation. The goal of this paper is to report on current developments, validation and verification made in TRIPOLI-4 in the electron/positron/photon sector. The new capabilities and improvements concern refinements to the electron transport algorithm, the introduction of a charge-deposition score, the new thick-target bremsstrahlung option, the upgrade of the bremsstrahlung model and the improvement of electron angular straggling at low energy. The importance of each of the developments above is illustrated by comparisons with calculations performed with other codes and with experimental data.

The conceptual solutions concerning decommissioning and dismantling of Russian civil nuclear powered ships

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulikov, Konstantin N.; Nizamutdinov, Rinat A.; Abramov, Andrey N.

From 1959 up to 1991 nine civil nuclear powered ships were built in Russia: eight ice-breakers and one lash lighter carrier (cargo ship). At the present time three of them were taking out of service: ice-breaker 'Lenin' is decommissioned as a museum and is set for storage in the port of Murmansk, nuclear ice-breakers 'Arktika' and 'Sibir' are berthing. The ice-breakers carrying rad-wastes appear to be a possible source of radiation contamination of Murmansk region and Kola Bay because the ship long-term storage afloat has the negative effect on hull's structures. As the result of this under the auspices ofmore » the Federal Targeted Program 'Nuclear and Radiation Safety of Russia for 2008 and the period until 2015' the conception and projects of decommissioning of nuclear-powered ships are developed by the State corporation Rosatom with the involvement of companies of United Shipbuilding Corporation. In developing the principal provisions of conception of decommissioning and dismantling of icebreakers the technical and economic assessment of dismantling options in ship-repairing enterprises of North-West of Russia was performed. The paper contains description of options, research procedure, analysis of options of decommissioning and dismantling of nuclear ice-breakers, taking into account the principle of optimization of potential radioactive effect to personnel, human population and environment. The report's conclusions contain the recommendations for selection of option for development of nuclear icebreaker decommissioning and dismantling projects. (authors)« less

Fission yield measurements at IGISOL

NASA Astrophysics Data System (ADS)

Lantz, M.; Al-Adili, A.; Gorelov, D.; Jokinen, A.; Kolhinen, V. S.; Mattera, A.; Moore, I.; Penttilä, H.; Pomp, S.; Prokofiev, A. V.; Rakopoulos, V.; Rinta-Antila, S.; Simutkin, V.; Solders, A.

2016-06-01

The fission product yields are an important characteristic of the fission process. In fundamental physics, knowledge of the yield distributions is needed to better understand the fission process. For nuclear energy applications good knowledge of neutroninduced fission-product yields is important for the safe and efficient operation of nuclear power plants. With the Ion Guide Isotope Separator On-Line (IGISOL) technique, products of nuclear reactions are stopped in a buffer gas and then extracted and separated by mass. Thanks to the high resolving power of the JYFLTRAP Penning trap, at University of Jyväskylä, fission products can be isobarically separated, making it possible to measure relative independent fission yields. In some cases it is even possible to resolve isomeric states from the ground state, permitting measurements of isomeric yield ratios. So far the reactions U(p,f) and Th(p,f) have been studied using the IGISOL-JYFLTRAP facility. Recently, a neutron converter target has been developed utilizing the Be(p,xn) reaction. We here present the IGISOL-technique for fission yield measurements and some of the results from the measurements on proton induced fission. We also present the development of the neutron converter target, the characterization of the neutron field and the first tests with neutron-induced fission.

CRM1 Inhibitors for Antiviral Therapy

PubMed Central

Mathew, Cynthia; Ghildyal, Reena

2017-01-01

Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review. PMID:28702009

Locating Sensors for Detecting Source-to-Target Patterns of Special Nuclear Material Smuggling: A Spatial Information Theoretic Approach

PubMed Central

Przybyla, Jay; Taylor, Jeffrey; Zhou, Xuesong

2010-01-01

In this paper, a spatial information-theoretic model is proposed to locate sensors for detecting source-to-target patterns of special nuclear material (SNM) smuggling. In order to ship the nuclear materials from a source location with SNM production to a target city, the smugglers must employ global and domestic logistics systems. This paper focuses on locating a limited set of fixed and mobile radiation sensors in a transportation network, with the intent to maximize the expected information gain and minimize the estimation error for the subsequent nuclear material detection stage. A Kalman filtering-based framework is adapted to assist the decision-maker in quantifying the network-wide information gain and SNM flow estimation accuracy. PMID:22163641

Locating sensors for detecting source-to-target patterns of special nuclear material smuggling: a spatial information theoretic approach.

PubMed

Przybyla, Jay; Taylor, Jeffrey; Zhou, Xuesong

2010-01-01

In this paper, a spatial information-theoretic model is proposed to locate sensors for detecting source-to-target patterns of special nuclear material (SNM) smuggling. In order to ship the nuclear materials from a source location with SNM production to a target city, the smugglers must employ global and domestic logistics systems. This paper focuses on locating a limited set of fixed and mobile radiation sensors in a transportation network, with the intent to maximize the expected information gain and minimize the estimation error for the subsequent nuclear material detection stage. A Kalman filtering-based framework is adapted to assist the decision-maker in quantifying the network-wide information gain and SNM flow estimation accuracy.

Targeting Nuclear Receptors with Marine Natural Products

PubMed Central

Yang, Chunyan; Li, Qianrong; Li, Yong

2014-01-01

Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators. PMID:24473166

A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery.

PubMed

Zhong, Jiaju; Li, Lian; Zhu, Xi; Guan, Shan; Yang, Qingqing; Zhou, Zhou; Zhang, Zhirong; Huang, Yuan

2015-10-01

Tumor cell nucleus-targeted delivery of antitumor agents is of great interest in cancer therapy, since the nucleus is one of the most frequent targets of drug action. Here we report a smart polymeric conjugate platform, which utilizes stimulus-responsive strategies to achieve multistage nuclear drug delivery upon systemic administration. The conjugates composed of a backbone based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer and detachable nucleus transport sub-units that sensitive to lysosomal enzyme. The sub-units possess a biforked structure with one end conjugated with the model drug, H1 peptide, and the other end conjugated with a novel pH-responsive targeting peptide (R8NLS) that combining the strength of cell penetrating peptide and nuclear localization sequence. The conjugates exhibited prolonged circulation time and excellent tumor homing ability. And the activation of R8NLS in acidic tumor microenvironment facilitated tissue penetration and cellular internalization. Once internalized into the cell, the sub-units were unleashed for nuclear transport through nuclear pore complex. The unique features resulted in 50-fold increase of nuclear drug accumulation relative to the original polymer-drug conjugates in vitro, and excellent in vivo nuclear drug delivery efficiency. Our report provides a strategy in systemic nuclear drug delivery by combining the microenvironment-responsive structure and detachable sub-units. Copyright © 2015 Elsevier Ltd. All rights reserved.

ANITA (Advanced Network for Isotope and TArget laboratories) - The urgent need for a European target preparation network

NASA Astrophysics Data System (ADS)

Schumann, Dorothea; Sibbens, Goedele; Stolarz, Anna; Eberhardt, Klaus; Lommel, Bettina; Stodel, Christelle

2018-05-01

A wide number of research fields in the nuclear sector requires high-quality and well-characterized samples and targets. Currently, only a few laboratories own or have access to the equipment allowing fulfilling such demands. Coordination of activities and sharing resources is therefore mandatory to meet the increasing needs. This very urgent issue has now been addressed by six European target laboratories with an initiative called ANITA (Advanced Network for Isotope and TArget laboratories). The global aim of ANITA is to establish an overarching research infrastructure service for isotope and target production and develop a tight cooperation between the target laboratories in Europe in order to transfer the knowledge and improve the production techniques of well-characterized samples and targets. Moreover, the interaction of the target producers with the users shall be encouraged and intensified to deliver tailor-made targets best-suited to the envisaged experiments. For the realization of this ambitious goal, efforts within the European Commission and strong support by the target-using communities will be necessary. In particular, an appropriate funding instrument has to be found and applied, enabling ANITA to develop from an initiative employed by the interested parties to a real coordination platform.

Exploratory investigation of the HIPPO gas-jet target fluid dynamic properties

NASA Astrophysics Data System (ADS)

Meisel, Zach; Shi, Ke; Jemcov, Aleksandar; Couder, Manoel

2016-08-01

In order to optimize the performance of gas-jet targets for future nuclear reaction measurements, a detailed understanding of the dependence of the gas-jet properties on experiment design parameters is required. Common methods of gas-jet characterization rely on measuring the effective thickness using nuclear elastic scattering and energy loss techniques; however, these tests are time intensive and limit the range of design modifications which can be explored to improve the properties of the jet as a nuclear reaction target. Thus, a more rapid jet-characterization method is desired. We performed the first steps towards characterizing the gas-jet density distribution of the HIPPO gas-jet target at the University of Notre Dame's Nuclear Science Laboratory by reproducing results from 20Ne(α,α)20Ne elastic scattering measurements with computational fluid dynamics (CFD) simulations performed with the state-of-the-art CFD software ANSYS Fluent. We find a strong sensitivity to experimental design parameters of the gas-jet target, such as the jet nozzle geometry and ambient pressure of the target chamber. We argue that improved predictive power will require moving to three-dimensional simulations and additional benchmarking with experimental data.

Parity violation in electron scattering

DOE PAGES

Souder, P.; Paschke, K. D.

2015-12-22

By comparing the cross sections for left- and right-handed electrons scattered from various unpolarized nuclear targets, the small parity-violating asymmetry can be measured. These asymmetry data probe a wide variety of important topics, including searches for new fundamental interactions and important features of nuclear structure that cannot be studied with other probes. A special feature of these experiments is that the results are interpreted with remarkably few theoretical uncertainties, which justifies pushing the experiments to the highest possible precision. To measure the small asymmetries accurately, a number of novel experimental techniques have been developed.

Quantitative imaging for clinical dosimetry

NASA Astrophysics Data System (ADS)

Bardiès, Manuel; Flux, Glenn; Lassmann, Michael; Monsieurs, Myriam; Savolainen, Sauli; Strand, Sven-Erik

2006-12-01

Patient-specific dosimetry in nuclear medicine is now a legal requirement in many countries throughout the EU for targeted radionuclide therapy (TRT) applications. In order to achieve that goal, an increased level of accuracy in dosimetry procedures is needed. Current research in nuclear medicine dosimetry should not only aim at developing new methods to assess the delivered radiation absorbed dose at the patient level, but also to ensure that the proposed methods can be put into practice in a sufficient number of institutions. A unified dosimetry methodology is required for making clinical outcome comparisons possible.

The development of a super-fine-grained nuclear emulsion

NASA Astrophysics Data System (ADS)

Asada, Takashi; Naka, Tatsuhiro; Kuwabara, Ken-ichi; Yoshimoto, Masahiro

2017-06-01

A nuclear emulsion with micronized crystals is required for the tracking detection of submicron ionizing particles, which are one of the targets of dark-matter detection and other techniques. We found that a new production method, called the PVA—gelatin mixing method (PGMM), could effectively control crystal size from 20 nm to 50 nm. We called the two types of emulsion produced with the new method the nano imaging tracker and the ultra-nano imaging tracker. Their composition and spatial resolution were measured, and the results indicate that these emulsions detect extremely short tracks.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, Alan E.

Here, proposed dark matter detectors with eV-scale sensitivities will detect a large background of atomic (nuclear) recoils from coherent photon scattering of MeV-scale photons. This background climbs steeply below ~10 eV, far exceeding the declining rate of low-energy Compton recoils. The upcoming generation of dark matter detectors will not be limited by this background, but further development of eV-scale and sub-eV detectors will require strategies, including the use of low nuclear mass target materials, to maximize dark matter sensitivity while minimizing the coherent photon scattering background.

Nuclear Terrorism - Dimensions, Options, and Perspectives in Moldova

NASA Astrophysics Data System (ADS)

Vaseashta, Ashok; Susmann, P.; Braman, Eric W.; Enaki, Nicolae A.

Securing nuclear materials, controlling contraband and preventing proliferation is an international priority to resolve using technology, diplomacy, strategic alliances, and if necessary, targeted military exercises. Nuclear security consists of complementary programs involving international legal and regulatory structure, intelligence and law enforcement agencies, border and customs forces, point and stand-off radiation detectors, personal protection equipment, preparedness for emergency and disaster, and consequence management teams. The strategic goal of UNSCR 1540 and the GICNT is to prevent nuclear materials from finding their way into the hands of our adversaries. This multi-jurisdictional and multi-agency effort demands tremendous coordination, technology assessment, policy development and guidance from several sectors. The overall goal envisions creating a secured environment that controls and protects nuclear materials while maintaining the free flow of commerce and individual liberty on international basis. Integral to such efforts are technologies to sense/detect nuclear material, provide advance information of nuclear smuggling routes, and other advanced means to control nuclear contraband and prevent proliferation. We provide an overview of GICNT and several initiatives supporting such efforts. An overview is provided of technological advances in support of point and stand-off detection and receiving advance information of nuclear material movement from perspectives of the Republic of Moldova.

Energy and Technology Review

NASA Astrophysics Data System (ADS)

Poggio, Andrew J.

1988-10-01

This issue of Energy and Technology Review contains: Neutron Penumbral Imaging of Laser-Fusion Targets--using our new penumbral-imaging diagnostic, we have obtained the first images that can be used to measure directly the deuterium-tritium burn region in laser-driven fusion targets; Computed Tomography for Nondestructive Evaluation--various computed tomography systems and computational techniques are used in nondestructive evaluation; Three-Dimensional Image Analysis for Studying Nuclear Chromatin Structure--we have developed an optic-electronic system for acquiring cross-sectional views of cell nuclei, and computer codes to analyze these images and reconstruct the three-dimensional structures they represent; Imaging in the Nuclear Test Program--advanced techniques produce images of unprecedented detail and resolution from Nevada Test Site data; and Computational X-Ray Holography--visible-light experiments and numerically simulated holograms test our ideas about an X-ray microscope for biological research.

Targeting xenobiotic receptors PXR and CAR in human diseases

PubMed Central

Banerjee, Monimoy; Robbins, Delira; Chen, Taosheng

2014-01-01

Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors regulating not only drug metabolism and disposition but also various human diseases such as cancer, diabetes, inflammatory disease, metabolic disease and liver diseases, suggesting that PXR and CAR are promising targets for drug discovery. Consequently, there is an urgent need to discover and develop small molecules that target these PXR- and/or CAR-mediated human-disease-related pathways for relevant therapeutic applications. This review proposes approaches to target PXR and CAR, either individually or simultaneously, in the context of various human diseases, taking into consideration the structural differences between PXR and CAR. PMID:25463033

Nuclear Localizing Peptide-Conjugated, Redox-Sensitive Polymersomes for Delivering Curcumin and Doxorubicin to Pancreatic Cancer Microtumors.

PubMed

Anajafi, Tayebeh; Yu, Junru; Sedigh, Abbas; Haldar, Manas K; Muhonen, Wallace W; Oberlander, Seth; Wasness, Heather; Froberg, Jamie; Molla, Md Shahjahan; Katti, Kalpana S; Choi, Yongki; Shabb, John B; Srivastava, D K; Mallik, Sanku

2017-06-05

Improving the therapeutic index of anticancer agents is an enormous challenge. Targeting decreases the side effects of the therapeutic agents by delivering the drugs to the intended destination. Nanocarriers containing the nuclear localizing peptide sequences (NLS) translocate to the cell nuclei. However, the nuclear localization peptides are nonselective and cannot distinguish the malignant cells from the healthy counterparts. In this study, we designed a "masked" NLS peptide which is activated only in the presence of overexpressed matrix metalloproteinase-7 (MMP-7) enzyme in the pancreatic cancer microenvironment. This peptide is conjugated to the surface of redox responsive polymersomes to deliver doxorubicin and curcumin to the pancreatic cancer cell nucleus. We have tested the formulation in both two- and three-dimensional cultures of pancreatic cancer and normal cells. Our studies revealed that the drug-encapsulated polymeric vesicles are significantly more toxic toward the cancer cells (shrinking the spheroids up to 49%) compared to the normal cells (shrinking the spheroids up to 24%). This study can lead to the development of other organelle targeted drug delivery systems for various human malignancies.

Mass Producing Targets for Nuclear Fusion

NASA Technical Reports Server (NTRS)

Wang, T. G.; Elleman, D. D.; Kendall, J. M.

1983-01-01

Metal-encapsulating technique advances prospects of controlling nuclear fusion. Prefilled fusion targets form at nozzle as molten metal such as tin flows through outer channel and pressurized deuterium/tritium gas flows through inner channel. Molten metal completely encloses gas charge as it drops off nozzle.

Predicting Drug-Target Interactions for New Drug Compounds Using a Weighted Nearest Neighbor Profile.

PubMed

van Laarhoven, Twan; Marchiori, Elena

2013-01-01

In silico discovery of interactions between drug compounds and target proteins is of core importance for improving the efficiency of the laborious and costly experimental determination of drug-target interaction. Drug-target interaction data are available for many classes of pharmaceutically useful target proteins including enzymes, ion channels, GPCRs and nuclear receptors. However, current drug-target interaction databases contain a small number of drug-target pairs which are experimentally validated interactions. In particular, for some drug compounds (or targets) there is no available interaction. This motivates the need for developing methods that predict interacting pairs with high accuracy also for these 'new' drug compounds (or targets). We show that a simple weighted nearest neighbor procedure is highly effective for this task. We integrate this procedure into a recent machine learning method for drug-target interaction we developed in previous work. Results of experiments indicate that the resulting method predicts true interactions with high accuracy also for new drug compounds and achieves results comparable or better than those of recent state-of-the-art algorithms. Software is publicly available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2013/.

The abolition of war as a goal of environmental policy.

PubMed

Snyder, Brian F; Ruyle, Leslie E

2017-12-15

Since the 1950s, select military and political leaders have had the capacity to kill all or nearly all human life on Earth. The number of people entrusted with this power grows each year through proliferation and the rise of new political leaders. If humans continue to maintain and develop nuclear weapons, it is highly probable that a nuclear exchange will occur again at some point in the future. This nuclear exchange may or may not annihilate the human species, but it will cause catastrophic effects on the biosphere. The international community has attempted to resolve this existential problem via treaties that control and potentially eliminate nuclear weapons, however, these treaties target only nuclear weapons, leaving the use of war as a normalized means for settling conflict. As long as war exists as a probable future, nations will be under pressure to develop more powerful weapons. Thus, we argue that the elimination of nuclear weapons alone is not a stable, long-term strategy. A far more secure strategy would be the elimination of war as a means of settling international disputes. Therefore, those concerned about environmental sustainability or the survival of the biosphere should work to abolish war. Copyright © 2017 Elsevier B.V. All rights reserved.

Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes.

PubMed

Tőke, E R; Lőrincz, O; Csiszovszki, Z; Somogyi, E; Felföldi, G; Molnár, L; Szipőcs, R; Kolonics, A; Malissen, B; Lori, F; Trocio, J; Bakare, N; Horkay, F; Romani, N; Tripp, C H; Stoitzner, P; Lisziewicz, J

2014-06-01

There is no clinically available cancer immunotherapy that exploits Langerhans cells (LCs), the epidermal precursors of dendritic cells (DCs) that are the natural agent of antigen delivery. We developed a DNA formulation with a polymer and obtained synthetic 'pathogen-like' nanoparticles that preferentially targeted LCs in epidermal cultures. These nanoparticles applied topically under a patch-elicited robust immune responses in human subjects. To demonstrate the mechanism of action of this novel vaccination strategy in live animals, we assembled a high-resolution two-photon laser scanning-microscope. Nanoparticles applied on the native skin poorly penetrated and poorly induced LC motility. The combination of nanoparticle administration and skin treatment was essential both for efficient loading the vaccine into the epidermis and for potent activation of the LCs to migrate into the lymph nodes. LCs in the epidermis picked up nanoparticles and accumulated them in the nuclear region demonstrating an effective nuclear DNA delivery in vivo. Tissue distribution studies revealed that the majority of the DNA was targeted to the lymph nodes. Preclinical toxicity of the LC-targeting DNA vaccine was limited to mild and transient local erythema caused by the skin treatment. This novel, clinically proven LC-targeting DNA vaccine platform technology broadens the options on DC-targeting vaccines to generate therapeutic immunity against cancer.

Sandia technology: Engineering and science applications

NASA Astrophysics Data System (ADS)

Maydew, M. C.; Parrot, H.; Dale, B. C.; Floyd, H. L.; Leonard, J. A.; Parrot, L.

1990-12-01

This report discusses: protecting environment, safety, and health; Sandia's quality initiative; Sandia vigorously pursues technology transfer; scientific and technical education support programs; nuclear weapons development; recognizing battlefield targets with trained artificial neural networks; battlefield robotics: warfare at a distance; a spinning shell sizes up the enemy; thwarting would-be nuclear terrorists; unattended video surveillance system for nuclear facilities; making the skies safer for travelers; onboard instrumentation system to evaluate performance of stockpile bombs; keeping track with lasers; extended-life lithium batteries; a remote digital video link acquires images securely; guiding high-performance missiles with laser gyroscopes; nonvolatile memory chips for space applications; initiating weapon explosives with lasers; next-generation optoelectronics and microelectronics technology developments; chemometrics: new methods for improving chemical analysis; research team focuses ion beam to record-breaking intensities; standardizing the volt to quantum accuracy; new techniques improve robotic software development productivity; a practical laser plasma source for generating soft x-rays; exploring metal grain boundaries; massively parallel computing; modeling the amount of desiccant needed for moisture control; attacking pollution with sunshine; designing fuel-conversion catalysts with computers; extending a nuclear power plant's useful life; plasma-facing components for the International Thermonuclear Experimental Reactor.

Nuclear reactor target assemblies, nuclear reactor configurations, and methods for producing isotopes, modifying materials within target material, and/or characterizing material within a target material

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toth, James J.; Wall, Donald; Wittman, Richard S.

Target assemblies are provided that can include a uranium-comprising annulus. The assemblies can include target material consisting essentially of non-uranium material within the volume of the annulus. Reactors are disclosed that can include one or more discrete zones configured to receive target material. At least one uranium-comprising annulus can be within one or more of the zones. Methods for producing isotopes within target material are also disclosed, with the methods including providing neutrons to target material within a uranium-comprising annulus. Methods for modifying materials within target material are disclosed as well as are methods for characterizing material within a targetmore » material.« less

A verotoxin 1 B subunit-lambda CRO chimeric protein specifically binds both DNA and globotriaosylceramide (Gb(3)) to effect nuclear targeting of exogenous DNA in Gb(3) positive cells.

PubMed

Facchini, L M; Lingwood, C A

2001-09-10

Inefficient nuclear incorporation of foreign DNA remains a critical roadblock in the development of effective nonviral gene delivery systems. DNA delivered by traditional protocols remains within endosomal/lysosomal vesicles, or is rapidly degraded in the cytoplasm. Verotoxin I (VT), an AB(5) subunit toxin produced by enterohaemorrhagic Escherichia coli, binds to the cell surface glycolipid, globotriaosylceramide (Gb(3)) and is internalized into preendosomes. VT is then retrograde transported to the Golgi, endoplasmic reticulum (ER), and nucleus of highly VT-sensitive cells. We have utilized this nuclear targeting of VT to design a unique delivery system which transports exogenous DNA via vesicular traffic to the nucleus. The nontoxic VT binding subunit (VTB) was fused to the lambda Cro DNA-binding repressor, generating a 14-kDa VTB-Cro chimera. VTB-Cro binds specifically via the Cro domain to a 25-bp DNA fragment containing the consensus Cro operator. VTB-Cro demonstrates simultaneous specific binding to Gb(3). Treatment of Vero cells with fluorescent-labeled Cro operator DNA in the presence of VTB-Cro, results in DNA internalization to the Golgi, ER, and nucleus, whereas fluorescent DNA alone is incorporated poorly and randomly within the cytoplasm. VTB-Cro mediated nuclear DNA transport is prevented by brefeldin A, consistent with Golgi/ER intracellular routing. Pretreatment with filipin had no effect, indicating that caveoli are not involved. This novel VTB-Cro shuttle protein may find practical applications in the fields of intracellular targeting, gene delivery, and gene therapy. Copyright 2001 Academic Press.

Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage.

PubMed

Solozobova, Valeriya; Rolletschek, Alexandra; Blattner, Christine

2009-06-17

P53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial. In proliferating embryonic stem cells, p53 is localized predominantly in the cytoplasm. DNA damage-induced nuclear accumulation of p53 in embryonic stem cells activates transcription of the target genes mdm2, p21, puma and noxa. We observed bi-phasic kinetics for nuclear accumulation of p53 after ionizing radiation. During the first wave of nuclear accumulation, p53 levels were increased and the p53 target genes mdm2, p21 and puma were transcribed. Transcription of noxa correlated with the second wave of nuclear accumulation. Transcriptional activation of p53 target genes resulted in an increased amount of proteins with the exception of p21. While p21 transcripts were efficiently translated in 3T3 cells, we failed to see an increase in p21 protein levels after IR in embryonal stem cells. In embryonic stem cells where (anti-proliferative) p53 activity is not necessary, or even unfavorable, p53 is retained in the cytoplasm and prevented from activating its target genes. However, if its activity is beneficial or required, p53 is allowed to accumulate in the nucleus and activates its target genes, even in embryonic stem cells.

Overview: Development of the National Ignition Facility and the Transition to a User Facility for the Ignition Campaign and High Energy Density Scientific Research

DOE PAGES

Moses, E. I.; Lindl, J. D.; Spaeth, M. L.; ...

2017-03-23

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory has been operational since March 2009 and has been transitioning to a user facility supporting ignition science, high energy density stockpile science, national security applications, and fundamental science. The facility has achieved its design goal of 1.8 MJ and 500 TW of 3ω light on target, and has performed target experiments with 1.9 MJ at peak powers of 410 TW. The National Ignition Campaign (NIC), established by the U.S. National Nuclear Security Administration in 2005, was responsible for transitioning NIF from a construction project to a national user facility. Besidesmore » the operation and optimization of the use of the NIF laser, the NIC program was responsible for developing capabilities including target fabrication facilities; cryogenic layering capabilities; over 60 optical, X-ray, and nuclear diagnostic systems; experimental platforms; and a wide range of other NIF facility infrastructure. This study provides a summary of some of the key experimental results for NIF to date, an overview of the NIF facility capabilities, and the challenges that were met in achieving these capabilities. Finally, they are covered in more detail in the papers that follow.« less

Overview: Development of the National Ignition Facility and the Transition to a User Facility for the Ignition Campaign and High Energy Density Scientific Research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moses, E. I.; Lindl, J. D.; Spaeth, M. L.

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory has been operational since March 2009 and has been transitioning to a user facility supporting ignition science, high energy density stockpile science, national security applications, and fundamental science. The facility has achieved its design goal of 1.8 MJ and 500 TW of 3ω light on target, and has performed target experiments with 1.9 MJ at peak powers of 410 TW. The National Ignition Campaign (NIC), established by the U.S. National Nuclear Security Administration in 2005, was responsible for transitioning NIF from a construction project to a national user facility. Besidesmore » the operation and optimization of the use of the NIF laser, the NIC program was responsible for developing capabilities including target fabrication facilities; cryogenic layering capabilities; over 60 optical, X-ray, and nuclear diagnostic systems; experimental platforms; and a wide range of other NIF facility infrastructure. This study provides a summary of some of the key experimental results for NIF to date, an overview of the NIF facility capabilities, and the challenges that were met in achieving these capabilities. Finally, they are covered in more detail in the papers that follow.« less

Thermal-neutron capture gamma-rays. Volume 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tuli, J.K.

1997-05-01

The energy and photon intensity of gamma rays as seen in thermal-neutron capture are presented ordered by Z, A of target nuclei. All gamma-rays with intensity of {ge}2% of the strongest transition are included. The strongest transition is indicated in each case. Where the target nuclide mass number is indicated as nat the natural target was used. The gamma energies given are in keV. The gamma intensities given are relative to 100 for the strongest transition. All data for A > 44 are taken from Evaluated Nuclear Structure Data File (4/97), a computer file of evaluated nuclear structure data maintainedmore » by the National Nuclear Data Center, Brookhaven National Laboratory, on behalf of the Nuclear Structure and Decay and Decay Data network, coordinated by the International Atomic Energy Agency, Vienna. These data are published in Nuclear Data Sheets, Academic Press, San Diego, CA. The data for A {le} 44 is taken from ``Prompt Gamma Rays from Thermal-Neutron Capture,`` M.A. Lone, R.A. Leavitt, D.A. Harrison, Atomic Data and Nuclear Data Tables 26, 511 (1981).« less

Thermal-neutron capture gamma-rays. Volume 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tuli, J.K.

1997-05-01

The energy and photon intensity of gamma rays as seen in thermal-neutron capture are presented in ascending order of gamma energy. All those gamma-rays with intensity of {ge} 2% of the strongest transition are included. The two strongest transitions seen for the target nuclide are indicated in each case. Where the target nuclide mass number is indicated as nat the natural target was used. The gamma energies given are in keV. The gamma intensities given are relative to 100 for the strongest transition. All data for A > 44 are taken from Evaluated Nuclear Structure Data File (4/97), a computermore » file of evaluated nuclear structure data maintained by the National Nuclear Data Center, Brookhaven National Laboratory, on behalf of the Nuclear Structure and Decay and Decay Data network, coordinated by the International Atomic Energy Agency, Vienna. These data are published in Nuclear Data Sheets, Academic Press, San Diego, CA. The data for A {le} 44 is taken from ``Prompt Gamma Rays from Thermal-Neutron Capture,`` M.A. Lone, R.A. Leavitt, D.A. Harrison, Atomic Data and Nuclear Data Tables 26, 511 (1981).« less

Nuclear and cytoplasmic delivery of lactoferrin in glioma using chitosan nanoparticles: Cellular location dependent-action of lactoferrin.

PubMed

Tammam, Salma N; Azzazy, Hassan M E; Lamprecht, Alf

2018-08-01

Lactoferrin (Lf) exerts anti-cancer effects on glioma, however, the exact mechanism remains unclear. Despite possessing a nuclear localization sequence (NLS), Lf was found to allocate only in the cytoplasm of glioma 261. Lf was therefore loaded into nuclear and cytoplasmic targeted nanoparticles (NPs) to determine whether nuclear delivery of Lf would enhance its anti-cancer effect. Upon treatment with 300 and 800 µg/mL Lf loaded chitosan NPs, nuclear targeted Lf-NPs showed 1.3 and 2.7 folds increase in cell viability, whereas cytoplasmic targeted Lf-NPs at 300 µg/mL decreased cell viability by 0.8 folds in comparison to free Lf and controls. Results suggest that the cytotoxicity of Lf on glioma is attributable to its cytoplasmic allocation. Nuclear delivery of Lf induced cell proliferation rather than cytotoxicity, indicating that the mode of action of Lf in glioma is cell location dependent. This calls for caution about the general use of Lf as an anti-cancer protein. Copyright © 2018. Published by Elsevier B.V.

The DenA/DEN1 Interacting Phosphatase DipA Controls Septa Positioning and Phosphorylation-Dependent Stability of Cytoplasmatic DenA/DEN1 during Fungal Development

PubMed Central

Schinke, Josua; Kolog Gulko, Miriam; Christmann, Martin; Valerius, Oliver; Stumpf, Sina Kristin; Stirz, Margarita; Braus, Gerhard H.

2016-01-01

DenA/DEN1 and the COP9 signalosome (CSN) represent two deneddylases which remove the ubiquitin-like Nedd8 from modified target proteins and are required for distinct fungal developmental programmes. The cellular DenA/DEN1 population is divided into a nuclear and a cytoplasmatic subpopulation which is especially enriched at septa. DenA/DEN1 stability control mechanisms are different for the two cellular subpopulations and depend on different physical interacting proteins and the C-terminal DenA/DEN1 phosphorylation pattern. Nuclear DenA/DEN1 is destabilized during fungal development by five of the eight CSN subunits which target nuclear DenA/DEN1 for degradation. DenA/DEN1 becomes stabilized as a phosphoprotein at S243/S245 during vegetative growth, which is necessary to support further asexual development. After the initial phase of development, the newly identified cytoplasmatic DenA/DEN1 interacting phosphatase DipA and an additional developmental specific C-terminal phosphorylation site at serine S253 destabilize DenA/DEN1. Outside of the nucleus, DipA is co-transported with DenA/DEN1 in the cytoplasm between septa and nuclei. Deletion of dipA resulted in increased DenA/DEN1 stability in a strain which is unresponsive to illumination. The mutant strain is dysregulated in cytokinesis and impaired in asexual development. Our results suggest a dual phosphorylation-dependent DenA/DEN1 stability control with stabilizing and destabilizing modifications and physical interaction partner proteins which function as control points in the nucleus and the cytoplasm. PMID:27010942

Characterization of inertial confinement fusion (ICF) targets using PIXE, RBS, and STIM analysis.

PubMed

Li, Yongqiang; Liu, Xue; Li, Xinyi; Liu, Yiyang; Zheng, Yi; Wang, Min; Shen, Hao

2013-08-01

Quality control of the inertial confinement fusion (ICF) target in the laser fusion program is vital to ensure that energy deposition from the lasers results in uniform compression and minimization of Rayleigh-Taylor instabilities. The technique of nuclear microscopy with ion beam analysis is a powerful method to provide characterization of ICF targets. Distribution of elements, depth profile, and density image of ICF targets can be identified by particle-induced X-ray emission, Rutherford backscattering spectrometry, and scanning transmission ion microscopy. We present examples of ICF target characterization by nuclear microscopy at Fudan University in order to demonstrate their potential impact in assessing target fabrication processes.

CRISPR-Cas9 nuclear dynamics and target recognition in living cells

PubMed Central

Ma, Hanhui; Tu, Li-Chun; Zhang, Shaojie; Grunwald, David

2016-01-01

The bacterial CRISPR-Cas9 system has been repurposed for genome engineering, transcription modulation, and chromosome imaging in eukaryotic cells. However, the nuclear dynamics of clustered regularly interspaced short palindromic repeats (CRISPR)–associated protein 9 (Cas9) guide RNAs and target interrogation are not well defined in living cells. Here, we deployed a dual-color CRISPR system to directly measure the stability of both Cas9 and guide RNA. We found that Cas9 is essential for guide RNA stability and that the nuclear Cas9–guide RNA complex levels limit the targeting efficiency. Fluorescence recovery after photobleaching measurements revealed that single mismatches in the guide RNA seed sequence reduce the target residence time from >3 h to as low as <2 min in a nucleotide identity- and position-dependent manner. We further show that the duration of target residence correlates with cleavage activity. These results reveal that CRISPR discriminates between genuine versus mismatched targets for genome editing via radical alterations in residence time. PMID:27551060

The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals.

PubMed

Macejova, Dana; Toporova, L; Brtko, J

2016-07-01

Retinoic acid (RA), an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR) and rexinoid nuclear receptors (RXR), which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl) and triphenyltin chloride (TPTCl), are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

In situ, accurate, surface-enhanced Raman scattering detection of cancer cell nucleus with synchronous location by an alkyne-labeled biomolecular probe.

PubMed

Zhang, Jing; Liang, Lijia; Guan, Xin; Deng, Rong; Qu, Huixin; Huang, Dianshuai; Xu, Shuping; Liang, Chongyang; Xu, Weiqing

2018-01-01

A surface-enhanced Raman scattering (SERS) method for in situ detection and analysis of the intranuclear biomolecular information of a cell has been developed based on a small, biocompatible, nuclear-targeting alkyne-tagged deoxyribonucleic acid (DNA) probe (5-ethynyl-2'-deoxyuridine, EDU) that can specially accumulate in the cell nucleus during DNA replications to precisely locate the nuclear region without disturbance in cell biological activities and functions. Since the specific alkyne group shows a Raman peak in the Raman-silent region of cells, it is an interior label to visualize the nuclear location synchronously in real time when measuring the SERS spectra of a cell. Because no fluorescent-labeled dyes were used for locating cell nuclei, this method is simple, nondestructive, non- photobleaching, and valuable for the in situ exploration of vital physiological processes with DNA participation in cell organelles. Graphical abstract A universal strategy was developed to accurately locate the nuclear region and obtain precise molecular information of cell nuclei by SERS.

Nuclear localization of Schizosaccharomyces pombe Mcm2/Cdc19p requires MCM complex assembly.

PubMed

Pasion, S G; Forsburg, S L

1999-12-01

The minichromosome maintenance (MCM) proteins MCM2-MCM7 are conserved eukaryotic replication factors that assemble in a heterohexameric complex. In fission yeast, these proteins are nuclear throughout the cell cycle. In studying the mechanism that regulates assembly of the MCM complex, we analyzed the cis and trans elements required for nuclear localization of a single subunit, Mcm2p. Mutation of any single mcm gene leads to redistribution of wild-type MCM subunits to the cytoplasm, and this redistribution depends on an active nuclear export system. We identified the nuclear localization signal sequences of Mcm2p and showed that these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p must associate with other MCM proteins for its proper localization; nuclear localization of MCM proteins thus requires assembly of MCM proteins in a complex. We suggest that coupling complex assembly to nuclear targeting and retention ensures that only intact heterohexameric MCM complexes remain nuclear.

Nuclear Localization of Schizosaccharomyces pombe Mcm2/Cdc19p Requires MCM Complex Assembly

PubMed Central

Pasion, Sally G.; Forsburg, Susan L.

1999-01-01

The minichromosome maintenance (MCM) proteins MCM2–MCM7 are conserved eukaryotic replication factors that assemble in a heterohexameric complex. In fission yeast, these proteins are nuclear throughout the cell cycle. In studying the mechanism that regulates assembly of the MCM complex, we analyzed the cis and trans elements required for nuclear localization of a single subunit, Mcm2p. Mutation of any single mcm gene leads to redistribution of wild-type MCM subunits to the cytoplasm, and this redistribution depends on an active nuclear export system. We identified the nuclear localization signal sequences of Mcm2p and showed that these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p must associate with other MCM proteins for its proper localization; nuclear localization of MCM proteins thus requires assembly of MCM proteins in a complex. We suggest that coupling complex assembly to nuclear targeting and retention ensures that only intact heterohexameric MCM complexes remain nuclear. PMID:10588642

Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer

DTIC Science & Technology

2014-09-01

Triple - negative breast cancer Mol Cancer Ther. 2014 May;13(5):1356-68. PMID: 24634415, PMCID: PMC4013210 6. Brand, TM, Iida, M...Receptor Is a Functional Molecular Target in Triple - Negative Breast Cancer . Molecular cancer therapeutics (2014). 11 26. Iida, M., Brand, T.M...2014). Brand, T.M., et al. Nuclear epidermal growth factor receptor is a functional molecular target in triple - negative breast cancer .

Three-nucleon force contribution in the distorted-wave theory of (d ,p ) reactions

NASA Astrophysics Data System (ADS)

Timofeyuk, N. K.

2018-05-01

The distorted-wave theory of A (d ,p )B reactions, widely used to analyze experimental data, is based on a Hamiltonian that includes only two-nucleon interactions. However, numerous studies of few-nucleon systems and many modern developments in nuclear structure theory show the importance of the three-nucleon (3 N ) force. The purpose of this paper is to study the contribution of the 3 N force of the simplest possible form to the A (d ,p )B reaction amplitude. This contribution is given by a new term that accounts for the interaction of the neutron and proton in the incoming deuteron with one of the target nucleons. This term involves a new type of nuclear matrix elements containing an infinite number of target excitations in addition to the main part associated with the traditional overlap function between A and B . The nuclear matrix elements are calculated for double-closed shell targets within a mean field theory where target excitations are shown to be equivalent to exchanges between valence and core nucleons. These matrix elements can be readily incorporated into available reaction codes if the 3 N interaction has a spin-independent zero-range form. Distorted-wave calculations are presented for a contact 3 N force with the volume integral fixed by the chiral effective field theory at the next-to-next-to-leading order. For this particular choice, the 3 N contribution is noticeable, especially at high deuteron incident energies. No 3 N effects are seen for incident energies below the Coulomb barrier. The finite range can significantly affect the 3 N contribution to the (d ,p ) cross sections. Finite-range studies require new formal developments and, therefore, their contribution is preliminarily assessed within the plane-wave Born approximation, together with sensitivity to the choice of the deuteron model.

Compact Short-Pulsed Electron Linac Based Neutron Sources for Precise Nuclear Material Analysis

NASA Astrophysics Data System (ADS)

Uesaka, M.; Tagi, K.; Matsuyama, D.; Fujiwara, T.; Dobashi, K.; Yamamoto, M.; Harada, H.

2015-10-01

An X-band (11.424GHz) electron linac as a neutron source for nuclear data study for the melted fuel debris analysis and nuclear security in Fukushima is under development. Originally we developed the linac for Compton scattering X-ray source. Quantitative material analysis and forensics for nuclear security will start several years later after the safe settlement of the accident is established. For the purpose, we should now accumulate more precise nuclear data of U, Pu, etc., especially in epithermal (0.1-10 eV) neutrons. Therefore, we have decided to modify and install the linac in the core space of the experimental nuclear reactor "Yayoi" which is now under the decommission procedure. Due to the compactness of the X-band linac, an electron gun, accelerating tube and other components can be installed in a small space in the core. First we plan to perform the time-of-flight (TOF) transmission measurement for study of total cross sections of the nuclei for 0.1-10 eV energy neutrons. Therefore, if we adopt a TOF line of less than 10m, the o-pulse length of generated neutrons should be shorter than 100 ns. Electronenergy, o-pulse length, power, and neutron yield are ~30 MeV, 100 ns - 1 micros, ~0.4 kW, and ~1011 n/s (~103 n/cm2/s at samples), respectively. Optimization of the design of a neutron target (Ta, W, 238U), TOF line and neutron detector (Ce:LiCAF) of high sensitivity and fast response is underway. We are upgrading the electron gun and a buncher to realize higher current and beam power with a reasonable beam size in order to avoid damage of the neutron target. Although the neutron flux is limited in case of the X-band electron linac based source, we take advantage of its short pulse aspect and availability for nuclear data measurement with a short TOF system. First, we form a tentative configuration in the current experimental room for Compton scattering in 2014. Then, after the decommissioning has been finished, we move it to the "Yayoi" room and perform the operation and measurement.

The necessity of nuclear reactors for targeted radionuclide therapies.

PubMed

Krijger, Gerard C; Ponsard, Bernard; Harfensteller, Mark; Wolterbeek, Hubert T; Nijsen, Johannes W F

2013-07-01

Nuclear medicine has been contributing towards personalized therapies. Nuclear reactors are required for the working horses of both diagnosis and treatment, i.e., Tc-99m and I-131. In fact, reactors will remain necessary to fulfill the demand for a variety of radionuclides and are essential in the expanding field of targeted radionuclide therapies for cancer. However, the main reactors involved in the global supply are ageing and expected to shut down before 2025. Therefore, the fields of (nuclear) medicine, nuclear industry and politics share a global responsibility, faced with the task to secure future access to suitable nuclear reactors. At the same time, alternative production routes should be industrialized. For this, a coordinating entity should be put into place. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fragmentation of relativistic nuclei in peripheral interactions in nuclear track emulsion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Artemenkov, D. A., E-mail: artemenkov@lhe.jinr.ru; Bradnova, V.; Chernyavsky, M. M.

2008-09-15

The technique of nuclear track emulsions is used to explore the fragmentation of light relativistic nuclei down to the most peripheral interactions: nuclear 'white' stars. A complete pattern of the relativistic dissociation of a 8B nucleus with target fragment accompaniment is presented. Relativistic dissociation {sup 9}Be {yields} 2{alpha} is explored using significant statistics, and a relative contribution of {sup 8}Be decays from 0+ and 2+ states is established. Target fragment accompaniments are shown for relativistic fragmentation {sup 14}N {yields} 3He +H and {sup 22}Ne {yields} 5He. The leading role of the electromagnetic dissociation on heavy nuclei with respect to breakupsmore » on target protons is demonstrated in all these cases. It is possible to conclude that the peripheral dissociation of relativistic nuclei in nuclear track emulsion is a unique tool to study many-body systems composed of the lightest nuclei and nucleons in the energy scale relevant for nuclear astrophysics.« less

In situ surface-enhanced Raman scattering spectroscopy exploring molecular changes of drug-treated cancer cell nucleus.

PubMed

Liang, Lijia; Huang, Dianshuai; Wang, Hailong; Li, Haibo; Xu, Shuping; Chang, Yixin; Li, Hui; Yang, Ying-Wei; Liang, Chongyang; Xu, Weiqing

2015-02-17

Investigating the molecular changes of cancer cell nucleus with drugs treatment is crucial for the design of new anticancer drugs, the development of novel diagnostic strategies, and the advancement of cancer therapy efficiency. In order to better understand the action effects of drugs, accurate location and in situ acquisition of the molecular information of the cell nuclei are necessary. In this work, we report a microspectroscopic technique called dark-field and fluorescence coimaging assisted surface-enhanced Raman scattering (SERS) spectroscopy, combined with nuclear targeting nanoprobes, to in situ study Soma Gastric Cancer (SGC-7901) cell nuclei treated with two model drugs, e.g., DNA binder (Hoechst33342) and anticancer drug (doxorubicin, Dox) via spectral analysis at the molecular level. Nuclear targeting nanoprobes with an assembly structure of thiol-modified polyethylene glycol polymers (PEG) and nuclear localizing signal peptides (NLS) around gold nanorods (AuNRs) were prepared to achieve the amplified SERS signals of biomolecules in the cell nuclei. With the assistance of dark field/fluorescence imaging with simultaneous location, in situ SERS spectra in one cell nucleus were measured and analyzed to disclose the effects of Hoechst33342 and Dox on main biomolecules in the cell nuclei. The experimental results show that this method possesses great potential to investigate the targets of new anticancer drugs and the real-time monitoring of the dynamic changes of cells caused by exogenous molecules.

Thin-target excitation functions and optimisation of NCA 64Cu and 66,67Ga production by deuteron induced nuclear reactions on natural zinc target, for radiometabolic therapy and for PET

NASA Astrophysics Data System (ADS)

Groppi, F.; Bonardi, M. L.; Birattari, C.; Gini, L.; Mainardi, C.; Menapace, E.; Abbas, K.; Holzwarth, U.; Stroosnijder, R. M. F.

2004-01-01

A novel method for production of No-Carrier-Added 64Cu and 66,67Ga has been developed, based on reactions induced by deuterons up to 19 MeV on Zn target. HPGe and beta (by LSC) spectrometries proved very effective to determine radionuclidic purity of 64Cu and 66,67Ga fractions. Experimental specific activity for 64Cu was measured by ET-AAS and was of the order of 700 MBq · μg -1. Radiochemical yields for 64Cu and 66,67Ga were >80% and >99%.

Catalysis of Nuclear Reactions by Electrons

NASA Astrophysics Data System (ADS)

Lipoglavšek, Matej

2018-01-01

Electron screening enhances nuclear reaction cross sections at low energies. We studied the nuclear reaction 1H(19F,αγ)16O in inverse kinematics in different solid hydrogen targets. Measured resonance strengths differed by up to a factor of 10 in different targets. We also studied the 2H(p,γ)3He fusion reaction and observed electrons emitted as reaction products instead of γ rays. In this case electron screening greatly enhances internal conversion probability.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Yi, E-mail: yihooyi@gmail.com; Ericsson, Ida, E-mail: ida.ericsson@ntnu.no; Doseth, Berit, E-mail: berit.doseth@ntnu.no

Activation-induced cytidine deaminase (AID) is the mutator enzyme in adaptive immunity. AID initiates the antibody diversification processes in activated B cells by deaminating cytosine to uracil in immunoglobulin genes. To some extent other genes are also targeted, which may lead to genome instability and B cell malignancy. Thus, it is crucial to understand its targeting and regulation mechanisms. AID is regulated at several levels including subcellular compartmentalization. However, the complex nuclear distribution and trafficking of AID has not been studied in detail previously. In this work, we examined the subnuclear localization of AID and its interaction partner CTNNBL1 and foundmore » that they associate with spliceosome-associated structures including Cajal bodies and nuclear speckles. Moreover, protein kinase A (PKA), which activates AID by phosphorylation at Ser38, is present together with AID in nuclear speckles. Importantly, we demonstrate that AID physically associates with the major spliceosome subunits (small nuclear ribonucleoproteins, snRNPs), as well as other essential splicing components, in addition to the transcription machinery. Based on our findings and the literature, we suggest a transcription-coupled splicing-associated model for AID targeting and activation. - Highlights: • AID and its interaction partner CTNNBL1 localize to Cajal bodies and nuclear speckles. • AID associates with its activating kinase PKA in nuclear speckles. • AID is linked to the splicing machinery in switching B-cells. • Our findings suggest a transcription-coupled splicing associated mechanism for AID targeting and activation.« less

Converting energy to medical progress [nuclear medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2001-04-01

For over 50 years the Office of Biological and Environmental Research (BER) of the United States Department of Energy (DOE) has been investing to advance environmental and biomedical knowledge connected to energy. The BER Medical Sciences program fosters research to develop beneficial applications of nuclear technologies for medical diagnosis and treatment of many diseases. Today, nuclear medicine helps millions of patients annually in the United States. Nearly every nuclear medicine scan or test used today was made possible by past BER-funded research on radiotracers, radiation detection devices, gamma cameras, PET and SPECT scanners, and computer science. The heart of biologicalmore » research within BER has always been the pursuit of improved human health. The nuclear medicine of tomorrow will depend greatly on today's BER-supported research, particularly in the discovery of radiopharmaceuticals that seek specific molecular and genetic targets, the design of advanced scanners needed to create meaningful images with these future radiotracers, and the promise of new radiopharmaceutical treatments for cancers and genetic diseases.« less

Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects.

PubMed

Bhardwaj, R; van der Meer, A; Das, S K; de Bruin, M; Gascon, J; Wolterbeek, H T; Denkova, A G; Serra-Crespo, P

2017-03-13

177 Lu has sprung as a promising radionuclide for targeted therapy. The low soft tissue penetration of its β - emission results in very efficient energy deposition in small-size tumours. Because of this, 177 Lu is used in the treatment of neuroendocrine tumours and is also clinically approved for prostate cancer therapy. In this work, we report a separation method that achieves the challenging separation of the physically and chemically identical nuclear isomers, 177m Lu and 177 Lu. The separation method combines the nuclear after-effects of the nuclear decay, the use of a very stable chemical complex and a chromatographic separation. Based on this separation concept, a new type of radionuclide generator has been devised, in which the parent and the daughter radionuclides are the same elements. The 177m Lu/ 177 Lu radionuclide generator provides a new production route for the therapeutic radionuclide 177 Lu and can bring significant growth in the research and development of 177 Lu based pharmaceuticals.

Converting Energy to Medical Progress [Nuclear Medicine

DOE R&D Accomplishments Database

2001-04-01

For over 50 years the Office of Biological and Environmental Research (BER) of the United States Department of Energy (DOE) has been investing to advance environmental and biomedical knowledge connected to energy. The BER Medical Sciences program fosters research to develop beneficial applications of nuclear technologies for medical diagnosis and treatment of many diseases. Today, nuclear medicine helps millions of patients annually in the United States. Nearly every nuclear medicine scan or test used today was made possible by past BER-funded research on radiotracers, radiation detection devices, gamma cameras, PET and SPECT scanners, and computer science. The heart of biological research within BER has always been the pursuit of improved human health. The nuclear medicine of tomorrow will depend greatly on today's BER-supported research, particularly in the discovery of radiopharmaceuticals that seek specific molecular and genetic targets, the design of advanced scanners needed to create meaningful images with these future radiotracers, and the promise of new radiopharmaceutical treatments for cancers and genetic diseases.

The interaction of RNA helicase DDX3 with HIV-1 Rev-CRM1-RanGTP complex during the HIV replication cycle

DOE PAGES

Mahboobi, Seyed Hanif; Javanpour, Alex A.; Mofrad, Mohammad R. K.

2015-02-27

Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. The human immunodeficiency virus (HIV) exploits the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Despite extensive study on the HIV life cycle and the many drugs developed to target this cycle, no current drugs have been successful in targeting the critical process of viral nuclear export, even though HIV’s reliance on a single host protein, CRM1, to export its unspliced and partially spliced RNAmore » transcripts makes it a tempting target. Due to recent findings implicating a DEAD-box helicase, DDX3, in HIV replication and a member of the export complex, it has become an appealing target for anti-HIV drug inhibition. In the present research, we have applied a hybrid computational protocol to analyze protein-protein interactions in the HIV mRNA export cycle. This method is based on molecular docking followed by molecular dynamics simulation and accompanied by approximate free energy calculation (MM/GBSA), computational alanine scanning, clustering, and evolutionary analysis. We highlight here some of the most likely binding modes and interfacial residues between DDX3 and CRM1 both in the absence and presence of RanGTP. This work shows that although DDX3 can bind to free CRM1, addition of RanGTP leads to more concentrated distribution of binding modes and stronger binding between CRM1 and RanGTP.« less

The interaction of RNA helicase DDX3 with HIV-1 Rev-CRM1-RanGTP complex during the HIV replication cycle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahboobi, Seyed Hanif; Javanpour, Alex A.; Mofrad, Mohammad R. K.

Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. The human immunodeficiency virus (HIV) exploits the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Despite extensive study on the HIV life cycle and the many drugs developed to target this cycle, no current drugs have been successful in targeting the critical process of viral nuclear export, even though HIV’s reliance on a single host protein, CRM1, to export its unspliced and partially spliced RNAmore » transcripts makes it a tempting target. Due to recent findings implicating a DEAD-box helicase, DDX3, in HIV replication and a member of the export complex, it has become an appealing target for anti-HIV drug inhibition. In the present research, we have applied a hybrid computational protocol to analyze protein-protein interactions in the HIV mRNA export cycle. This method is based on molecular docking followed by molecular dynamics simulation and accompanied by approximate free energy calculation (MM/GBSA), computational alanine scanning, clustering, and evolutionary analysis. We highlight here some of the most likely binding modes and interfacial residues between DDX3 and CRM1 both in the absence and presence of RanGTP. This work shows that although DDX3 can bind to free CRM1, addition of RanGTP leads to more concentrated distribution of binding modes and stronger binding between CRM1 and RanGTP.« less

Recent Trends in Antibody-based Oncologic Imaging

PubMed Central

Kaur, Sukhwinder; Venktaraman, Ganesh; Jain, Maneesh; Senapati, Shantibhusan; Garg, Pradeep K.; Batra, Surinder K.

2011-01-01

Antibodies, with their unmatched ability for selective binding to any target, are considered as potentially the most specific probes for imaging. Their clinical utility, however, has been limited chiefly due to their slow clearance from the circulation, longer retention in non-targeted tissues and the extensive optimization required for each antibody-tracer. The development of newer contrast agents, combined with improved conjugation strategies and novel engineered forms of antibodies (diabodies, minibodies, single chain variable fragments, and nanobodies), have triggered a new wave of antibody-based imaging approaches. Apart from their conventional use with nuclear imaging probes, antibodies and their modified forms are increasingly being employed with non-radioisotopic contrast agents (MRI and ultrasound) as well as newer imaging modalities, such as quantum dots, near infra red (NIR) probes, nanoshells and surface enhanced Raman spectroscopy (SERS). The review article provides new developments in the usage of antibodies and their modified forms in conjunction with probes of various imaging modalities such as nuclear imaging, optical imaging, ultrasound, MRI, SERS and nanoshells in preclinical and clinical studies on the diagnosis, prognosis and therapeutic responses of cancer. PMID:22104729

Inhibiting cancer cell hallmark features through nuclear export inhibition.

PubMed

Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

2016-01-01

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Outer nuclear membrane protein Kuduk modulates the LINC complex and nuclear envelope architecture

PubMed Central

Ding, Zhao-Ying; Huang, Yu-Cheng; Lee, Myong-Chol; Tseng, Min-Jen; Chi, Ya-Hui

2017-01-01

Linker of nucleoskeleton and cytoskeleton (LINC) complexes spanning the nuclear envelope (NE) contribute to nucleocytoskeletal force transduction. A few NE proteins have been found to regulate the LINC complex. In this study, we identify one, Kuduk (Kud), which can reside at the outer nuclear membrane and is required for the development of Drosophila melanogaster ovarian follicles and NE morphology of myonuclei. Kud associates with LINC complex components in an evolutionarily conserved manner. Loss of Kud increases the level but impairs functioning of the LINC complex. Overexpression of Kud suppresses NE targeting of cytoskeleton-free LINC complexes. Thus, Kud acts as a quality control mechanism for LINC-mediated nucleocytoskeletal connections. Genetic data indicate that Kud also functions independently of the LINC complex. Overexpression of the human orthologue TMEM258 in Drosophila proved functional conservation. These findings expand our understanding of the regulation of LINC complexes and NE architecture. PMID:28716842

Tale taming radioactive fears: Linking nuclear waste disposal to the "continuum of the good".

PubMed

Yli-Kauhaluoma, Sari; Hänninen, Hannu

2014-04-01

We examine how the constructor of the world's first repository for the final disposal of spent nuclear fuel in Eurajoki, Finland, aims to shape lay understanding of the facility's risks and to tame the nuclear fears of the local community by producing positive associations, imagery and tales. Our empirical material consists of the constructor's newsletters targeted mainly at the local residents. In the narrative analysis, we identified a storyline where the construction of the repository is linked into the "continuum of the good" in the municipality of the construction site and the surrounding areas. The storyline consists of five different themes all emphasizing the "continuum of the good" in the area: cultural heritage, well-being, developing expertise, natural environment, and local families. Our study contributes to the literature on pro-nuclear storytelling by showing how the inclination is towards narratives that are constructed around local symbols, cultural landmarks, and institutions.

Nuclear Receptors in Neurodegenerative Diseases

PubMed Central

Skerrett, Rebecca; Malm, Tarja; Landreth, Gary

2014-01-01

Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies. PMID:24874548

High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals.

PubMed

Ellison, Paul A; Barnhart, Todd E; Chen, Feng; Hong, Hao; Zhang, Yin; Theuer, Charles P; Cai, Weibo; Nickles, Robert J; DeJesus, Onofre T

2016-01-20

Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched (72)Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure (72)As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming (72)Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.

High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals

PubMed Central

Ellison, Paul A.; Barnhart, Todd E.; Chen, Feng; Hong, Hao; Zhang, Yin; Theuer, Charles P.; Cai, Weibo; Nickles, Robert J.; DeJesus, Onofre T.

2016-01-01

Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched 72Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure 72As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming 72Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation. PMID:26646989

Practicing DSAM in aberrant domain: use of multi-disciplinary techniques

NASA Astrophysics Data System (ADS)

Das, S.; Samanta, S.; Bhattacharjee, R.; Raut, R.; Ghugre, S. S.; Sinha, A. K.; Garg, U.; Chakrabarti, R.; Mukhopadhyay, S.; Madhavan, N.; Muralithar, S.; Singh, R. P.; Sethi, J.; Saha, S.; Palit, R.

2016-10-01

Measurement of level lifetime of nuclear states is of relevance in nuclear structure research as it provides us with an unique probe into the underlying microscopic structure of these states. Of the several experimental techniques for lifetime measurements, the Doppler Shift Attenuation Method (DSAM) is the one adopted for measuring lifetimes typically in the range of few tens of fs to few ps. The technique is based on the analysis of the observed Doppler affected gamma rays emitted by the recoils in flight. The crucial component in the related analysis is the simulation of the stopping process, of the residues of interest, in the target and the backing media. This requires calculation of the corresponding stopping powers and the same has been identified as one of the principal uncertainties in the extracted lifetime in DSAM. Traditionally the method is pursued with a thin target, for production of nuclei of interest, on a thick elemental backing wherein stopping process is perceived to occur. The present work in light of it's objectives uses a setup which is in sharp variance with the conventional scenario, such as the use of a thick molecular target, which contributes both to the production of the residues as well as their subsequent slowing down. This demanded extensive developments in the analysis procedure particularly in the domain of simulating the stopping process with due incorporation of the nuances of nuclear reaction kinematics besides subjecting the molecular medium to a detailed structural characterization, routinely carried out in the domain of material science. These developments have been used to extract the level lifetimes of nuclei at the interface of the sd & pf shells such as 26Mg, 29Si, and 32P.

National cyclotron centre at the Institute for Nuclear Research and Nuclear Energy

NASA Astrophysics Data System (ADS)

Tonev, D.; Goutev, N.; Asova, G.; Artinyan, A.; Demerdjiev, A.; Georgiev, L. S.; Yavahchova, M.; Bashev, V.; Genchev, S. G.; Geleva, E.; Mincheva, M.; Nikolov, A.; Dimitrov, D. T.

2018-05-01

An accelerator laboratory is presently under construction in Sofia at the Institute for Nuclear Research and Nuclear Energy. The laboratory will use a TR24 type of cyclotron, which provides a possibility to accelerate a proton beam with an energy of 15 to 24 MeV and current of up to 0.4 mA. An accelerator with such parameters allows to produce a large variety of radioisotopes for development of radiopharmaceuticals. The most common radioisotopes that can be produced with such a cyclotron are PET isotopes like: 11C, 13N, 15O, 18F, 124I, 64Cu, 68Ge/68Ga, and SPECT isotopes like: 123I, 111In, 67Ga, 57Co, 99mTc. Our aim is to use the cyclotron facility for research in the fields of radiopharmacy, radiochemistry, radiobiology, nuclear physics, materials sciences, applied research, new materials and for education in all these fields including nuclear energy. Presently we perform investigations in the fields of target design for production of radioisotopes, shielding and radioprotection, new ion sources etc.

Proton bombarded reactions of Calcium target nuclei

NASA Astrophysics Data System (ADS)

Tel, Eyyup; Sahan, Muhittin; Sarpün, Ismail Hakki; Kavun, Yusuf; Gök, Ali Armagan; Depedelen, Mesut

2017-09-01

In this study, proton bombarded nuclear reactions calculations of Calcium target nuclei have been investigated in the incident proton energy range of 1-50 MeV. The excitation functions for 40Ca target nuclei reactions have been calculated by using PCROSS nuclear reaction calculation code. Weisskopf-Ewing and the full exciton models were used for equilibrium and for pre-equilibrium calculations, respectively. The excitation functions for 40Ca target nuclei reactions (p,α), (p,n), (p,p) have been calculated using the semi-empirical formula Tel et al. [5].

Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.

PubMed

Okuhira, Keiichiro; Shoda, Takuji; Omura, Risa; Ohoka, Nobumichi; Hattori, Takayuki; Shibata, Norihito; Demizu, Yosuke; Sugihara, Ryo; Ichino, Asato; Kawahara, Haruka; Itoh, Yukihiro; Ishikawa, Minoru; Hashimoto, Yuichi; Kurihara, Masaaki; Itoh, Susumu; Saito, Hiroyuki; Naito, Mikihiko

2017-03-01

Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Conceptual design considerations and neutronics of lithium fall laser fusion target chambers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meier, W.R.; Thomson, W.B.

1978-05-31

Atomics International and Lawrence Livermore Laboratory are involved in the conceptual design of a laser fusion power plant incorporating the lithium fall target chamber. In this paper we discuss some of the more important design considerations for the target chamber and evaluate its nuclear performance. Sizing and configuration of the fall, hydraulic effects, and mechanical design considerations are addressed. The nuclear aspects examined include tritium breeding, energy deposition, and radiation damage.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doyle, Jamie L.; Kuhn, Kevin John; Byerly, Benjamin

Nuclear forensic publications, performance tests, and research and development efforts typically target the bulk global inventory of intentionally safeguarded materials, such as plutonium (Pu) and uranium (U). Other materials, such as neptunium (Np), pose a nuclear security risk as well. Trafficking leading to recovery of an interdicted Np sample is a realistic concern especially for materials originating in countries that reprocesses fuel. Using complementary forensic methods, potential signatures for an unknown Np oxide sample were investigated. Measurement results were assessed against published Np processes to present hypotheses as to the original intended use, method of production, and origin for thismore » Np oxide.« less

A radial time projection chamber for α detection in CLAS at JLab

DOE PAGES

Dupre, R.; Stepanyan, S.; Hattawy, M.; ...

2018-08-01

A new Radial Time Projection Chamber (RTPC) was developed at the Jefferson Laboratory to track low-energy nuclear recoils to measure exclusive nuclear reactions, such as coherent deeply virtual Compton scattering and coherent meson production off 4He. In 2009, we carried out these measurements using the CEBAF Large Acceptance Spectrometer (CLAS) supplemented by the RTPC positioned directly around a gaseous 4He target, allowing a detection threshold as low as 12 MeV for 4He. This work discusses the design, principle of operation, calibration methods and performances of this RTPC.

Coherent photon scattering background in sub- GeV / c 2 direct dark matter searches

DOE PAGES

Robinson, Alan E.

2017-01-18

Here, proposed dark matter detectors with eV-scale sensitivities will detect a large background of atomic (nuclear) recoils from coherent photon scattering of MeV-scale photons. This background climbs steeply below ~10 eV, far exceeding the declining rate of low-energy Compton recoils. The upcoming generation of dark matter detectors will not be limited by this background, but further development of eV-scale and sub-eV detectors will require strategies, including the use of low nuclear mass target materials, to maximize dark matter sensitivity while minimizing the coherent photon scattering background.

A radial time projection chamber for α detection in CLAS at JLab

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dupre, R.; Stepanyan, S.; Hattawy, M.

A new Radial Time Projection Chamber (RTPC) was developed at the Jefferson Laboratory to track low-energy nuclear recoils to measure exclusive nuclear reactions, such as coherent deeply virtual Compton scattering and coherent meson production off 4He. In 2009, we carried out these measurements using the CEBAF Large Acceptance Spectrometer (CLAS) supplemented by the RTPC positioned directly around a gaseous 4He target, allowing a detection threshold as low as 12 MeV for 4He. This work discusses the design, principle of operation, calibration methods and performances of this RTPC.

Estrogen Sensitivity of Target Genes and Expression of Nuclear Receptor Co-Regulators in Rat Prostate after Pre- and Postnatal Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor

PubMed Central

Durrer, Stefan; Ehnes, Colin; Fuetsch, Michaela; Maerkel, Kirsten; Schlumpf, Margret; Lichtensteiger, Walter

2007-01-01

Background and objectives In previous studies, we found that the ultraviolet filter 4-methyl-benzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER)-β ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development. Methods 4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription–polymerase chain reaction and protein was determined by Western blot analysis. Results 4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR), insulin-like growth factor-1 (IGF-1), ER-α, and ER-β expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17β-estradiol (E2; 10 or 50 μg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E2, studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected. Conclusions Our data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation. PMID:18174949

Polarized targets in high energy physics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cates, G.D. Jr.

1994-12-01

Various approaches are discussed for producing polarized nuclear targets for high energy physics experiments. As a unifying theme, examples are drawn from experiments to measure spin dependent structure functions of nucleons in deep inelastic scattering. This single physics goal has, over roughly two decades, been a driving force in advances in target technology. Actual or planned approaches have included solid targets polarized by dynamic nuclear polarization (DNP), several types of internal targets for use in storage rings, and gaseous {sup 3}He targets polarized by spin-exchange optical pumping. This last approach is the type of target adopted for SLAC E-142, anmore » experiment to measure the spin structure function of the neutron, and is described in detail.« less

Nuclear Transcription Factors in the Mitochondria: A New Paradigm in Fine-Tuning Mitochondrial Metabolism.

PubMed

Sepuri, Naresh Babu V; Tammineni, Prasad; Mohammed, Fareed; Paripati, Arunkumar

2017-01-01

Noncanonical functions of several nuclear transcription factors in the mitochondria have been gaining exceptional traction over the years. These transcription factors include nuclear hormone receptors like estrogen, glucocorticoid, and thyroid hormone receptors: p53, IRF3, STAT3, STAT5, CREB, NF-kB, and MEF-2D. Mitochondria-localized nuclear transcription factors regulate mitochondrial processes like apoptosis, respiration and mitochondrial transcription albeit being nuclear in origin and having nuclear functions. Hence, the cell permits these multi-stationed transcription factors to orchestrate and fine-tune cellular metabolism at various levels of operation. Despite their ubiquitous distribution in different subcompartments of mitochondria, their targeting mechanism is poorly understood. Here, we review the current status of mitochondria-localized transcription factors and discuss the possible targeting mechanism besides the functional interplay between these factors.

An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies.

PubMed

Komatsu, Tetsuro; Nagata, Kyosuke; Wodrich, Harald

2016-02-01

Promyelocytic leukemia protein nuclear bodies (PML-NBs) are subnuclear domains implicated in cellular antiviral responses. Despite the antiviral activity, several nuclear replicating DNA viruses use the domains as deposition sites for the incoming viral genomes and/or as sites for viral DNA replication, suggesting that PML-NBs are functionally relevant during early viral infection to establish productive replication. Although PML-NBs and their components have also been implicated in the adenoviral life cycle, it remains unclear whether incoming adenoviral genome complexes target PML-NBs. Here we show using immunofluorescence and live-cell imaging analyses that incoming adenovirus genome complexes neither localize at nor recruit components of PML-NBs during early phases of infection. We further show that the viral DNA binding protein (DBP), an early expressed viral gene and essential DNA replication factor, independently targets PML-NBs. We show that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. Depletion experiments suggest that the absence of one PML-NB component might not affect the recruitment of other components toward DBP oligomers. Thus, our findings suggest a model in which an adenoviral DNA replication factor, but not incoming viral genome complexes, targets and modulates PML-NBs to support a conducive state for viral DNA replication and argue against a generalized concept that PML-NBs target incoming viral genomes. The immediate fate upon nuclear delivery of genomes of incoming DNA viruses is largely unclear. Early reports suggested that incoming genomes of herpesviruses are targeted and repressed by PML-NBs immediately upon nuclear import. Genome localization and/or viral DNA replication has also been observed at PML-NBs for other DNA viruses. Thus, it was suggested that PML-NBs may immediately sense and target nuclear viral genomes and hence serve as sites for deposition of incoming viral genomes and/or subsequent viral DNA replication. Here we performed a detailed analyses of the spatiotemporal distribution of incoming adenoviral genome complexes and found, in contrast to the expectation, that an adenoviral DNA replication factor, but not incoming genomes, targets PML-NBs. Thus, our findings may explain why adenoviral genomes could be observed at PML-NBs in earlier reports but argue against a generalized role for PML-NBs in targeting invading viral genomes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

NXT1, a Novel Influenza A NP Binding Protein, Promotes the Nuclear Export of NP via a CRM1-Dependent Pathway.

PubMed

Chutiwitoonchai, Nopporn; Aida, Yoko

2016-07-28

Influenza remains a serious worldwide public health problem. After infection, viral genomic RNA is replicated in the nucleus and packed into viral ribonucleoprotein, which will then be exported to the cytoplasm via a cellular chromosome region maintenance 1 (CRM1)-dependent pathway for further assembly and budding. However, the nuclear export mechanism of influenza virus remains controversial. Here, we identify cellular nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1) as a novel binding partner of nucleoprotein (NP) that stimulates NP-mediated nuclear export via the CRM1-dependent pathway. NXT1-knockdown cells exhibit decreased viral replication kinetics and nuclear accumulated viral RNA and NP. By contrast, NXT1 overexpression promotes nuclear export of NP in a CRM1-dependent manner. Pull-down assays suggest the formation of an NXT1, NP, and CRM1 complex, and demonstrate that NXT1 binds to the C-terminal region of NP. These findings reveal a distinct mechanism for nuclear export of the influenza virus and identify the NXT1/NP interaction as a potential target for antiviral drug development.

Protein Targeting: ER Leads the Way to the Inner Nuclear Envelope.

PubMed

Blackstone, Craig

2017-12-04

Efficient targeting of newly synthesized membrane proteins from the endoplasmic reticulum to the inner nuclear membrane depends on nucleotide hydrolysis. A new study shows that this dependence reflects critical actions of the atlastin family of GTPases in maintaining the morphology of the endoplasmic reticulum network. Published by Elsevier Ltd.

Conditionally controlling nuclear trafficking in yeast by chemical-induced protein dimerization

PubMed Central

Xu, Tao; Johnson, Cole A; Gestwicki, Jason E; Kumar, Anuj

2016-01-01

We present here a protocol to conditionally control the nuclear trafficking of target proteins in yeast. In this system, rapamycin is used to heterodimerize two chimeric proteins. one chimera consists of a FK506-binding protein (FKBp12) fused to a cellular ‘address’ (nuclear localization signal or nuclear export sequence). the second chimera consists of a target protein fused to a fluorescent protein and the FKBp12-rapamycin-binding (FrB) domain from FKBp-12-rapamycin associated protein 1 (Frap1, also known as mtor). rapamycin induces dimerization of the FKBp12- and FrB-containing chimeras; these interactions selectively place the target protein under control of the cell address, thereby directing the protein into or out of the nucleus. By chemical-induced dimerization, protein mislocalization is reversible and enables the identification of conditional loss-of-function and gain-of-function phenotypes, in contrast to other systems that require permanent modification of the targeted protein. Yeast strains for this analysis can be constructed in 1 week, and the technique allows protein mislocalization within 15 min after drug treatment. PMID:21030958

Conditionally controlling nuclear trafficking in yeast by chemical-induced protein dimerization.

PubMed

Xu, Tao; Johnson, Cole A; Gestwicki, Jason E; Kumar, Anuj

2010-11-01

We present here a protocol to conditionally control the nuclear trafficking of target proteins in yeast. In this system, rapamycin is used to heterodimerize two chimeric proteins. One chimera consists of a FK506-binding protein (FKBP12) fused to a cellular 'address' (nuclear localization signal or nuclear export sequence). The second chimera consists of a target protein fused to a fluorescent protein and the FKBP12-rapamycin-binding (FRB) domain from FKBP-12-rapamycin associated protein 1 (FRAP1, also known as mTor). Rapamycin induces dimerization of the FKBP12- and FRB-containing chimeras; these interactions selectively place the target protein under control of the cell address, thereby directing the protein into or out of the nucleus. By chemical-induced dimerization, protein mislocalization is reversible and enables the identification of conditional loss-of-function and gain-of-function phenotypes, in contrast to other systems that require permanent modification of the targeted protein. Yeast strains for this analysis can be constructed in 1 week, and the technique allows protein mislocalization within 15 min after drug treatment.

Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis.

PubMed

Cui, Qi; Yang, Su; Ye, Peng; Tian, E; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D; Rossi, John J; Shi, Yanhong

2016-02-03

Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.

Target development for 67Cu, 82Sr radionuclide production at the RIC-80 facility

NASA Astrophysics Data System (ADS)

Panteleev, V. N.; Barzakh, A. E.; Batist, L. Kh.; Fedorov, D. V.; Ivanov, V. S.; Krotov, S. A.; Molkanov, P. L.; Moroz, F. V.; Orlov, S. Yu.; Volkov, Yu. M.

2018-01-01

A high-current cyclotron C-80 capable of producing 40-80 MeV proton beams with a current of up to 200 μA has been constructed and commissioned at PNPI (Petersburg Nuclear Physics Institute). One of the main goals of cyclotron C-80 is the production of a wide spectrum of medical radionuclides for diagnostics and therapy. To date, the project development of a radioisotope facility RIC-80 (radioisotopes at cyclotron C-80) has been completed. The feature of the project is the use of a mass-separator combined with the ion-target device for obtaining ion beams of radioisotopes with a high purity of separation that is especially important for medical applications. The first results of a new high-temperature method for extracting 82Sr and 67Cu radioisotopes from irradiated targets have been presented.

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.

PubMed

Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T; Gage, Fred H; Evans, Ronald M

2006-05-15

During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx-/- mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx-/- mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.

Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

PubMed Central

Zhao, Xiaodong; Bao, Liming; Huang, Daochao; Song, Lihua; Li, Yang

2016-01-01

Aberrant STAT3 activation occurs in most human gastric cancers (GCs) and contributes to the malignant progression of GC, but mechanism(s) underlying aberrant STAT3 remain largely unknown. Here we demonstrated that the gene associated with retinoid interferon-induced mortality 19 (GRIM-19) was severely depressed or lost in GC and chronic atrophic gastritis (CAG) tissues and its loss contributed to GC tumorigenesis partly by activating STAT3 signaling. In primary human GC tissues, GRIM-19 was frequently depressed or lost and this loss correlated with advanced clinical stage, lymph node metastasis, H. pylori infection and poor overall survival of GC patients. In CAG tissues, GRIM-19 was progressively decreased along with its malignant transformation. Functionally, we indentified an oncogenic role of GRIM-19 loss in promoting GC tumorigenesis. Ectopic GRIM-19 expression suppressed GC tumor formation in vitro and in vivo by inducing cell cycle arrest and apoptosis. Moreover, we revealed that GRIM-19 inhibited STAT3 transcriptional activation and its downstream targets by reducing STAT3 nuclear distribution. Conversely, knockdown of GRIM-19 induced aberrant STAT3 activation and accelerated GC cell growth in vitro and in vivo, and this could be partly attenuated by the blockage of STAT3 activation. In addition, we observed subcellular redistributions of GRIM-19 characterized by peri-nuclear aggregates, non-mitochondria cytoplasmic distribution and nuclear invasion, which should be responsible for reduced STAT3 nuclear distribution. Our studies suggest that mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for GC development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of GC. PMID:27167343

Simultaneous live imaging of the transcription and nuclear position of specific genes

PubMed Central

Ochiai, Hiroshi; Sugawara, Takeshi; Yamamoto, Takashi

2015-01-01

The relationship between genome organization and gene expression has recently been established. However, the relationships between spatial organization, dynamics, and transcriptional regulation of the genome remain unknown. In this study, we developed a live-imaging method for simultaneous measurements of the transcriptional activity and nuclear position of endogenous genes, which we termed the ‘Real-time Observation of Localization and EXpression (ROLEX)’ system. We demonstrated that ROLEX is highly specific and does not affect the expression level of the target gene. ROLEX enabled detection of sub-genome-wide mobility changes that depended on the state of Nanog transactivation in embryonic stem cells. We believe that the ROLEX system will become a powerful tool for exploring the relationship between transcription and nuclear dynamics in living cells. PMID:26092696

An Investigation into the Transportation of Irradiated Uranium/Aluminum Targets from a Foreign Nuclear Reactor to the Chalk River Laboratories Site in Ontario, Canada - 12249

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clough, Malcolm; Jackson, Austin

2012-07-01

This investigation required the selection of a suitable cask and development of a device to hold and transport irradiated targets from a foreign nuclear reactor to the Chalk River Laboratories in Ontario, Canada. The main challenge was to design and validate a target holder to protect the irradiated HEU-Al target pencils during transit. Each of the targets was estimated to have an initial decay heat of 118 W prior to transit. As the targets have little thermal mass the potential for high temperature damage and possibly melting was high. Thus, the primary design objective was to conceive a target holdermore » to dissipate heat from the targets. Other design requirements included securing the targets during transportation and providing a simple means to load and unload the targets while submerged five metres under water. A unique target holder (patent pending) was designed and manufactured together with special purpose experimental apparatus including a representative cask. Aluminum dummy targets were fabricated to accept cartridge heaters, to simulate decay heat. Thermocouples were used to measure the temperature of the test targets and selected areas within the target holder and test cask. After obtaining test results, calculations were performed to compensate for differences between experimental and real life conditions. Taking compensation into consideration the maximum target temperature reached was 231 deg. C which was below the designated maximum of 250 deg. C. The design of the aluminum target holder also allowed generous clearance to insert and unload the targets. This clearance was designed to close up as the target holder is placed into the cavity of the transport cask. Springs served to retain and restrain the targets from movement during transportation as well as to facilitate conductive heat transfer. The target holder met the design requirements and as such provided data supporting the feasibility of transporting targets over a relatively long period of time. A suitable transport cask was selected and a device for housing irradiated targets for loading, unloading and transportation has been designed, built and validated. The device was successful in meeting all design requirements for this feasibility study. Experiments were conducted with a custom test facility to confirm that the design met the maximum temperature requirements during shipping. Results from tests showed that the peak temperature in the apparatus was 300 deg. C. By compensating for experimental considerations, such as reduced thermal conductivity of the test cask versus that of the actual cask the expected maximum target temperature reduces to 231 deg. C. This is below the designated peak value of 250 deg. C. It can therefore be concluded, based on the content of this paper and from a heat-removal standpoint, the feasibility of transporting targets from a foreign nuclear reactor to Canada is possible, although further testing with irradiated targets and a full size cask would be a recommended next step. (authors)« less

Importin α1 is required for nuclear import of herpes simplex virus proteins and capsid assembly in fibroblasts and neurons

PubMed Central

Anderson, Fenja; Rother, Franziska; Rudolph, Kathrin; Prank, Ute; Binz, Anne; Hügel, Stefanie; Hartmann, Enno; Bader, Michael; Bauerfeind, Rudolf; Sodeik, Beate

2018-01-01

Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in a small targeted siRNA screen to be important for herpes simplex virus (HSV-1) gene expression. Production of infectious virions was delayed in the absence of importin α1, but not in cells lacking importin α3 or importin α4. While nuclear targeting of the incoming capsids, of the HSV-1 transcription activator VP16, and of the viral genomes were not affected, the nuclear import of the HSV-1 proteins ICP4 and ICP0, required for efficient viral transcription, and of ICP8 and pUL42, necessary for DNA replication, were reduced. Furthermore, quantitative electron microscopy showed that fibroblasts lacking importin α1 contained overall fewer nuclear capsids, but an increased proportion of mature nuclear capsids indicating that capsid formation and capsid egress into the cytoplasm were impaired. In neurons, importin α1 was also not required for nuclear targeting of incoming capsids, but for nuclear import of ICP4 and for the formation of nuclear capsid assembly compartments. Our data suggest that importin α1 is specifically required for the nuclear localization of several important HSV1 proteins, capsid assembly, and capsid egress into the cytoplasm, and may become rate limiting in situ upon infection at low multiplicity or in terminally differentiated cells such as neurons. PMID:29304174

Research and development on materials for the SPES target

NASA Astrophysics Data System (ADS)

Corradetti, Stefano; Andrighetto, Alberto; Manzolaro, Mattia; Scarpa, Daniele; Vasquez, Jesus; Rossignoli, Massimo; Monetti, Alberto; Calderolla, Michele; Prete, Gianfranco

2014-03-01

The SPES project at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro) is focused on the production of radioactive ion beams. The core of the SPES facility is constituted by the target, which will be irradiated with a 40 MeV, 200 µA proton beam in order to produce radioactive species. In order to efficiently produce and release isotopes, the material constituting the target should be able to work under extreme conditions (high vacuum and temperatures up to 2000 °C). Both neutron-rich and proton-rich isotopes will be produced; in the first case, carbon dispersed uranium carbide (UCx) will be used as a target, whereas to produce p-rich isotopes, several types of targets will have to be irradiated. The synthesis and characterization of different types of material will be reported. Moreover, the results of irradiation and isotopes release tests on different uranium carbide target prototypes will be discussed.

Nuclear Security: Target Analysis-rev

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Surinder Paul; Gibbs, Philip W.; Bultz, Garl A.

2014-03-01

The objectives of this presentation are to understand target identification, including roll-up and protracted theft; evaluate target identification in the SNRI; recognize the target characteristics and consequence levels; and understand graded safeguards.

PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

PubMed

Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2018-05-03

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

Anti-inflammatory Effects of Cardamonin in Ovarian Cancer Cells Are Mediated via mTOR Suppression.

PubMed

Chen, Huajiao; Shi, Daohua; Niu, Peiguang; Zhu, Yanting; Zhou, Jintuo

2018-05-17

Cardamonin exhibits a variety of pharmacological activities including anti-inflammatory and antitumor, which are correlated with the inhibition of nuclear factor-kappaB and the mammalian target of rapamycin, respectively. However, whether the anti-inflammatory effects of cardamonin are mediated by the mammalian target of rapamycin remains unknown. In this study, ovarian cancer SKOV3 cells were cultured with lipopolysaccharide to induce inflammation, and the inhibitory effects and underlying molecular mechanisms of cardamonin were investigated using specific inhibitors of the mammalian target of rapamycin and the nuclear factor-kappaB pathway (rapamycin and pyrrolidine dithiocarbamate, respectively). Our results indicated that cardamonin inhibited the viability of normal and lipopolysaccharide-pretreated SKOV3 cells in a concentration-dependent manner. In accordance with rapamycin, the activation of the mammalian target of rapamycin and its downstream target, ribosomal protein S6 kinase 1, was inhibited by cardamonin, while pyrrolidine dithiocarbamate substantially blocked nuclear factor-kappaB activation and mildly inhibited the phosphorylation of the mammalian target of rapamycin and ribosomal protein S6 kinase 1. Pretreated with pyrrolidine dithiocarbamate, the effect of cardamonin on the mammalian target of rapamycin signalling was not affected, but the expression of inflammatory factors was further reduced. In cells pretreated with rapamycin, the inhibitory effects of cardamonin were completely suppressed with regards to the phosphorylation of the mammalian target of rapamycin, ribosomal protein S6 kinase 1, TNF- α , and interleukin-6, and nuclear factor-kappaB p65 protein expression was decreased. In conclusion, our findings indicate that the anti-inflammatory effects of cardamonin are correlated with mammalian target of rapamycin inhibition. Georg Thieme Verlag KG Stuttgart · New York.

Hyb-Seq: Combining target enrichment and genome skimming for plant phylogenomics1

PubMed Central

Weitemier, Kevin; Straub, Shannon C. K.; Cronn, Richard C.; Fishbein, Mark; Schmickl, Roswitha; McDonnell, Angela; Liston, Aaron

2014-01-01

• Premise of the study: Hyb-Seq, the combination of target enrichment and genome skimming, allows simultaneous data collection for low-copy nuclear genes and high-copy genomic targets for plant systematics and evolution studies. • Methods and Results: Genome and transcriptome assemblies for milkweed (Asclepias syriaca) were used to design enrichment probes for 3385 exons from 768 genes (>1.6 Mbp) followed by Illumina sequencing of enriched libraries. Hyb-Seq of 12 individuals (10 Asclepias species and two related genera) resulted in at least partial assembly of 92.6% of exons and 99.7% of genes and an average assembly length >2 Mbp. Importantly, complete plastomes and nuclear ribosomal DNA cistrons were assembled using off-target reads. Phylogenomic analyses demonstrated signal conflict between genomes. • Conclusions: The Hyb-Seq approach enables targeted sequencing of thousands of low-copy nuclear exons and flanking regions, as well as genome skimming of high-copy repeats and organellar genomes, to efficiently produce genome-scale data sets for phylogenomics. PMID:25225629

Track reconstruction in the emulsion-lead target of the OPERA experiment using the ESS microscope

NASA Astrophysics Data System (ADS)

Arrabito, L.; Bozza, C.; Buontempo, S.; Consiglio, L.; Cozzi, M.; D'Ambrosio, N.; DeLellis, G.; DeSerio, M.; Di Capua, F.; Di Ferdinando, D.; Di Marco, N.; Ereditato, A.; Esposito, L. S.; Fini, R. A.; Giacomelli, G.; Giorgini, M.; Grella, G.; Ieva, M.; Janicsko Csathy, J.; Juget, F.; Kreslo, I.; Laktineh, I.; Manai, K.; Mandrioli, G.; Marotta, A.; Migliozzi, P.; Monacelli, P.; Moser, U.; Muciaccia, M. T.; Pastore, A.; Patrizii, L.; Petukhov, Y.; Pistillo, C.; Pozzato, M.; Romano, G.; Rosa, G.; Russo, A.; Savvinov, N.; Schembri, A.; Scotto Lavina, L.; Simone, S.; Sioli, M.; Sirignano, C.; Sirri, G.; Strolin, P.; Tioukov, V.; Waelchli, T.

2007-05-01

The OPERA experiment, designed to conclusively prove the existence of νμ→ντ oscillations in the atmospheric sector, makes use of a massive lead-nuclear emulsion target to observe the appearance of ντ's in the CNGS νμ beam. The location and analysis of the neutrino interactions in quasi real-time required the development of fast computer-controlled microscopes able to reconstruct particle tracks with sub-micron precision and high efficiency at a speed of ~20 cm2/h. This paper describes the performance in particle track reconstruction of the European Scanning System, a novel automatic microscope for the measurement of emulsion films developed for OPERA.

Mitochondrial DNA disease—molecular insights and potential routes to a cure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, Oliver; Turnbull, Doug, E-mail: doug.turnbull@newcastle.ac.uk

2014-07-01

Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current treatments for these disorders are focussed on the management of the symptoms, rather than the correction of biochemical defects caused by the mutation. This review focuses on the molecular effects of mutations, the symptoms they cause and current work focusing on the development of targeted treatments for mitochondrial DNA disease. - Highlights: • We discuss several common disease causing mtDNA mutations. • We highlight recent work linking pathogenicity to deletion size and heteroplasmy. • We discuss recent advancesmore » in the development of targeted mtDNA disease treatments.« less

Monte-Carlo Geant4 numerical simulation of experiments at 247-MeV proton microscope

NASA Astrophysics Data System (ADS)

Kantsyrev, A. V.; Skoblyakov, A. V.; Bogdanov, A. V.; Golubev, A. A.; Shilkin, N. S.; Yuriev, D. S.; Mintsev, V. B.

2018-01-01

A radiographic facility for an investigation of fast dynamic processes with areal density of targets up to 5 g/cm2 is under development on the basis of high-current proton linear accelerator at the Institute for Nuclear Research (Troitsk, Russia). A virtual model of the proton microscope developed in a software toolkit Geant4 is presented in the article. Fullscale Monte-Carlo numerical simulation of static radiographic experiments at energy of a proton beam 247 MeV was performed. The results of simulation of proton radiography experiments with static model of shock-compressed xenon are presented. The results of visualization of copper and polymethyl methacrylate step wedges static targets also described.

Preparation and characterization of vinculin-targeted polymer-lipid nanoparticle as intracellular delivery vehicle.

PubMed

Wang, Junping; Ornek-Ballanco, Ceren; Xu, Jiahua; Yang, Weiguo; Yu, Xiaojun

2013-01-01

Intracellular delivery vehicles have been extensively investigated as these can serve as an effective tool in studying the cellular mechanism, by delivering functional protein to specific locations of the cells. In the current study, a polymer-lipid nanoparticle (PLN) system was developed as an intracellular delivery vehicle specifically targeting vinculin, a focal adhesion protein associated with cellular adhesive structures, such as focal adhesions and adherens junctions. The PLNs possessed an average size of 106 nm and had a positively charged surface. With a lower encapsulation efficiency 32% compared with poly(lactic-co-glycolic) acid (PLGA) nanoparticles (46%), the PLNs showed the sustained release profile of model drug BSA, while PLGA nanoparticles demonstrated an initial burst-release property. Cell-uptake experiments using mouse embryonic fibroblasts cultured in fibrin-fibronectin gels observed, under confocal microscope, that the anti-vinculin conjugated PLNs could successfully ship the cargo to the cytoplasm of fibroblasts, adhered to fibronectin-fibrin. With the use of cationic lipid, the unconjugated PLNs were shown to have high gene transfection efficiency. Furthermore, the unconjugated PLNs had nuclear-targeting capability in the absence of nuclear-localization signals. Therefore, the PLNs could be manipulated easily via different type of targeting ligands and could potentially be used as a powerful tool for cellular mechanism study, by delivering drugs to specific cellular organelles.

Cytogenetic toxicity and gonadal effects of 17 α-methyltestosterone in Astyanax bimaculatus (Characidae) and Oreochromis niloticus (Cichlidae).

PubMed

Rivero-Wendt, C L G; Miranda-Vilela, A L; Ferreira, M F N; Borges, A M; Grisolia, C K

2013-09-23

The synthetic hormone, 17-α-methyltestosterone (MT), is used in fish hatcheries to induce male monosex. Androgenic effects on various fish species have been reported; however, few studies have assessed possible genotoxic effects, although there are concerns about such effects in target and non-target species. We evaluated genotoxic and gonadal effects of MT in adult tilapia (Oreochromis niloticus) and Astyanax bimaculatus (a common native non-target fish in Brazil). Fish were fed for 28 days with ration containing MT (60 mg/L), a normal dose used in fish farming. Evaluation of MT genotoxicity was carried out through micronucleus test, nuclear abnormality, and comet assay analyses on peripheral erythrocyte cells collected by cardiac puncture. There were no significant differences in micronucleus frequencies and DNA damage in both species; however, MT caused cytogenetic toxicity in the non-target species, A. bimaculatus, with significantly increased erythrocyte nuclear abnormalities. Histopathological analyses of the female gonads of O. niloticus revealed that MT significantly inhibited the development of mature oocytes, while in A. bimaculatus it provoked significant inhibition of spermatozoa production. We concluded that discharge of fish-hatcheries water onto the surface of aquatic ecosystems should be avoided due to risks to reproduction of native species.

Spes: An intense source of Neutron-Rich Radioactive Beams at Legnaro

NASA Astrophysics Data System (ADS)

Andrighetto, A.; Manzolaro, M.; Corradetti, S.; Scarpa, D.; Monetti, A.; Rossignoli, M.; Ballan, M.; Borgna, F.; D'Agostini, F.; Gramegna, F.; Prete, G.; Meneghetti, G.; Ferrari, M.; Zenoni, A.

2018-02-01

The Isotope Separation On-Line (ISOL) method for the production of Radioactive Ion Beams (RIB) is attracting significant interest in the worldwide nuclear physics community. Within this context the SPES (Selective Production of Exotic Species) RIB facility is now under construction at INFN LNL (Istituto Nazionale di Fisica Nucleare Laboratori Nazionali di Legnaro). This technique is established as one of the main techniques for high intensity and high quality beams production. The SPES facility will produce n-rich isotopes by means of a 40 MeV proton beam, emitted by a cyclotron, impinging on a uranium carbide multi-foil fission target. The aim of this work is to describe the most important results obtained by the study of the on-line behavior of the SPES production target assembly. This target system will produce RIBs at a rate of about 1013 fissions per second, it will be able to dissipate a total power of up to 10 kW, and it is planned to work continuously for 2 week-runs of irradiation. ISOL beams of 24 different elements will be produced, therefore a target and ion source development is ongoing to ensure a great variety of produced isotopes and to improve the beam intensity and purity.

Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina

PubMed Central

Mollema, Nissa J.; Yuan, Yang; Jelcick, Austin S.; Sachs, Andrew J.; von Alpen, Désirée; Schorderet, Daniel; Escher, Pascal; Haider, Neena B.

2011-01-01

The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function. PMID:21408158

Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins.

PubMed

Harr, Jennifer C; Luperchio, Teresa Romeo; Wong, Xianrong; Cohen, Erez; Wheelan, Sarah J; Reddy, Karen L

2015-01-05

Nuclear organization has been implicated in regulating gene activity. Recently, large developmentally regulated regions of the genome dynamically associated with the nuclear lamina have been identified. However, little is known about how these lamina-associated domains (LADs) are directed to the nuclear lamina. We use our tagged chromosomal insertion site system to identify small sequences from borders of fibroblast-specific variable LADs that are sufficient to target these ectopic sites to the nuclear periphery. We identify YY1 (Ying-Yang1) binding sites as enriched in relocating sequences. Knockdown of YY1 or lamin A/C, but not lamin A, led to a loss of lamina association. In addition, targeted recruitment of YY1 proteins facilitated ectopic LAD formation dependent on histone H3 lysine 27 trimethylation and histone H3 lysine di- and trimethylation. Our results also reveal that endogenous loci appear to be dependent on lamin A/C, YY1, H3K27me3, and H3K9me2/3 for maintenance of lamina-proximal positioning. © 2015 Harr et al.

Nuclear Glycolytic Enzyme Enolase of Toxoplasma gondii Functions as a Transcriptional Regulator

PubMed Central

Mouveaux, Thomas; Oria, Gabrielle; Werkmeister, Elisabeth; Slomianny, Christian; Fox, Barbara A.; Bzik, David J.; Tomavo, Stanislas

2014-01-01

Apicomplexan parasites including Toxoplasma gondii have complex life cycles within different hosts and their infectivity relies on their capacity to regulate gene expression. However, little is known about the nuclear factors that regulate gene expression in these pathogens. Here, we report that T. gondii enolase TgENO2 is targeted to the nucleus of actively replicating parasites, where it specifically binds to nuclear chromatin in vivo. Using a ChIP-Seq technique, we provide evidence for TgENO2 enrichment at the 5′ untranslated gene regions containing the putative promoters of 241 nuclear genes. Ectopic expression of HA-tagged TgENO1 or TgENO2 led to changes in transcript levels of numerous gene targets. Targeted disruption of TgENO1 gene results in a decrease in brain cyst burden of chronically infected mice and in changes in transcript levels of several nuclear genes. Complementation of this knockout mutant with ectopic TgENO1-HA fully restored normal transcript levels. Our findings reveal that enolase functions extend beyond glycolytic activity and include a direct role in coordinating gene regulation in T. gondii. PMID:25153525

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

PubMed Central

Terasawa, K; Toyota, M; Sagae, S; Ogi, K; Suzuki, H; Sonoda, T; Akino, K; Maruyama, R; Nishikawa, N; Imai, K; Shinomura, Y; Saito, T; Tokino, T

2006-01-01

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1β (HNF1β), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2′deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4α, a transcriptional target of HNF1β, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment. PMID:16479257

Impedimetric aptasensor for nuclear factor kappa B with peroxidase-like mimic coupled DNA nanoladders as enhancer.

PubMed

Peng, Kanfu; Zhao, Hongwen; Xie, Pan; Hu, Shuang; Yuan, Yali; Yuan, Ruo; Wu, Xiongfei

2016-07-15

In this work, we developed a sensitive and universal aptasensor for nuclear factor kappa B (NF-κB) detection based on peroxidase-like mimic coupled DNA nanoladders for signal amplification. The dsDNA formed by capture DNA S1 and NF-κB binding aptamer (NBA) was firstly assembled on electrode surface. The presence of target NF-κB then led to the leave of NBA from electrode surface and thus provided the binding sites for immobilizing initiator to trigger in situ formation of DNA nanoladders on electrode surface. Since the peroxidase-like mimic manganese (III) meso-tetrakis (4-Nmethylpyridyl)-porphyrin (MnTMPyP) interacts with DNA nanoladders via groove binding, the insoluble benzo-4-chlorohexadienone (4-CD) precipitation derived from the oxidation of 4-chloro-1-naphthol (4-CN) could be formed on electrode surface in the presence of H2O2, resulting in a significantly amplified EIS signal output for quantitative target analysis. As a result, the developed aptasensor showed a low detection limit of 7pM and a wide linear range of 0.01-20nM. Featured with high sensitivity and label-free capability, the proposed sensing scheme can thus offer new opportunities for achieving sensitive, selective and stable detection of different types of target proteins. Copyright © 2016 Elsevier B.V. All rights reserved.

New Approach for Nuclear Reaction Model in the Combination of Intra-nuclear Cascade and DWBA

NASA Astrophysics Data System (ADS)

Hashimoto, S.; Iwamoto, O.; Iwamoto, Y.; Sato, T.; Niita, K.

2014-04-01

We applied a new nuclear reaction model that is a combination of the intra nuclear cascade model and the distorted wave Born approximation (DWBA) calculation to estimate neutron spectra in reactions induced by protons incident on 7Li and 9Be targets at incident energies below 50 MeV, using the particle and heavy ion transport code system (PHITS). The results obtained by PHITS with the new model reproduce the sharp peaks observed in the experimental double-differential cross sections as a result of taking into account transitions between discrete nuclear states in the DWBA. An excellent agreement was observed between the calculated results obtained using the combination model and experimental data on neutron yields from thick targets in the inclusive (p, xn) reaction.

Radiological Protection and Nuclear Engineering Studies in Multi-MW Target Systems

NASA Astrophysics Data System (ADS)

Luis, Raul Fernandes

Several innovative projects involving nuclear technology have emerged around the world in recent years, for applications such as spallation neutron sources, accelerator-driven systems for the transmutation of nuclear waste and radioactive ion beam (RIB) production. While the available neutron Wuxes from nuclear reactors did not increase substantially in intensity over the past three decades, the intensities of neutron sources produced in spallation targets have increased steadily, and should continue to do so during the 21st century. Innovative projects like ESS, MYRRHA and EURISOL lie at the forefront of the ongoing pursuit for increasingly bright neutron sources; driven by proton beams with energies up to 2 GeV and intensities up to several mA, the construction of their proposed facilities involves complex Nuclear Technology and Radiological Protection design studies executed by multidisciplinary teams of scientists and engineers from diUerent branches of Science. The intense neutron Wuxes foreseen for those facilities can be used in several scientiVc research Velds, such as Nuclear Physics and Astrophysics, Medicine and Materials Science. In this work, the target systems of two facilitites for the production of RIBs using the Isotope Separation On-Line (ISOL) method were studied in detail: ISOLDE, operating at CERN since 1967, and EURISOL, the next-generation ISOL facility to be built in Europe. For the EURISOL multi-MW target station, a detailed study of Radiological Protection was carried out using the Monte Carlo code FLUKA. Simulations were done to assess neutron Wuences, Vssion rates, ambient dose equivalent rates during operation and after shutdown and the production of radioactive nuclei in the targets and surrounding materials. DiUerent materials were discussed for diUerent components of the target system, aiming at improving its neutronics performance while keeping the residual activities resulting from material activation as low as possible. The second goal of this work was to perform an optimisation study for the ISOLDE neutron converter and Vssion target system. The target system was simulated using FLUKA and the cross section codes TALYS and ABRABLA, with the objective of maximising the performance of the system for the production of pure beams of neutron-rich isotopes, suppressing the contaminations by undesired neutron-deficient isobars. Two alternative target systems were proposed in the optimisation studies; the simplest of the two, with some modiVcations, was built as a prototype and tested at ISOLDE. The experimental results clearly show that it is possible, with simple changes in the layouts of the target systems, to produce purer beams of neutron-rich isotopes around the doubly magic nuclei 78Ni and 132Sn. A study of Radiological Protection was also performed, comparing the performances of the prototype target system and the standard ISOLDE target system. None

Note: Proton irradiation at kilowatt-power and neutron production from a free-surface liquid-lithium target

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halfon, S.; Feinberg, G.; Racah Institute of Physics, Hebrew University, Jerusalem 91904

2014-05-15

The free-surface Liquid-Lithium Target, recently developed at Soreq Applied Research Accelerator Facility (SARAF), was successfully used with a 1.9 MeV, 1.2 mA (2.3 kW) continuous-wave proton beam. Neutrons (∼2 × 10{sup 10} n/s having a peak energy of ∼27 keV) from the {sup 7}Li(p,n){sup 7}Be reaction were detected with a fission-chamber detector and by gold activation targets positioned in the forward direction. The setup is being used for nuclear astrophysics experiments to study neutron-induced reactions at stellar energies and to demonstrate the feasibility of accelerator-based boron neutron capture therapy.

GEANT4 simulation of cyclotron radioisotope production in a solid target.

PubMed

Poignant, F; Penfold, S; Asp, J; Takhar, P; Jackson, P

2016-05-01

The use of radioisotopes in nuclear medicine is essential for diagnosing and treating cancer. The optimization of their production is a key factor in maximizing the production yield and minimizing the associated costs. An efficient approach to this problem is the use of Monte Carlo simulations prior to experimentation. By predicting isotopes yields, one can study the isotope of interest expected activity for different energy ranges. One can also study the target contamination with other radioisotopes, especially undesired radioisotopes of the wanted chemical element which are difficult to separate from the irradiated target and might result in increasing the dose when delivering the radiopharmaceutical product to the patient. The aim of this work is to build and validate a Monte Carlo simulation platform using the GEANT4 toolkit to model the solid target system of the South Australian Health and Medical Research Institute (SAHMRI) GE Healthcare PETtrace cyclotron. It includes a GEANT4 Graphical User Interface (GUI) where the user can modify simulation parameters such as the energy, shape and current of the proton beam, the target geometry and material, the foil geometry and material and the time of irradiation. The paper describes the simulation and presents a comparison of simulated and experimental/theoretical yields for various nuclear reactions on an enriched nickel 64 target using the GEANT4 physics model QGSP_BIC_AllHP, a model recently developed to evaluate with high precision the interaction of protons with energies below 200MeV available in Geant4 version 10.1. The simulation yield of the (64)Ni(p,n)(64)Cu reaction was found to be 7.67±0.074 mCi·μA(-1) for a target energy range of 9-12MeV. Szelecsenyi et al. (1993) gives a theoretical yield of 6.71mCi·μA(-1) and an experimental yield of 6.38mCi·μA(-1). The (64)Ni(p,n)(64)Cu cross section obtained with the simulation was also verified against the yield predicted from the nuclear database TENDL and compared to experimental yield obtained from literature. Copyright © 2016 Associazione Italiana di Fisica Medica. All rights reserved.

Radiation Detection Center on the Front Lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hazi, A

2005-09-20

Many of today's radiation detection tools were developed in the 1960s. For years, the Laboratory's expertise in radiation detection resided mostly within its nuclear test program. When nuclear testing was halted in the 1990s, many of Livermore's radiation detection experts were dispersed to other parts of the Laboratory, including the directorates of Chemistry and Materials Science (CMS); Physics and Advanced Technologies (PAT); Defense and Nuclear Technologies (DNT); and Nonproliferation, Arms Control, and International Security (NAI). The RDC was formed to maximize the benefit of radiation detection technologies being developed in 15 to 20 research and development (R&D) programs. These effortsmore » involve more than 200 Laboratory employees across eight directorates, in areas that range from electronics to computer simulations. The RDC's primary focus is the detection, identification, and analysis of nuclear materials and weapons. A newly formed outreach program within the RDC is responsible for conducting radiation detection workshops and seminars across the country and for coordinating university student internships. Simon Labov, director of the RDC, says, ''Virtually all of the Laboratory's programs use radiation detection devices in some way. For example, DNT uses radiation detection to create radiographs for their work in stockpile stewardship and in diagnosing explosives; CMS uses it to develop technology for advancing the detection, diagnosis, and treatment of cancer; and the Energy and Environment Directorate uses radiation detection in the Marshall Islands to monitor the aftermath of nuclear testing in the Pacific. In the future, the National Ignition Facility will use radiation detection to probe laser targets and study shock dynamics.''« less

Roadmap to an Engineering-Scale Nuclear Fuel Performance & Safety Code

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turner, John A; Clarno, Kevin T; Hansen, Glen A

2009-09-01

Developing new fuels and qualifying them for large-scale deployment in power reactors is a lengthy and expensive process, typically spanning a period of two decades from concept to licensing. Nuclear fuel designers serve an indispensable role in the process, at the initial exploratory phase as well as in analysis of the testing results. In recent years fuel performance capabilities based on first principles have been playing more of a role in what has traditionally been an empirically dominated process. Nonetheless, nuclear fuel behavior is based on the interaction of multiple complex phenomena, and recent evolutionary approaches are being applied moremore » on a phenomenon-by-phenomenon basis, targeting localized problems, as opposed to a systematic approach based on a fundamental understanding of all interacting parameters. Advanced nuclear fuels are generally more complex, and less understood, than the traditional fuels used in existing reactors (ceramic UO{sub 2} with burnable poisons and other minor additives). The added challenges are primarily caused by a less complete empirical database and, in the case of recycled fuel, the inherent variability in fuel compositions. It is clear that using the traditional approach to develop and qualify fuels over the entire range of variables pertinent to the U.S. Department of Energy (DOE) Office of Nuclear Energy on a timely basis with available funds would be very challenging, if not impossible. As a result the DOE Office of Nuclear Energy has launched the Nuclear Energy Advanced Modeling and Simulation (NEAMS) approach to revolutionize fuel development. This new approach is predicated upon transferring the recent advances in computational sciences and computer technologies into the fuel development program. The effort will couple computational science with recent advances in the fundamental understanding of physical phenomena through ab initio modeling and targeted phenomenological testing to leapfrog many fuel-development activities. Realizing the full benefits of this approach will likely take some time. However, it is important that the developmental activities for modeling and simulation be tightly coupled with the experimental activities to maximize feedback effects and accelerate both the experimental and analytical elements of the program toward a common objective. The close integration of modeling and simulation and experimental activities is key to developing a useful fuel performance simulation capability, providing a validated design and analysis tool, and understanding the uncertainties within the models and design process. The efforts of this project are integrally connected to the Transmutation Fuels Campaign (TFC), which maintains as a primary objective to formulate, fabricate, and qualify a transuranic-based fuel with added minor actinides for use in future fast reactors. Additional details of the TFC scope can be found in the Transmutation Fuels Campaign Execution Plan. This project is an integral component of the TFC modeling and simulation effort, and this multiyear plan borrowed liberally from the Transmutation Fuels Campaign Modeling and Simulation Roadmap. This document provides the multiyear staged development plan to develop a continuum-level Integrated Performance and Safety Code (IPSC) to predict the behavior of the fuel and cladding during normal reactor operations and anticipated transients up to the point of clad breach.« less

Nuclear translocation of Acinetobacter baumannii transposase induces DNA methylation of CpG regions in the promoters of E-cadherin gene.

PubMed

Moon, Dong Chan; Choi, Chul Hee; Lee, Su Man; Lee, Jung Hwa; Kim, Seung Il; Kim, Dong Sun; Lee, Je Chul

2012-01-01

Nuclear targeting of bacterial proteins has emerged as a pathogenic mechanism whereby bacterial proteins induce host cell pathology. In this study, we examined nuclear targeting of Acinetobacter baumannii transposase (Tnp) and subsequent epigenetic changes in host cells. Tnp of A. baumannii ATCC 17978 possesses nuclear localization signals (NLSs), (225)RKRKRK(230). Transient expression of A. baumannii Tnp fused with green fluorescent protein (GFP) resulted in the nuclear localization of these proteins in COS-7 cells, whereas the truncated Tnp without NLSs fused with GFP were exclusively localized in the cytoplasm. A. baumannii Tnp was found in outer membrane vesicles, which delivered this protein to the nucleus of host cells. Nuclear expression of A. baumannii Tnp fused with GFP in A549 cells induced DNA methylation of CpG regions in the promoters of E-cadherin (CDH1) gene, whereas the cytoplasmic localization of the truncated Tnp without NLSs fused with GFP did not induce DNA methylation. DNA methylation in the promoters of E-cadherin gene induced by nuclear targeting of A. baumannii Tnp resulted in down-regulation of gene expression. In conclusion, our data show that nuclear traffic of A. baumannii Tnp induces DNA methylation of CpG regions in the promoters of E-cadherin gene, which subsequently down-regulates gene expression. This study provides a new insight into the epigenetic control of host genes by bacterial proteins.

Interaction of apicoplast-encoded elongation factor (EF) EF-Tu with nuclear-encoded EF-Ts mediates translation in the Plasmodiumfalciparum plastid.

PubMed

Biswas, Subir; Lim, Erin E; Gupta, Ankit; Saqib, Uzma; Mir, Snober S; Siddiqi, Mohammad Imran; Ralph, Stuart A; Habib, Saman

2011-03-01

Protein translation in the plastid (apicoplast) of Plasmodium spp. is of immense interest as a target for potential anti-malarial drugs. However, the molecular data on apicoplast translation needed for optimisation and development of novel inhibitors is lacking. We report characterisation of two key translation elongation factors in Plasmodium falciparum, apicoplast-encoded elongation factor PfEF-Tu and nuclear-encoded PfEF-Ts. Recombinant PfEF-Tu hydrolysed GTP and interacted with its presumed nuclear-encoded partner PfEF-Ts. The EF-Tu inhibitor kirromycin affected PfEF-Tu activity in vitro, indicating that apicoplast EF-Tu is indeed the target of this drug. The predicted PfEF-Ts leader sequence targeted GFP to the apicoplast, confirming that PfEF-Ts functions in this organelle. Recombinant PfEF-Ts mediated nucleotide exchange on PfEF-Tu and homology modeling of the PfEF-Tu:PfEF-Ts complex revealed PfEF-Ts-induced structural alterations that would expedite GDP release from PfEF-Tu. Our results establish functional interaction between two apicoplast translation factors encoded by genes residing in different cellular compartments and highlight the significance of their sequence/structural differences from bacterial elongation factors in relation to inhibitor activity. These data provide an experimental system to study the effects of novel inhibitors targeting PfEF-Tu and PfEF-Tu.PfEF-Ts interaction. Our finding that apicoplast EF-Tu possesses chaperone-related disulphide reductase activity also provides a rationale for retention of the tufA gene on the plastid genome. Copyright © 2010 Australian Society for Parasitology Inc. All rights reserved.

Molecular basis of Williams-Beuren syndrome: TFII-I regulated targets involved in craniofacial development.

PubMed

Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg

2011-01-01

The aim of this study is to identify gene targets of TFII-I transcription factors involved in craniofacial development. Recent findings in individuals with Williams-Beuren syndrome who show facial dysmorphism and cognitive defects have pointed to TFII-I genes (GTF2I and GTF2IRD1) as the prime candidates responsible for these clinical features. However, TFII-I proteins are multifunctional transcriptional factors regulating a number of genes during development, and how their haploinsufficiency leads to the Williams-Beuren syndrome phenotype is currently unknown. Here we report the identification of three genes with a well-established relevance to craniofacial development as direct TFII-I targets. These genes, craniofacial development protein 1 (Cfdp1), Sec23 homolog A (Sec23a), and nuclear receptor binding SET domain protein 1 (Nsd1), contain consensus TFII-I binding sites in their proximal promoters; the chromatin immunoprecipitation analysis showed that TFII-I transcription factors are recruited to these sites in vivo. The results suggest that transcriptional regulation of these genes by TFII-I proteins could provide a possible genotype-phenotype link in Williams-Beuren syndrome.

Method and apparatus for generating low energy nuclear particles

DOEpatents

Powell, J.R.; Reich, M.; Ludewig, H.; Todosow, M.

1999-02-09

A particle accelerator generates an input particle beam having an initial energy level above a threshold for generating secondary nuclear particles. A thin target is rotated in the path of the input beam for undergoing nuclear reactions to generate the secondary particles and correspondingly decrease energy of the input beam to about the threshold. The target produces low energy secondary particles and is effectively cooled by radiation and conduction. A neutron scatterer and a neutron filter are also used for preferentially degrading the secondary particles into a lower energy range if desired. 18 figs.

Application for internal dosimetry using biokinetic distribution of photons based on nuclear medicine images.

PubMed

Leal Neto, Viriato; Vieira, José Wilson; Lima, Fernando Roberto de Andrade

2014-01-01

This article presents a way to obtain estimates of dose in patients submitted to radiotherapy with basis on the analysis of regions of interest on nuclear medicine images. A software called DoRadIo (Dosimetria das Radiações Ionizantes [Ionizing Radiation Dosimetry]) was developed to receive information about source organs and target organs, generating graphical and numerical results. The nuclear medicine images utilized in the present study were obtained from catalogs provided by medical physicists. The simulations were performed with computational exposure models consisting of voxel phantoms coupled with the Monte Carlo EGSnrc code. The software was developed with the Microsoft Visual Studio 2010 Service Pack and the project template Windows Presentation Foundation for C# programming language. With the mentioned tools, the authors obtained the file for optimization of Monte Carlo simulations using the EGSnrc; organization and compaction of dosimetry results with all radioactive sources; selection of regions of interest; evaluation of grayscale intensity in regions of interest; the file of weighted sources; and, finally, all the charts and numerical results. The user interface may be adapted for use in clinical nuclear medicine as a computer-aided tool to estimate the administered activity.

A Personal Perspective on Triangle Universities Nuclear Laboratory Development

NASA Astrophysics Data System (ADS)

Clegg, Thomas B.

2011-10-01

Nuclear physics research in NC began seriously in 1950 when Henry Newson and his colleagues at Duke attracted support for a 4 MeV Van de Graaff accelerator with which they grew their doctoral training program. The lab's scientific achievements also grew, including the discovery in 1966 of fine structure of nuclear analog states. By then UNC and NC State had attracted Eugen Merzbacher and Worth Seagondollar who, with Newson, brought more faculty to work at an enlarged three-university, cooperative lab. Launched at Duke in 1967 with a 30 MeV Cyclograff accelerator, and subsequently equipped with a polarized H and D ion source and polarized H and ^3He targets, an extensive program in light-ion and neutron physics ensued. Faculty interest in electromagnetic interactions led to development since 2001 of TUNL's HIγS facility to produce intense 1-100 MeV polarized photon beams with small energy spread. Photonuclear reaction studies there today are producing results of unmatched quality. These 60 years of nuclear physics research have produced ˜250 doctoral graduates, many of whom have gone on to very distinguished careers. A personal perspective on these activities will be presented.

Roles of the Nuclear Lamina in Stable Nuclear Association and Assembly of a Herpesviral Transactivator Complex on Viral Immediate-Early Genes

PubMed Central

Silva, Lindsey; Oh, Hyung Suk; Chang, Lynne; Yan, Zhipeng; Triezenberg, Steven J.; Knipe, David M.

2012-01-01

ABSTRACT Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin. In contrast, we found that early herpes simplex virus (HSV) genome complexes localize near the nuclear lamina and that this localization is associated with reduced heterochromatin on the viral genome and increased viral immediate-early (IE) gene transcription. In this study, we examined the mechanism of this effect and found that input virion transactivator protein, virion protein 16 (VP16), targets sites adjacent to the nuclear lamina and is required for targeting of the HSV genome to the nuclear lamina, exclusion of heterochromatin from viral replication compartments, and reduction of heterochromatin on the viral genome. Because cells infected with the VP16 mutant virus in1814 showed a phenotype similar to that of lamin A/C−/− cells infected with wild-type virus, we hypothesized that the nuclear lamina is required for VP16 activator complex formation. In lamin A/C−/− mouse embryo fibroblasts, VP16 and Oct-1 showed reduced association with the viral IE gene promoters, the levels of VP16 and HCF-1 stably associated with the nucleus were lower than in wild-type cells, and the association of VP16 with HCF-1 was also greatly reduced. These results show that the nuclear lamina is required for stable nuclear localization and formation of the VP16 activator complex and provide evidence for the nuclear lamina being the site of assembly of the VP16 activator complex. PMID:22251972

Application of NMR Methods to Identify Detection Reagents for Use in the Development of Robust Nanosensors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cosman, M; Krishnan, V V; Balhorn, R

2004-04-29

Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful technique for studying bi-molecular interactions at the atomic scale. Our NMR lab is involved in the identification of small molecules, or ligands that bind to target protein receptors, such as tetanus (TeNT) and botulinum (BoNT) neurotoxins, anthrax proteins and HLA-DR10 receptors on non-Hodgkin's lymphoma cancer cells. Once low affinity binders are identified, they can be linked together to produce multidentate synthetic high affinity ligands (SHALs) that have very high specificity for their target protein receptors. An important nanotechnology application for SHALs is their use in the development of robust chemical sensors ormore » biochips for the detection of pathogen proteins in environmental samples or body fluids. Here, we describe a recently developed NMR competition assay based on transferred nuclear Overhauser effect spectroscopy (trNOESY) that enables the identification of sets of ligands that bind to the same site, or a different site, on the surface of TeNT fragment C (TetC) than a known ''marker'' ligand, doxorubicin. Using this assay, we can identify the optimal pairs of ligands to be linked together for creating detection reagents, as well as estimate the relative binding constants for ligands competing for the same site.« less

Advances in silica based nanoparticles for targeted cancer therapy.

PubMed

Yang, Yannan; Yu, Chengzhong

2016-02-01

Targeted delivery of anticancer drug specifically to tumor site without damaging normal tissues has been the dream of all scientists fighting against cancer for decades. Recent breakthrough on nanotechnology based medicines has provided a possible tool to solve this puzzle. Among diverse nanomaterials that are under development and extensive study, silica based nanoparticles with vast advantages have attracted great attention. In this review, we concentrate on the recent progress using silica based nanoparticles, particularly mesoporous silica nanoparticles (MSNs), for targeted drug delivery applications. First, we discuss the passive targeting capability of silica based nanoparticles in relation to their physiochemical properties. Then, we focus on the recent advances of active targeting strategies involving tumor cell targeting, vascular targeting, nuclear targeting and multistage targeting, followed by an introduction to magnetic field directed targeting approach. We conclude with our personal perspectives on the remaining challenges and the possible future directions. Chemotherapy has been one of the mainstays of cancer treatment. The advances in nanotechnology has allowed the development of novel carrier systems for the delivery of anticancer drugs. Mesoporous silica has shown great promise in this respect. In this review article, the authors provided a comprehensive overview of the use of this nanoparticle in both passive, as well as active targeting in the field of oncology. The advantages of this particle were further discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

The RNA Exosome Adaptor ZFC3H1 Functionally Competes with Nuclear Export Activity to Retain Target Transcripts.

PubMed

Silla, Toomas; Karadoulama, Evdoxia; Mąkosa, Dawid; Lubas, Michal; Jensen, Torben Heick

2018-05-15

Mammalian genomes are promiscuously transcribed, yielding protein-coding and non-coding products. Many transcripts are short lived due to their nuclear degradation by the ribonucleolytic RNA exosome. Here, we show that abolished nuclear exosome function causes the formation of distinct nuclear foci, containing polyadenylated (pA + ) RNA secluded from nucleocytoplasmic export. We asked whether exosome co-factors could serve such nuclear retention. Co-localization studies revealed the enrichment of pA + RNA foci with "pA-tail exosome targeting (PAXT) connection" components MTR4, ZFC3H1, and PABPN1 but no overlap with known nuclear structures such as Cajal bodies, speckles, paraspeckles, or nucleoli. Interestingly, ZFC3H1 is required for foci formation, and in its absence, selected pA + RNAs, including coding and non-coding transcripts, are exported to the cytoplasm in a process dependent on the mRNA export factor AlyREF. Our results establish ZFC3H1 as a central nuclear pA + RNA retention factor, counteracting nuclear export activity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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 capsid protein (VP1) of porcine parvovirus. The major protein (VP2) nuclear localization was shown to depend on a complex structural motif. This motif can be used as a strategy by the virus to avoid transport of incorrectly folded proteins and to selectively import assembled trimers into the nucleus. Structural nuclear localization motifs can also be important for nuclear proteins without a classic basic amino acid stretch, including multimeric cellular proteins. PMID:25078698

An alternate approach to the production of radioisotopes for nuclear medicine applications

NASA Astrophysics Data System (ADS)

D'Auria, John M.; Keller, Roderich; Ladouceur, Keith; Lapi, Suzanne E.; Ruth, Thomas J.; Schmor, Paul

2013-03-01

There is a growing need for the production of radioisotopes for both diagnostic and therapeutic medical applications. Radioisotopes that are produced using the (n,γ) or (γ,n) reactions, however, typically result in samples with low specific activity (radioactivity/gram) due to the high abundance of target material of the same element. One method to effectively remove the isotopic impurity is electro-magnetic mass separation. An Ion Source Test Facility has been constructed at TRIUMF to develop high-intensity, high-efficiency, reliable ion sources for purification of radioactive isotopes, particularly those used in nuclear medicine. In progress studies are presented.

An alternate approach to the production of radioisotopes for nuclear medicine applications.

PubMed

D'Auria, John M; Keller, Roderich; Ladouceur, Keith; Lapi, Suzanne E; Ruth, Thomas J; Schmor, Paul

2013-03-01

There is a growing need for the production of radioisotopes for both diagnostic and therapeutic medical applications. Radioisotopes that are produced using the (n,γ) or (γ,n) reactions, however, typically result in samples with low specific activity (radioactivity∕gram) due to the high abundance of target material of the same element. One method to effectively remove the isotopic impurity is electro-magnetic mass separation. An Ion Source Test Facility has been constructed at TRIUMF to develop high-intensity, high-efficiency, reliable ion sources for purification of radioactive isotopes, particularly those used in nuclear medicine. In progress studies are presented.

Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies

PubMed Central

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

2015-01-01

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. PMID:25805923

Mechanism of protein import across the chloroplast envelope.

PubMed

Chen, K; Chen, X; Schnell, D J

2000-01-01

The development and maintenance of chloroplasts relies on the contribution of protein subunits from both plastid and nuclear genomes. Most chloroplast proteins are encoded by nuclear genes and are post-translationally imported into the organelle across the double membrane of the chloroplast envelope. Protein import into the chloroplast consists of two essential elements: the specific recognition of the targeting signals (transit sequences) of cytoplasmic preproteins by receptors at the outer envelope membrane and the subsequent translocation of preproteins simultaneously across the double membrane of the envelope. These processes are mediated via the co-ordinate action of protein translocon complexes in the outer (Toc apparatus) and inner (Tic apparatus) envelope membranes.

Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis

PubMed Central

Cui, Qi; Yang, Su; Ye, Peng; Tian, E.; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T.; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D.; Rossi, John J.; Shi, Yanhong

2016-01-01

Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma. PMID:26838672

Tumour suppressor TRIM33 targets nuclear β-catenin degradation

PubMed Central

Xue, Jianfei; Chen, Yaohui; Wu, Yamei; Wang, Zhongyong; Zhou, Aidong; Zhang, Sicong; Lin, Kangyu; Aldape, Kenneth; Majumder, Sadhan; Lu, Zhimin; Huang, Suyun

2014-01-01

Aberrant activation of β-catenin in the nucleus has been implicated in a variety of human cancers but the fate of nuclear β-catenin is unknown. Here we demonstrate that tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear β-catenin protein. TRIM33-mediated β-catenin is destabilized and is GSK-3β or β-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear β-catenin. Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. The function of TRIM33 in suppressing tumour cell proliferation and brain tumour development depends on TRIM33-promoted β-catenin degradation. In human glioblastoma specimens, endogenous TRIM33 levels are inversely correlated with β-catenin. In summary, our findings identify TRIM33 as a tumour suppressor that can abolish tumour cell proliferation and tumorigenesis by degrading nuclear β-catenin. This work suggests a new therapeutic strategy against human cancers caused by aberrant activation of β-catenin. PMID:25639486

First Nuclear DNA C-values for 18 Eudicot Families

PubMed Central

HANSON, LYNDA; BOYD, AMY; JOHNSON, MARGARET A. T.; BENNETT, MICHAEL D.

2005-01-01

• Background and Aims A key target set at the second Plant Genome Size Workshop, held at the Royal Botanic Gardens, Kew in 2003, was to produce first DNA C-value data for an additional 1 % of angiosperm species, and, within this, to achieve 75 % familial coverage overall (up from approx. 50 %) by 2009. The present study targeted eudicot families for which representation in 2003 (42·5 %) was much lower than monocot (72·8 %) and basal angiosperm (69·0 %) families. • Methods Flow cytometry or Feulgen microdensitometry were used to estimate nuclear DNA C-values, and chromosome counts were obtained where possible. • Key Results First nuclear DNA C-values are reported for 20 angiosperm families, including 18 eudicots. This substantially increases familial representation to 55·2 % for angiosperms and 48·5 % for eudicots. • Conclusions The importance of targeting specific plant families to improve familial nuclear DNA C-value representation is reconfirmed. International collaboration will be increasingly essential to locate and obtain material of unsampled plant families, if the target set by the second Plant Genome Size Workshop is to be met. PMID:16239248

Ca-48 targets - Home and abroad!

NASA Astrophysics Data System (ADS)

Greene, John P.; Carpenter, Michael; Janssens, Robert V. F.

2018-05-01

Using the method of reduction/distillation, high-purity films of robust and ductile calcium metal were prepared for use as targets in nuclear physics experiments. These targets, however, are extremely air-sensitive and procedures must be developed for their handling and use without exposure to the air. In most instances, the thin 48Ca target is used on a carrier foil (backing) and a thin covering film of similar material is employed to further reduce re-oxidation. Un-backed metallic targets are rarely produced due to these concerns. In addition, the low natural abundance of the isotope 48Ca provided an increased incentive for the best efficiencies available in their preparation. Here, we describe the preparation of 48Ca targets employing a gold backing and thin gold cover for use at home, Argonne National Laboratory (ANL), as well as abroad, at Osaka University. For the overseas shipments, much care and preparation were necessary to ensure good targets and safe arrival to the experimental facilities.

AN EARLY STAGE IN THE PLANT RECOLONIZATION OF A NUCLEAR TARGET AREA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rickard, W.H.; Shields, L.M.

1963-01-01

Vegetational analyses were conducted three years postdetonation in a nuclear target area in a Grayia spinosa-Lycium andersonii community in Yucca Fiat, Nevada. Annual plants dominated the early stage of recolonization and were quantitatively more abundant in the disturbed areas than in an adjacent undisturbed shrub community. Ment zelia albicaulis and Chaenactis steviodes occurred in both disturbed and undisturbed areas, however; Mentzelia was more abundant in disturbed areas while Chaenactis was more abundant in the undisturbed community. Salsola kali was confined to disturbed areas while Phacelia vallismortae was more often encountered in the undisturbed community. The plant recolonization of a mechanicallymore » disturbed area was quantitatively and qualitatively more like that of the interior zone of the nuclear target area than less disturbed habitats. These data support a conclusion that soil displacement presents a more rigorous habitat for plant recolonization than disturbances created by the wider ranging destructive components of a nuclear detonation. (auth)« less

The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis

PubMed Central

Solt, Laura A; Kojetin, Douglas J; Burris, Thomas P

2011-01-01

Research efforts spanning the past two decades have established a clear link between nuclear receptor function, regulation of the circadian clock and lipid homeostasis. As such, this family of receptors represents an important area of research. Recent advances in the field have identified two nuclear receptor subfamilies, the REV-ERBs and the ‘retinoic acid receptor-related orphan receptors’ (RORs), as critical regulators of the circadian clock with significant roles in lipid homeostasis. In this review, the latest information garnered from cutting-edge research on these two nuclear receptor subfamilies will be discussed. Through direct targeting of the REV-ERBs and RORs with synthetic ligands, generation of novel tools aimed at characterizing their function in vivo have been developed, which may lead to novel therapeutics for the treatment of metabolic disorders. PMID:21526899

C+C Fusion Cross Sections Measurements for Nuclear Astrophysics

DOE PAGES

Almaraz-Calderon, S.; Carnelli, P. F. F.; Rehm, K. E.; ...

2015-06-02

Total fusion cross section of carbon isotopes were obtained using the newly developed MUSIC detector. MUSIC is a highly efficient, active target-detector system designed to measure fusion excitation functions with radioactive beams. The present measurements are relevant for understanding x-ray superbursts. The results of the first MUSIC campaign as well as the astrophysical implications are presented in this work.

C+C Fusion Cross Sections Measurements for Nuclear Astrophysics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Almaraz-Calderon, S.; Carnelli, P. F. F.; Rehm, K. E.

Total fusion cross section of carbon isotopes were obtained using the newly developed MUSIC detector. MUSIC is a highly efficient, active target-detector system designed to measure fusion excitation functions with radioactive beams. The present measurements are relevant for understanding x-ray superbursts. The results of the first MUSIC campaign as well as the astrophysical implications are presented in this work.

Regulation of behaviour by the nuclear receptor TLX.

PubMed

O'Leary, J D; O'Leary, O F; Cryan, J F; Nolan, Y M

2018-03-01

The orphan nuclear receptor Tlx (Nr2e1) is a key regulator of both embryonic and adult hippocampal neurogenesis. Several different mouse models have been developed which target Tlx in vivo including spontaneous deletion models (from birth) and targeted and conditional knockouts. Although some conflicting findings have been reported, for the most part studies have demonstrated that Tlx is important in regulating processes that underlie neurogenesis, spatial learning, anxiety-like behaviour and interestingly, aggression. More recent data have demonstrated that disrupting Tlx during early life induces hyperactivity and that Tlx plays a role in emotional regulation. Moreover, there are sex- and age-related differences in some behaviours in Tlx knockout mice during adolescence and adulthood. Here, we discuss the role of Tlx in motor-, cognitive-, aggressive- and anxiety-related behaviours during adolescence and adulthood. We examine current evidence which provides insight into Tlx during neurodevelopment, and offer our thoughts on the function of Tlx in brain and behaviour. We further hypothesize that Tlx is a key target in understanding the emergence of neurobiological disorders during adolescence and early adulthood. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Electromagnetic pulse (EMP) coupling codes for use with the vulnerability/lethality (VIL) taxonomy. Final report, June-October 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mar, M.H.

1995-07-01

Based on the vulnerability Lethality (V/L) taxonomy developed by the Ballistic Vulnerability Lethality Division (BVLD) of the Survivability Lethality Analysis Directorate (SLAD), a nuclear electromagnetic pulse (EMP) coupling V/L analysis taxonomy has been developed. A nuclear EMP threat to a military system can be divided into two levels: (1) coupling to a system level through a cable, antenna, or aperture; and (2) the component level. This report will focus on the initial condition, which includes threat definition and target description, as well as the mapping process from the initial condition to damaged components state. EMP coupling analysis at a systemmore » level is used to accomplish this. This report introduces the nature of EMP threat, interaction between the threat and target, and how the output of EMP coupling analysis at a system level becomes the input to the component level analysis. Many different tools (EMP coupling codes) will be discussed for the mapping process, which correponds to the physics of phenomenology. This EMP coupling V/L taxonomy and the models identified in this report will provide the tools necessary to conduct basic V/L analysis of EMP coupling.« less

Discovery potential for directional dark matter detection with nuclear emulsions

NASA Astrophysics Data System (ADS)

Guler, A. M.; NEWSdm Collaboration

2017-06-01

Direct Dark Matter searches are nowadays one of the most exciting research topics. Several Experimental efforts are concentrated on the development, construction, and operation of detectors looking for the scattering of target nuclei with Weakly Interactive Massive Particles (WIMPs). In this field a new frontier can be opened by directional detectors able to reconstruct the direction of the WIMP-recoiled nucleus thus allowing to extend dark matter searches beyond the neutrino floor. Exploiting directionality would also give a proof of the galactic origin of dark matter making it possible to have a clear and unambiguous signal to background separation. The angular distribution of WIPM-scattered nuclei is indeed expected to be peaked in the direction of the motion of the Solar System in the Galaxy, i.e. toward the Cygnus constellation, while the background distribution is expected to be isotropic. Current directional experiments are based on the use of gas TPC whose sensitivity is limited by the small achievable detector mass. In this paper we show the potentiality in terms of exclusion limit of a directional experiment based on the use of a solid target made by newly developed nuclear emulsions and read-out systems reaching sub-micrometric resolution.

Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine.

PubMed

Becnel, Lauren B; Ochsner, Scott A; Darlington, Yolanda F; McOwiti, Apollo; Kankanamge, Wasula H; Dehart, Michael; Naumov, Alexey; McKenna, Neil J

2017-04-25

We previously developed a web tool, Transcriptomine, to explore expression profiling data sets involving small-molecule or genetic manipulations of nuclear receptor signaling pathways. We describe advances in biocuration, query interface design, and data visualization that enhance the discovery of uncharacterized biology in these pathways using this tool. Transcriptomine currently contains about 45 million data points encompassing more than 2000 experiments in a reference library of nearly 550 data sets retrieved from public archives and systematically curated. To make the underlying data points more accessible to bench biologists, we classified experimental small molecules and gene manipulations into signaling pathways and experimental tissues and cell lines into physiological systems and organs. Incorporation of these mappings into Transcriptomine enables the user to readily evaluate tissue-specific regulation of gene expression by nuclear receptor signaling pathways. Data points from animal and cell model experiments and from clinical data sets elucidate the roles of nuclear receptor pathways in gene expression events accompanying various normal and pathological cellular processes. In addition, data sets targeting non-nuclear receptor signaling pathways highlight transcriptional cross-talk between nuclear receptors and other signaling pathways. We demonstrate with specific examples how data points that exist in isolation in individual data sets validate each other when connected and made accessible to the user in a single interface. In summary, Transcriptomine allows bench biologists to routinely develop research hypotheses, validate experimental data, or model relationships between signaling pathways, genes, and tissues. Copyright © 2017, American Association for the Advancement of Science.

Regulated transport into the nucleus of herpesviridae DNA replication core proteins.

PubMed

Gualtiero, Alvisi; Jans, David A; Camozzi, Daria; Avanzi, Simone; Loregian, Arianna; Ripalti, Alessandro; Palù, Giorgio

2013-09-16

The Herpesvirdae family comprises several major human pathogens belonging to three distinct subfamilies. Their double stranded DNA genome is replicated in the nuclei of infected cells by a number of host and viral products. Among the latter the viral replication complex, whose activity is strictly required for viral replication, is composed of six different polypeptides, including a two-subunit DNA polymerase holoenzyme, a trimeric primase/helicase complex and a single stranded DNA binding protein. The study of herpesviral DNA replication machinery is extremely important, both because it provides an excellent model to understand processes related to eukaryotic DNA replication and it has important implications for the development of highly needed antiviral agents. Even though all known herpesviruses utilize very similar mechanisms for amplification of their genomes, the nuclear import of the replication complex components appears to be a heterogeneous and highly regulated process to ensure the correct spatiotemporal localization of each protein. The nuclear transport process of these enzymes is controlled by three mechanisms, typifying the main processes through which protein nuclear import is generally regulated in eukaryotic cells. These include cargo post-translational modification-based recognition by the intracellular transporters, piggy-back events allowing coordinated nuclear import of multimeric holoenzymes, and chaperone-assisted nuclear import of specific subunits. In this review we summarize these mechanisms and discuss potential implications for the development of antiviral compounds aimed at inhibiting the Herpesvirus life cycle by targeting nuclear import of the Herpesvirus DNA replicating enzymes.

Engineering liposomal nanoparticles for targeted gene therapy.

PubMed

Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

2017-08-01

Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

Accuracy and Precision of Radioactivity Quantification in Nuclear Medicine Images

PubMed Central

Frey, Eric C.; Humm, John L.; Ljungberg, Michael

2012-01-01

The ability to reliably quantify activity in nuclear medicine has a number of increasingly important applications. Dosimetry for targeted therapy treatment planning or for approval of new imaging agents requires accurate estimation of the activity in organs, tumors, or voxels at several imaging time points. Another important application is the use of quantitative metrics derived from images, such as the standard uptake value commonly used in positron emission tomography (PET), to diagnose and follow treatment of tumors. These measures require quantification of organ or tumor activities in nuclear medicine images. However, there are a number of physical, patient, and technical factors that limit the quantitative reliability of nuclear medicine images. There have been a large number of improvements in instrumentation, including the development of hybrid single-photon emission computed tomography/computed tomography and PET/computed tomography systems, and reconstruction methods, including the use of statistical iterative reconstruction methods, which have substantially improved the ability to obtain reliable quantitative information from planar, single-photon emission computed tomography, and PET images. PMID:22475429

Certified Training for Nuclear and Radioactive Source Security Management.

PubMed

Johnson, Daniel

2017-04-01

Radioactive sources are used by hospitals, research facilities and industry for such purposes as diagnosing and treating illnesses, sterilising equipment and inspecting welds. Unfortunately, many States, regulatory authorities and licensees may not appreciate how people with malevolent intentions could use radioactive sources, and statistics confirm that a number of security incidents happen around the globe. The adversary could be common thieves, activists, insiders, terrorists and organised crime groups. Mitigating this risk requires well trained and competent staff who have developed the knowledge, attributes and skills necessary to successfully discharge their security responsibilities. The International Atomic Energy Agency and the World Institute for Nuclear Security are leading international training efforts. The target audience is a multi-disciplinary group of professionals with management responsibilities for security at facilities with radioactive sources. These efforts to promote training and competence amongst practitioners have been recognised at the 2014 and 2016 Nuclear Security and Nuclear Industry Summits. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cyber security evaluation of II&C technologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Ken

The Light Water Reactor Sustainability (LWRS) Program is a research and development program sponsored by the Department of Energy, which is conducted in close collaboration with industry to provide the technical foundations for licensing and managing the long-term, safe and economical operation of current nuclear power plants The LWRS Program serves to help the US nuclear industry adopt new technologies and engineering solutions that facilitate the continued safe operation of the plants and extension of the current operating licenses. Within the LWRS Program, the Advanced Instrumentation, Information, and Control (II&C) Systems Technologies Pathway conducts targeted research and development (R&D) tomore » address aging and reliability concerns with the legacy instrumentation and control and related information systems of the U.S. operating light water reactor (LWR) fleet. The II&C Pathway is conducted by Idaho National Laboratory (INL). Cyber security is a common concern among nuclear utilities and other nuclear industry stakeholders regarding the digital technologies that are being developed under this program. This concern extends to the point of calling into question whether these types of technologies could ever be deployed in nuclear plants given the possibility that the information in them can be compromised and the technologies themselves can potentially be exploited to serve as attack vectors for adversaries. To this end, a cyber security evaluation has been conducted of these technologies to determine whether they constitute a threat beyond what the nuclear plants already manage within their regulatory-required cyber security programs. Specifically, the evaluation is based on NEI 08-09, which is the industry’s template for cyber security programs and evaluations, accepted by the Nuclear Regulatory Commission (NRC) as responsive to the requirements of the nuclear power plant cyber security regulation found in 10 CFR 73.54. The evaluation was conducted by a cyber security team with expertise in nuclear utility cyber security programs and experience in conducting these evaluations. The evaluation has determined that, for the most part, cyber security will not be a limiting factor in the application of these technologies to nuclear power plant applications.« less

Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced (99m)Tc yields.

PubMed

Tanguay, J; Hou, X; Buckley, K; Schaffer, P; Bénard, F; Ruth, T J; Celler, A

2015-05-21

Cyclotron production of (99m)Tc through the (100)Mo(p,2n) (99m)Tc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional (99m)Tc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high-radionuclidic-purity (99m)Tc. However, variations in proton beam currents and the thickness and isotopic composition of enriched (100)Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute (99m)Tc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including (100)Mo target thicknesses and proton beam currents, and reproducibility of absolute (99m)Tc yields (defined as the end of bombardment (EOB) (99m)Tc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB (99m)Tc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in (99m)Tc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of (99m)Tc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced (99m)Tc.

Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced 99mTc yields

NASA Astrophysics Data System (ADS)

Tanguay, J.; Hou, X.; Buckley, K.; Schaffer, P.; Bénard, F.; Ruth, T. J.; Celler, A.

2015-05-01

Cyclotron production of 99mTc through the 100Mo(p,2n) 99mTc reaction channel is actively being investigated as an alternative to reactor-based 99Mo generation by nuclear fission of 235U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional 99mTc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high-radionuclidic-purity 99mTc. However, variations in proton beam currents and the thickness and isotopic composition of enriched 100Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute 99mTc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including 100Mo target thicknesses and proton beam currents, and reproducibility of absolute 99mTc yields (defined as the end of bombardment (EOB) 99mTc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB 99mTc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in 99mTc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of 99mTc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced 99mTc.

Simulated nuclear reactor fuel assembly

DOEpatents

Berta, V.T.

1993-04-06

An apparatus for electrically simulating a nuclear reactor fuel assembly. It includes a heater assembly having a top end and a bottom end and a plurality of concentric heater tubes having electrical circuitry connected to a power source, and radially spaced from each other. An outer target tube and an inner target tube is concentric with the heater tubes and with each other, and the outer target tube surrounds and is radially spaced from the heater tubes. The inner target tube is surrounded by and radially spaced from the heater tubes and outer target tube. The top of the assembly is generally open to allow for the electrical power connection to the heater tubes, and the bottom of the assembly includes means for completing the electrical circuitry in the heater tubes to provide electrical resistance heating to simulate the power profile in a nuclear reactor. The embedded conductor elements in each heater tube is split into two halves for a substantial portion of its length and provided with electrical isolation such that each half of the conductor is joined at one end and is not joined at the other end.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Yuanbin; Pálffy, Adriana, E-mail: yuanbin.wu@mpi-hd.mpg.de, E-mail: Palffy@mpi-hd.mpg.de

Due to screening effects, nuclear reactions in astrophysical plasmas may behave differently than in the laboratory. The possibility to determine the magnitude of these screening effects in colliding laser-generated plasmas is investigated theoretically, having as a starting point a proposed experimental setup with two laser beams at the Extreme Light Infrastructure facility. A laser pulse interacting with a solid target produces a plasma through the Target Normal Sheath Acceleration scheme, and this rapidly streaming plasma (ion flow) impacts a secondary plasma created by the interaction of a second laser pulse on a gas jet target. We model this scenario heremore » and calculate the reaction events for the astrophysically relevant reaction {sup 13}C({sup 4}He, n ){sup 16}O. We find that it should be experimentally possible to determine the plasma screening enhancement factor for fusion reactions by detecting the difference in reaction events between two scenarios of ion flow interacting with the plasma target and a simple gas target. This provides a way to evaluate nuclear reaction cross-sections in stellar environments and can significantly advance the field of nuclear astrophysics.« less

Simulated nuclear reactor fuel assembly

DOEpatents

Berta, Victor T.

1993-01-01

An apparatus for electrically simulating a nuclear reactor fuel assembly. It includes a heater assembly having a top end and a bottom end and a plurality of concentric heater tubes having electrical circuitry connected to a power source, and radially spaced from each other. An outer target tube and an inner target tube is concentric with the heater tubes and with each other, and the outer target tube surrounds and is radially spaced from the heater tubes. The inner target tube is surrounded by and radially spaced from the heater tubes and outer target tube. The top of the assembly is generally open to allow for the electrical power connection to the heater tubes, and the bottom of the assembly includes means for completing the electrical circuitry in the heater tubes to provide electrical resistance heating to simulate the power profile in a nuclear reactor. The embedded conductor elements in each heater tube is split into two halves for a substantial portion of its length and provided with electrical isolation such that each half of the conductor is joined at one end and is not joined at the other end.

Determination of Plasma Screening Effects for Thermonuclear Reactions in Laser-generated Plasmas

NASA Astrophysics Data System (ADS)

Wu, Yuanbin; Pálffy, Adriana

2017-03-01

Due to screening effects, nuclear reactions in astrophysical plasmas may behave differently than in the laboratory. The possibility to determine the magnitude of these screening effects in colliding laser-generated plasmas is investigated theoretically, having as a starting point a proposed experimental setup with two laser beams at the Extreme Light Infrastructure facility. A laser pulse interacting with a solid target produces a plasma through the Target Normal Sheath Acceleration scheme, and this rapidly streaming plasma (ion flow) impacts a secondary plasma created by the interaction of a second laser pulse on a gas jet target. We model this scenario here and calculate the reaction events for the astrophysically relevant reaction 13C(4He, n)16O. We find that it should be experimentally possible to determine the plasma screening enhancement factor for fusion reactions by detecting the difference in reaction events between two scenarios of ion flow interacting with the plasma target and a simple gas target. This provides a way to evaluate nuclear reaction cross-sections in stellar environments and can significantly advance the field of nuclear astrophysics.

Risk Informed Design and Analysis Criteria for Nuclear Structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salmon, Michael W.

2015-06-17

Target performance can be achieved by defining design basis ground motion from results of a probabilistic seismic hazards assessment, and introducing known levels of conservatism in the design above the DBE. ASCE 4, 43, DOE-STD-1020 defined the DBE at 4x10-4 and introduce only slight levels of conservatism in response. ASCE 4, 43, DOE-STD-1020 assume code capacities shoot for about 98% NEP. There is a need to have a uniform target (98% NEP) for code developers (ACI, AISC, etc.) to aim for. In considering strengthening options, one must also consider cost/risk reduction achieved.

Theater-Level Gaming and Analysis Workshop for Force Planning. Volume II. Summary, Discussion of Issues and Requirements for Research. September 27- 29, 1977, Held at Xerox International Center for Training and Management Development, Leesburg, Virginia

DTIC Science & Technology

1981-05-01

be allocated to targets on the battlefield and in the rear area. The speaker describes the VECTOR I/NUCLEAR model, a combination of the UNICORN target...outlined. UNICORN is compatible with VECTOR 1 in level of detail. It is an expected value damage model and uses linear programming to optimize the...and a growing appreciation for the power of simulation in addressing large, complex problems, it was only a few short years before these games had

Alternative Energy Development and China's Energy Future

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Nina; Fridley, David

2011-06-15

In addition to promoting energy efficiency, China has actively pursued alternative energy development as a strategy to reduce its energy demand and carbon emissions. One area of particular focus has been to raise the share of alternative energy in China’s rapidly growing electricity generation with a 2020 target of 15% share of total primary energy. Over the last ten years, China has established several major renewable energy regulations along with programs and subsidies to encourage the growth of non-fossil alternative energy including solar, wind, nuclear, hydro, geothermal and biomass power as well as biofuels and coal alternatives. This study thusmore » seeks to examine China’s alternative energy in terms of what has and will continue to drive alternative energy development in China as well as analyze in depth the growth potential and challenges facing each specific technology. This study found that despite recent policies enabling extraordinary capacity and investment growth, alternative energy technologies face constraints and barriers to growth. For relatively new technologies that have not achieved commercialization such as concentrated solar thermal, geothermal and biomass power, China faces technological limitations to expanding the scale of installed capacity. While some alternative technologies such as hydropower and coal alternatives have been slowed by uneven and often changing market and policy support, others such as wind and solar PV have encountered physical and institutional barriers to grid integration. Lastly, all alternative energy technologies face constraints in human resources and raw material resources including land and water, with some facing supply limitations in critical elements such as uranium for nuclear, neodymium for wind and rare earth metals for advanced solar PV. In light of China’s potential for and barriers to growth, the resource and energy requirement for alternative energy technologies were modeled and scenario analysis used to evaluate the energy and emission impact of two pathways of alternative energy development. The results show that China can only meets its 2015 and 2020 targets for non-fossil penetration if it successfully achieves all of its capacity targets for 2020 with continued expansion through 2030. To achieve this level of alternative generation, significant amounts of raw materials including 235 Mt of concrete, 54 Mt of steel, 5 Mt of copper along with 3 billion tons of water and 64 thousand square kilometers of land are needed. China’s alternative energy supply will likely have relatively high average energy output to fossil fuel input ratio of 42 declining to 26 over time, but this ratio is largely skewed by nuclear and hydropower capacity. With successful alternative energy development, 32% of China’s electricity and 21% of its total primary energy will be supplied by alternative energy by 2030. Compared to the counterfactual baseline in which alternative energy development stumbles and China does not meet its capacity targets until 2030, alternative energy development can displace 175 Mtce of coal inputs per year and 2080 Mtce cumulatively from power generation by 2030. In carbon terms, this translates into 5520 Mt of displaced CO 2 emissions over the twenty year period, with more than half coming from expanded nuclear and wind power generation. These results illustrate the critical role that alternative energy development can play alongside energy efficiency in reducing China’s energy-related carbon emissions.« less

Multifunctional High Drug Loading Nanocarriers for Cancer Drug Delivery

NASA Astrophysics Data System (ADS)

Jin, Erlei

2011-12-01

Most anticancer drugs have poor water-solubility, rapid blood clearance, low tumor-selectivity and severe systemic toxicity to healthy tissues. Thus, polymeric nanocarriers have been widely explored for anticancer drugs to solve these problems. However, polymer nanocarriers developed to date still suffer drawbacks including low drug loading contents, premature drug release, slow cellular internalization, slow intracellular drug release and thereby low therapeutic efficiency in cancer thermotherapy. Accordingly, in this dissertation, functional nanocapsules and nanoparticles including high drug loading liposome-like nanocapsules, high drug loading phospholipid-mimic nanocapsules with fast intracellular drug release, high drug loading charge-reversal nanocapsules, TAT based long blood circulation nanoparticles and charge-reversal nuclear targeted nanoparticles are designed and synthesized. These functional carriers have advantages such as high drug loading contents without premature drug release, fast cellular internalization and intracellular drug release, nuclear targeted delivery and long blood circulation. As a result, all these drug carriers show much higher in vitro and in vivo anti-cancer activities.

Identification of apoptosis-related PLZF target genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernardo, Maria Victoria; Yelo, Estefania; Gimeno, Lourdes

2007-07-27

The PLZF gene encodes a BTB/POZ-zinc finger-type transcription factor, involved in physiological development, proliferation, differentiation, and apoptosis. In this paper, we investigate proliferation, survival, and gene expression regulation in stable clones from the human haematopoietic K562, DG75, and Jurkat cell lines with inducible expression of PLZF. In Jurkat cells, but not in K562 and DG75 cells, PLZF induced growth suppression and apoptosis in a cell density-dependent manner. Deletion of the BTB/POZ domain of PLZF abrogated growth suppression and apoptosis. PLZF was expressed with a nuclear speckled pattern distinctively in the full-length PLZF-expressing Jurkat clones, suggesting that the nuclear speckled localizationmore » is required for PLZF-induced apoptosis. By microarray analysis, we identified that the apoptosis-inducer TP53INP1, ID1, and ID3 genes were upregulated, and the apoptosis-inhibitor TERT gene was downregulated. The identification of apoptosis-related PLZF target genes may have biological and clinical relevance in cancer typified by altered PLZF expression.« less

Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation.

PubMed

Kanda, Keitaro; Sakamoto, Jiro; Matsumoto, Yoshihide; Ikuta, Kozo; Goto, Norihiro; Morita, Yusuke; Ohno, Mikiko; Nishi, Kiyoto; Eto, Koji; Kimura, Yuto; Nakanishi, Yuki; Ikegami, Kanako; Yoshikawa, Takaaki; Fukuda, Akihisa; Kawada, Kenji; Sakai, Yoshiharu; Ito, Akihiro; Yoshida, Minoru; Kimura, Takeshi; Chiba, Tsutomu; Nishi, Eiichiro; Seno, Hiroshi

2018-04-19

Colon cancer is a complex disease affected by a combination of genetic and epigenetic factors. Here we demonstrate that nardilysin (N-arginine dibasic convertase; NRDC), a metalloendopeptidase of the M16 family, regulates intestinal tumorigenesis via its nuclear functions. NRDC is highly expressed in human colorectal cancers. Deletion of the Nrdc gene in ApcMin mice crucially suppressed intestinal tumor development. In ApcMin mice, epithelial cell-specific deletion of Nrdc recapitulated the tumor suppression observed in Nrdc-null mice. Moreover, epithelial cell-specific overexpression of Nrdc significantly enhanced tumor formation in ApcMin mice. Notably, epithelial NRDC controlled cell apoptosis in a gene dosage-dependent manner. In human colon cancer cells, nuclear NRDC directly associated with HDAC1, and controlled both acetylation and stabilization of p53, with alterations of p53 target apoptotic factors. These findings demonstrate that NRDC is critically involved in intestinal tumorigenesis through its epigenetic regulatory function, and targeting NRDC may lead to a novel prevention or therapeutic strategy against colon cancer.

A live zebrafish-based screening system for human nuclear receptor ligand and cofactor discovery.

PubMed

Tiefenbach, Jens; Moll, Pamela R; Nelson, Meryl R; Hu, Chun; Baev, Lilia; Kislinger, Thomas; Krause, Henry M

2010-03-22

Nuclear receptors (NRs) belong to a superfamily of transcription factors that regulate numerous homeostatic, metabolic and reproductive processes. Taken together with their modulation by small lipophilic molecules, they also represent an important and successful class of drug targets. Although many NRs have been targeted successfully, the majority have not, and one third are still orphans. Here we report the development of an in vivo GFP-based reporter system suitable for monitoring NR activities in all cells and tissues using live zebrafish (Danio rerio). The human NR fusion proteins used also contain a new affinity tag cassette allowing the purification of receptors with bound molecules from responsive tissues. We show that these constructs 1) respond as expected to endogenous zebrafish hormones and cofactors, 2) facilitate efficient receptor and cofactor purification, 3) respond robustly to NR hormones and drugs and 4) yield readily quantifiable signals. Transgenic lines representing the majority of human NRs have been established and are available for the investigation of tissue- and isoform-specific ligands and cofactors.

Utility of γH2AX as a molecular marker of DNA double-strand breaks in nuclear medicine: applications to radionuclide therapy employing auger electron-emitting isotopes.

PubMed

Mah, Li-Jeen; Orlowski, Christian; Ververis, Katherine; El-Osta, Assam; Karagiannis, Tom C

2011-01-01

There is an intense interest in the development of radiopharmaceuticals for cancer therapy. In particular, radiopharmaceuticals which involve targeting radionuclides specifically to cancer cells with the use of monoclonal antibodies (radioimmunotherapy) or peptides (targeted radiotherapy) are being widely investigated. For example, the ultra-short range Auger electron-emitting isotopes, which are discussed in this review, are being considered in the context of DNAtargeted radiotherapy. The efficient quantitative evaluation of the levels of damage caused by such potential radiopharmaceuticals is required for assessment of therapeutic efficacy and determination of relevant doses for successful treatment. The DNA double-strand break surrogate marker, γH2AX, has emerged as a useful biomonitor of damage and thus effectiveness of treatment, offering a highly specific and sensitive means of assessment. This review will cover the potential applications of γH2AX in nuclear medicine, in particular radionuclide therapy.

Binding of Y-P30 to Syndecan 2/3 Regulates the Nuclear Localization of CASK

PubMed Central

Landgraf, Peter; Mikhaylova, Marina; Macharadze, Tamar; Borutzki, Corinna; Zenclussen, Ana-Claudia; Wahle, Petra; Kreutz, Michael R.

2014-01-01

The survival promoting peptide Y-P30 has documented neuroprotective effects as well as cell survival and neurite outgrowth promoting activity in vitro and in vivo. Previous work has shown that multimerization of the peptide with pleiotrophin (PTN) and subsequent binding to syndecan (SDC) -2 and -3 is involved in its neuritogenic effects. In this study we show that Y-P30 application regulates the nuclear localization of the SDC binding partner Calcium/calmodulin-dependent serine kinase (CASK) in neuronal primary cultures during development. In early development at day in vitro (DIV) 8 when mainly SDC-3 is expressed supplementation of the culture medium with Y-P30 reduces nuclear CASK levels whereas it has the opposite effect at DIV 18 when SDC-2 is the dominant isoform. In the nucleus CASK regulates gene expression via its association with the T-box transcription factor T-brain-1 (Tbr-1) and we indeed found that gene expression of downstream targets of this complex, like the GluN2B NMDA-receptor, exhibits a corresponding down- or up-regulation at the mRNA level. The differential effect of Y-P30 on the nuclear localization of CASK correlates with its ability to induce shedding of the ectodomain of SDC-2 but not -3. shRNA knockdown of SDC-2 at DIV 18 and SDC-3 at DIV 8 completely abolished the effect of Y-P30 supplementation on nuclear CASK levels. During early development a protein knockdown of SDC-3 also attenuated the effect of Y-P30 on axon outgrowth. Taken together these data suggest that Y-P30 can control the nuclear localization of CASK in a SDC-dependent manner. PMID:24498267

A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1

PubMed Central

Kim, Kwang Seok; Choi, Kyu Jin; Bae, Sangwoo

2016-01-01

Since checkpoint kinase 1 (Chk1) is an essential factor for cell viability following DNA damage, the inhibition of Chk1 has been a major focus of pharmaceutical development to enhance the sensitivity of tumor cells to chemo- and radiotherapy that damage DNA. However, due to the off-target effects of conventional Chk1-targeting strategies and the toxicity of Chk1 inhibitors, alternative strategies are required to target Chk1. To facilitate such efforts, in this study, we identified a specific Chk1-binding 12-mer peptide from the screening of a phage display library and characterized the peptide in terms of cellular cytotoxicity, and in terms of its effect on Chk1 activity and sensitivity to genotoxic agents. This peptide, named N-terminal Chk1-binding peptide (Chk1-NP), bound the kinase domain of Chk1. Simulation of the binding revealed that the very N-terminus of the Chk1 kinase domain is the potential peptide binding site. Of note, the polyarginine-mediated internalization of Chk1-NP redistributed nuclear Chk1 with a prominent decrease in the nucleus in the absence of DNA damage. Treatment with Chk1-NP peptide alone decreased the viability of p53-defective HeLa cells, but not that of p53-functional NCI-H460 cells under normal conditions. The treatment of HeLa or NCI-H460 cells with the peptide significantly enhanced radiation sensitivity following ionizing radiation (IR) with a greater enhancement observed in HeLa cells. Moreover, the IR-induced destabilization of Chk1 was aggravated by treatment with Chk1-NP. Therefore, the decreased nuclear localization and protein levels of Chk1 seem to be responsible for the enhanced cancer cell killing following combined treatment with IR and Chk1-NP. The approach using the specific Chk1-binding peptide may facilitate the mechanistic understanding and potential modulation of Chk1 activities and may provide a novel rationale for the development of specific Chk1-targeting agents. PMID:28025997

Role of regulatory subunits and protein kinase inhibitor (PKI) in determining nuclear localization and activity of the catalytic subunit of protein kinase A.

PubMed

Wiley, J C; Wailes, L A; Idzerda, R L; McKnight, G S

1999-03-05

Regulation of protein kinase A by subcellular localization may be critical to target catalytic subunits to specific substrates. We employed epitope-tagged catalytic subunit to correlate subcellular localization and gene-inducing activity in the presence of regulatory subunit or protein kinase inhibitor (PKI). Transiently expressed catalytic subunit distributed throughout the cell and induced gene expression. Co-expression of regulatory subunit or PKI blocked gene induction and prevented nuclear accumulation. A mutant PKI lacking the nuclear export signal blocked gene induction but not nuclear accumulation, demonstrating that nuclear export is not essential to inhibit gene induction. When the catalytic subunit was targeted to the nucleus with a nuclear localization signal, it was not sequestered in the cytoplasm by regulatory subunit, although its activity was completely inhibited. PKI redistributed the nuclear catalytic subunit to the cytoplasm and blocked gene induction, demonstrating that the nuclear export signal of PKI can override a strong nuclear localization signal. With increasing PKI, the export process appeared to saturate, resulting in the return of catalytic subunit to the nucleus. These results demonstrate that both the regulatory subunit and PKI are able to completely inhibit the gene-inducing activity of the catalytic subunit even when the catalytic subunit is forced to concentrate in the nuclear compartment.

Method and apparatus for generating low energy nuclear particles

DOEpatents

Powell, James R.; Reich, Morris; Ludewig, Hans; Todosow, Michael

1999-02-09

A particle accelerator (12) generates an input particle beam having an initial energy level above a threshold for generating secondary nuclear particles. A thin target (14) is rotated in the path of the input beam for undergoing nuclear reactions to generate the secondary particles and correspondingly decrease energy of the input beam to about the threshold. The target (14) produces low energy secondary particles and is effectively cooled by radiation and conduction. A neutron scatterer (44) and a neutron filter (42) are also used for preferentially degrading the secondary particles into a lower energy range if desired.

Design of an electron-accelerator-driven compact neutron source for non-destructive assay

NASA Astrophysics Data System (ADS)

Murata, A.; Ikeda, S.; Hayashizaki, N.

2017-09-01

The threat of nuclear and radiological terrorism remains one of the greatest challenges to international security, and the threat is constantly evolving. In order to prevent nuclear terrorism, it is important to avoid unlawful import of nuclear materials, such as uranium and plutonium. Development of technologies for non-destructive measurement, detection and recognition of nuclear materials is essential for control at national borders. At Tokyo Institute of Technology, a compact neutron source system driven by an electron-accelerator has been designed for non-destructive assay (NDA). This system is composed of a combination of an S-band (2.856 GHz) RF-gun, a tungsten target to produce photons by bremsstrahlung, a beryllium target, which is suitable for use in generating neutrons because of the low threshold energy of photonuclear reactions, and a moderator to thermalize the fast neutrons. The advantage of this system can accelerate a short pulse beam with a pulse width less than 1 μs which is difficult to produce by neutron generators. The amounts of photons and neutron produced by electron beams were simulated using the Monte Carlo simulation code PHITS 2.82. When the RF-gun is operated with an average electron beam current of 0.1 mA, it is expected that the neutron intensities are 1.19 × 109 n/s and 9.94 × 109 n/s for incident electron beam energies of 5 MeV and 10 MeV, respectively.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hecht, Adam

Within the 3 year POP we propose to continue to test and further develop the fission spectrometers, to do development tests and full data acquisition run at the national laboratory neutron beam facilities, to measure correlated fission fragment yields at low neutron energies with 235 U fission targets, and make these data available to the nuclear community. The spectrometer development will be both on the university based r\\prototype and on the National Laboratory Spectrometer, and measurements will be performed with both. Over the longer time frame of the collaboration, we will take data over a range of low energies, andmore » use other fission targets available to the laboratory. We will gather energy specific fragment distributions and reaction cross sections. We will further develop the data acquisition capabilities to take correlated fission fragment'gamma ray/neurton data, all on an event-by-event basis. This really is an enabling technology.« less

Imaging of Prostate Cancer Using Gallium-68-Labeled Bombesin.

PubMed

Sonni, Ida; Baratto, Lucia; Iagaru, Andrei

2017-04-01

Nuclear medicine can play an important role in evaluating prostate cancer combining anatomical and functional information with hybrid techniques. Various PET radiopharmaceuticals have been used for targeting specific biological markers in prostate cancer. Research is ideally oriented towards the development of radiopharmaceuticals targeting antigens overexpressed in prostate cancer, as opposed to normal prostate tissue. In this regard, gastrin-releasing peptide receptors (GRPR) are excellent candidates. Bombesin analogues targeting the GRPR have been investigated. Gallium-68 ( 68 Ga) is an interesting PET radioisotope due to several advantages, such as availability, ease of radiochemistry, half-life, and costs. The focus of this review is on 68 Ga-labeled bombesin analogues in prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1

PubMed Central

Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.

2006-01-01

During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx−/− mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx−/− mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration. PMID:16702404

National Ignition Facility Target Chamber

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wavrik, R W; Cox, J R; Fleming, P J

2000-10-05

On June 11, 1999 the Department of Energy dedicated the single largest piece of the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory (LLNL) in Livermore, California. The ten (10) meter diameter aluminum target high vacuum chamber will serve as the working end of the largest laser in the world. The output of 192 laser beams will converge at the precise center of the chamber. The laser beams will enter the chamber in two by two arrays to illuminate 10 millimeter long gold cylinders called hohlraums enclosing 2 millimeter capsule containing deuterium, tritium and isotopes of hydrogen. The twomore » isotopes will fuse, thereby creating temperatures and pressures resembling those found only inside stars and in detonated nuclear weapons, but on a minute scale. The NIF Project will serve as an essential facility to insure safety and reliability of our nation's nuclear arsenal as well as demonstrating inertial fusion's contribution to creating electrical power. The paper will discuss the requirements that had to be addressed during the design, fabrication and testing of the target chamber. A team from Sandia National Laboratories (SNL) and LLNL with input from industry performed the configuration and basic design of the target chamber. The method of fabrication and construction of the aluminum target chamber was devised by Pitt-Des Moines, Inc. (PDM). PDM also participated in the design of the chamber in areas such as the Target Chamber Realignment and Adjustment System, which would allow realignment of the sphere laser beams in the event of earth settlement or movement from a seismic event. During the fabrication of the target chamber the sphericity tolerances had to be addressed for the individual plates. Procedures were developed for forming, edge preparation and welding of individual plates. Construction plans were developed to allow the field construction of the target chamber to occur parallel to other NIF construction activities. This was necessary to achieve the overall schedule. Plans had to be developed for the precise location and alignment of laser beam ports. Upon completion of the fabrication of the aluminum target chamber in a temporary structure the 130 ton sphere was moved from the temporary construction enclosure to its final location in the target building. Prior to the installation of a concrete shield and after completion of the welding of the chamber penetrations vacuum leak checking was performed to insure the vacuum integrity of target chamber. The entire spherical chamber external surface supports a 40 cm thick reinforced concrete shield after installation in the target building. The final task is a total survey of the laser ports and the contour machining of spacer plates so that laser devices attached to these ports meet the alignment criteria.« less

Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models.

PubMed

Yokoi, Fumiaki; Dang, Mai T; Zhou, Tong; Li, Yuqing

2012-02-15

DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ε-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ε-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ε-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ε-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.

Apparatus for nuclear transmutation and power production using an intense accelerator-generated thermal neutron flux

DOEpatents

Bowman, C.D.

1992-11-03

Apparatus for nuclear transmutation and power production using an intense accelerator-generated thermal neutron flux. High thermal neutron fluxes generated from the action of a high power proton accelerator on a spallation target allows the efficient burn-up of higher actinide nuclear waste by a two-step process. Additionally, rapid burn-up of fission product waste for nuclides having small thermal neutron cross sections, and the practicality of small material inventories while achieving significant throughput derive from employment of such high fluxes. Several nuclear technology problems are addressed including 1. nuclear energy production without a waste stream requiring storage on a geological timescale, 2. the burn-up of defense and commercial nuclear waste, and 3. the production of defense nuclear material. The apparatus includes an accelerator, a target for neutron production surrounded by a blanket region for transmutation, a turbine for electric power production, and a chemical processing facility. In all applications, the accelerator power may be generated internally from fission and the waste produced thereby is transmuted internally so that waste management might not be required beyond the human lifespan.

Apparatus for nuclear transmutation and power production using an intense accelerator-generated thermal neutron flux

DOEpatents

Bowman, Charles D.

1992-01-01

Apparatus for nuclear transmutation and power production using an intense accelerator-generated thermal neutron flux. High thermal neutron fluxes generated from the action of a high power proton accelerator on a spallation target allows the efficient burn-up of higher actinide nuclear waste by a two-step process. Additionally, rapid burn-up of fission product waste for nuclides having small thermal neutron cross sections, and the practicality of small material inventories while achieving significant throughput derive from employment of such high fluxes. Several nuclear technology problems are addressed including 1. nuclear energy production without a waste stream requiring storage on a geological timescale, 2. the burn-up of defense and commercial nuclear waste, and 3. the production of defense nuclear material. The apparatus includes an accelerator, a target for neutron production surrounded by a blanket region for transmutation, a turbine for electric power production, and a chemical processing facility. In all applications, the accelerator power may be generated internally from fission and the waste produced thereby is transmuted internally so that waste management might not be required beyond the human lifespan.

Nuclear receptors and nonalcoholic fatty liver disease1

PubMed Central

Cave, Matthew C.; Clair, Heather B.; Hardesty, Josiah E.; Falkner, K. Cameron; Feng, Wenke; Clark, Barbara J.; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A.; McClain, Craig J.; Prough, Russell A.

2016-01-01

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:26962021

Development of the Accelerator Mass Spectrometry technology at the Comenius University in Bratislava

NASA Astrophysics Data System (ADS)

Povinec, Pavel P.; Masarik, Jozef; Ješkovský, Miroslav; Kaizer, Jakub; Šivo, Alexander; Breier, Robert; Pánik, Ján; Staníček, Jaroslav; Richtáriková, Marta; Zahoran, Miroslav; Zeman, Jakub

2015-10-01

An Accelerator Mass Spectrometry (AMS) laboratory has been established at the Centre for Nuclear and Accelerator Technologies (CENTA) at the Comenius University in Bratislava comprising of a MC-SNICS ion source, 3 MV Pelletron tandem accelerator, and an analyzer of accelerated ions. The preparation of targets for 14C and 129I AMS measurements is described in detail. The development of AMS techniques for potassium, uranium and thorium analysis in radiopure materials required for ultra-low background underground experiments is briefly mentioned.

Transmutation of Radioactive Nuclear Waste — Present Status and Requirement for the Problem-Oriented Nuclear Database: Approach to Scheduling the Experiments (Reactor, Target, Blanket)

NASA Astrophysics Data System (ADS)

Artisyuk, V.; Ignatyuk, A.; Korovin, Yu.; Lopatkin, A.; Matveenko, I.; Stankovskiy, A.; Titarenko, Yu.

2005-05-01

Transmutation of nuclear wastes (Minor Actinides and Long-Lived Fission Products) remains an important option to reduce the burden of high-level waste on final waste disposal in deep geological structures. Accelerator-Driven Systems (ADS) are considered as possible candidates to perform transmutation due to their subcritical operation mode that eliminates some of the serious safety penalties unavoidable in critical reactors. Specific requirements to nuclear data necessary for ADS transmutation analysis is the main subject of the ISTC Project ♯2578 which started in 2004 to identify the areas of research priorities in the future. The present paper gives a summary of ongoing project stressing the importance of nuclear data for blanket performance (reactivity behavior with associated safety characteristics) and uncertainties that affect characteristics of neutron producing target.

DNA and proteins of the nuclear matrix are the main targets of benzo[a]pyrene's action in rat hepatocytes.

PubMed

Widłak, P; Rzeszowska-Wolny, J

1993-01-01

The binding of [14C]benzo[a]pyrene (B[a]P) to DNA and proteins in total nuclei and subnuclear fractions of cultured rat hepatocytes was compared. The main targets of B[a]P were non-histone high molecular weight proteins of the nuclear matrix and DNA sequences attached to this structure. Following 24 h exposure to B[a]P the amounts of adducts in the nuclear matrix DNA and proteins were twice as high as in total nuclei. After withdrawal of the carcinogen containing medium the level of B[a]P-induced adducts gradually decreased but always remained the highest in the nuclear matrix proteins. Removal of adducts from the nuclear matrix DNA was more efficient than from the other DNA fractions, and 72 h after exposure to the carcinogen the level of DNA adducts in this fraction was similar to that in total nuclei.

Mediator-dependent Nuclear Receptor Functions

PubMed Central

Chen, Wei; Roeder, Robert

2011-01-01

As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Lizhen; Yang, Ying; Tyburska-Puschel, Beata

The mission of the Nuclear Energy Enabling Technologies (NEET) program is to develop crosscutting technologies for nuclear energy applications. Advanced structural materials with superior performance at elevated temperatures are always desired for nuclear reactors, which can improve reactor economics, safety margins, and design flexibility. They benefit not only new reactors, including advanced light water reactors (LWRs) and fast reactors such as sodium-cooled fast reactor (SFR) that is primarily designed for management of high-level wastes, but also life extension of the existing fleet when component exchange is needed. Developing and utilizing the modern materials science tools (experimental, theoretical, and computational tools)more » is an important path to more efficient alloy development and process optimization. Ferritic-martensitic (FM) steels are important structural materials for nuclear reactors due to their advantages over other applicable materials like austenitic stainless steels, notably their resistance to void swelling, low thermal expansion coefficients, and higher thermal conductivity. However, traditional FM steels exhibit a noticeable yield strength reduction at elevated temperatures above ~500°C, which limits their applications in advanced nuclear reactors which target operating temperatures at 650°C or higher. Although oxide-dispersion-strengthened (ODS) ferritic steels have shown excellent high-temperature performance, their extremely high cost, limited size and fabricability of products, as well as the great difficulty with welding and joining, have limited or precluded their commercial applications. Zirconium has shown many benefits to Fe-base alloys such as grain refinement, improved phase stability, and reduced radiation-induced segregation. The ultimate goal of this project is, with the aid of computational modeling tools, to accelerate the development of a new generation of Zr-bearing ferritic alloys to be fabricated using conventional steelmaking practices, which have excellent radiation resistance and enhanced high-temperature creep performance greater than Grade 91.« less

Preparation and characterization of vinculin-targeted polymer–lipid nanoparticle as intracellular delivery vehicle

PubMed Central

Wang, Junping; Örnek-Ballanco, Ceren; Xu, Jiahua; Yang, Weiguo; Yu, Xiaojun

2013-01-01

Intracellular delivery vehicles have been extensively investigated as these can serve as an effective tool in studying the cellular mechanism, by delivering functional protein to specific locations of the cells. In the current study, a polymer–lipid nanoparticle (PLN) system was developed as an intracellular delivery vehicle specifically targeting vinculin, a focal adhesion protein associated with cellular adhesive structures, such as focal adhesions and adherens junctions. The PLNs possessed an average size of 106 nm and had a positively charged surface. With a lower encapsulation efficiency 32% compared with poly(lactic-co-glycolic) acid (PLGA) nanoparticles (46%), the PLNs showed the sustained release profile of model drug BSA, while PLGA nanoparticles demonstrated an initial burst-release property. Cell-uptake experiments using mouse embryonic fibroblasts cultured in fibrin–fibronectin gels observed, under confocal microscope, that the anti-vinculin conjugated PLNs could successfully ship the cargo to the cytoplasm of fibroblasts, adhered to fibronectin–fibrin. With the use of cationic lipid, the unconjugated PLNs were shown to have high gene transfection efficiency. Furthermore, the unconjugated PLNs had nuclear-targeting capability in the absence of nuclear-localization signals. Therefore, the PLNs could be manipulated easily via different type of targeting ligands and could potentially be used as a powerful tool for cellular mechanism study, by delivering drugs to specific cellular organelles. PMID:23293518

The effects of variations in the number and sequence of targeting signals on nuclear uptake

PubMed Central

1988-01-01

To determine if the number of targeting signals affects the transport of proteins into the nucleus, Xenopus oocytes were injected with colloidal gold particles, ranging in diameter from 20 to 280 A, that were coated with BSA cross-linked with synthetic peptides containing the SV-40 large T-antigen nuclear transport signal. Three BSA conjugate preparations were used; they had an average of 5, 8, and 11 signals per molecule of carrier protein. In addition, large T-antigen, which contains one signal per monomer, was used as a coating agent. The cells were fixed at various times after injection and subsequently analyzed by electron microscopy. Gold particles coated with proteins containing the SV-40 signal entered the nucleus through central channels located within the nuclear pores. Analysis of the intracellular distribution and size of the tracers that entered the nucleus indicated that the number of signals per molecule affect both the relative uptake of particles and the functional size of the channels available for translocation. In control experiments, gold particles coated with BSA or BSA conjugated with inactive peptides similar to the SV-40 transport signal were virtually excluded from the nucleus. Gold particles coated with nucleoplasmin, an endogenous karyophilic protein that contains five targeting signals per molecule, was transported through the nuclear pores more effectively than any of the BSA-peptide conjugates. Based on a correlation between the peri-envelope density of gold particles and their relative uptake, it is suggested that the differences in the activity of the two targeting signals is related to their binding affinity for envelope receptors. It was also determined, by performing coinjection experiments, that individual pores are capable of recognizing and transporting proteins that contain different nuclear targeting signals. PMID:3170630

Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

PubMed

Johansson, Erik; Zhai, Qiwei; Zeng, Zhao-Jun; Yoshida, Takeshi; Funa, Keiko

2016-05-01

TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells. Copyright © 2016. Published by Elsevier Inc.

Constitutive NF-κB activation and tumor-growth promotion by Romo1-mediated reactive oxygen species production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Jin Sil; Lee, Sora; Yoo, Young Do, E-mail: ydy1130@korea.ac.kr

2014-08-08

Highlights: • Romo1 expression is required for constitutive nuclear DNA-binding activity of NF-κB. • Romo1 depletion suppresses tumor growth in vivo. • Romo1 presents a potential therapeutic target for diseases. - Abstract: Deregulation of nuclear factor-κB (NF-κB) and related pathways contribute to tumor cell proliferation and invasion. Mechanisms for constitutive NF-κB activation are not fully explained; however, the underlying defects appear to generate and maintain pro-oxidative conditions. In hepatocellular carcinoma (HCC) tissues, up-regulation of reactive oxygen species modulator 1 (Romo1) correlates positively with tumor size. In the present study, we showed that Romo1 expression is required to maintain constitutive nuclearmore » DNA-binding activity of NF-κB and transcriptional activity through constitutive IκBα phosphorylation. Overexpression of Romo1 promoted p65 nuclear translocation and DNA-binding activity. We also show that Romo1 depletion suppressed anchorage-independent colony formation by HCC cells and suppressed tumor growth in vivo. Based on these findings, Romo1 may be a principal regulatory factor in the maintenance of constitutive NF-κB activation in tumor cells. In the interest of anti-proliferative treatments for cancer, Romo1 may also present a productive target for drug development.« less

Influenza A Virus Polymerase Recruits the RNA Helicase DDX19 to Promote the Nuclear Export of Viral mRNAs

PubMed Central

Diot, Cédric; Fournier, Guillaume; Dos Santos, Mélanie; Magnus, Julie; Komarova, Anastasia; van der Werf, Sylvie; Munier, Sandie; Naffakh, Nadia

2016-01-01

Enhancing the knowledge of host factors that are required for efficient influenza A virus (IAV) replication is essential to address questions related to pathogenicity and to identify targets for antiviral drug development. Here we focused on the interplay between IAV and DExD-box RNA helicases (DDX), which play a key role in cellular RNA metabolism by remodeling RNA-RNA or RNA-protein complexes. We performed a targeted RNAi screen on 35 human DDX proteins to identify those involved in IAV life cycle. DDX19 was a major hit. In DDX19-depleted cells the accumulation of viral RNAs and proteins was delayed, and the production of infectious IAV particles was strongly reduced. We show that DDX19 associates with intronless, unspliced and spliced IAV mRNAs and promotes their nuclear export. In addition, we demonstrate an RNA-independent association between DDX19 and the viral polymerase, that is modulated by the ATPase activity of DDX19. Our results provide a model in which DDX19 is recruited to viral mRNAs in the nucleus of infected cells to enhance their nuclear export. Information gained from this virus-host interaction improves the understanding of both the IAV replication cycle and the cellular function of DDX19. PMID:27653209

Accelerator Production of Isotopes for Medical Use

NASA Astrophysics Data System (ADS)

Lapi, Suzanne

2014-03-01

The increase in use of radioisotopes for medical imaging and therapy has led to the development of novel routes of isotope production. For example, the production and purification of longer-lived position emitting radiometals has been explored to allow for nuclear imaging agents based on peptides, antibodies and nanoparticles. These isotopes (64Cu, 89Zr, 86Y) are typically produced via irradiation of solid targets on smaller medical cyclotrons at dedicated facilities. Recently, isotope harvesting from heavy ion accelerator facilities has also been suggested. The Facility for Rare Isotope Beams (FRIB) will be a new national user facility for nuclear science to be completed in 2020. Radioisotopes could be produced by dedicated runs by primary users or may be collected synergistically from the water in cooling-loops for the primary beam dump that cycle the water at flow rates in excess of hundreds of gallons per minute. A liquid water target system for harvesting radioisotopes at the National Superconducting Cyclotron Laboratory (NSCL) was designed and constructed as the initial step in proof-of-principle experiments to harvest useful radioisotopes in this manner. This talk will provide an overview of isotope production using both dedicated machines and harvesting from larger accelerators typically used for nuclear physics. Funding from Department of Energy under DESC0007352 and DESC0006862.

Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy.

PubMed

Zhao, Yichao; Xu, Longwei; Ding, Song; Lin, Nan; Ji, Qingqi; Gao, Lingchen; Su, Yuanyuan; He, Ben; Pu, Jun

2017-04-01

Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor-α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

New Concepts and Fermilab Facilities for Antimatter Research

NASA Astrophysics Data System (ADS)

Jackson, Gerald

2008-04-01

There has long been significant interest in continuing antimatter research at the Fermi National Accelerator Laboratory. Beam kinetic energies ranging from 10 GeV all the way down to the eV scale and below are of interest. There are three physics missions currently being developed: the continuation of charmonium physics utilizing an internal target; atomic physics with in-flight generated antihydrogen atoms; and deceleration to thermal energies and paasage of antiprotons through a grating system to determine their gravitation acceleration. Non-physics missions include the study of medical applications, tests of deep-space propulsion concepts, low-risk testing of nuclear fuel elements, and active interrogation for smuggled nuclear materials in support of homeland security. This paper reviews recent beam physics and accelerator technology innovations in the development of methods and new Fermilab facilities for the above missions.

Generation of a transgenic cashmere goat using the piggyBac transposition system.

PubMed

Bai, Ding-Ping; Yang, Ming-Ming; Qu, Lei; Chen, Yu-Lin

2017-04-15

The development of transgenic technologies in the Cashmere goat (Capra hircus) has the potential to improve the quality of the meat and wool. The piggyBac (PB) transposon system is highly efficient and can be used to transpose specific target genes into the genome. Here, we developed a PB transposon system to produce transgenic Cashmere goat fetal fibroblasts (GFFs) with the enhanced green fluorescent protein (EGFP). We then used the genetically modified GFFs as nuclear donors to generate transgenic embryos by somatic cell nuclear transfer (SCNT). The embryos (n = 40) were implanted into female goats (n = 20). One transgenic kid that expressed EGFP throughout the surface features of its body was born. This result demonstrated the usefulness of PB transposon system in generating transgenic Cashmere goats. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear Security: Target Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Surinder Paul; Gibbs, Philip W.; Bultz, Garl A.

2014-03-01

This objectives of this session were to understand the basic steps of target identification; describe the SNRI targets in detail; characterize specific targets with more detail; prioritize targets based on guidance documents; understand the graded safeguards concept; identify roll up and understand why it is a concern; and recognize the category for different materials.

Subgroup A : nuclear model codes report to the Sixteenth Meeting of the WPEC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talou, P.; Chadwick, M. B.; Dietrich, F. S.

2004-01-01

The Subgroup A activities focus on the development of nuclear reaction models and codes, used in evaluation work for nuclear reactions from the unresolved energy region up to the pion threshold production limit, and for target nuclides from the low teens and heavier. Much of the efforts are devoted by each participant to the continuing development of their own Institution codes. Progresses in this arena are reported in detail for each code in the present document. EMPIRE-II is of public access. The release of the TALYS code has been announced for the ND2004 Conference in Santa Fe, NM, October 2004.more » McGNASH is still under development and is not expected to be released in the very near future. In addition, Subgroup A members have demonstrated a growing interest in working on common modeling and codes capabilities, which would significantly reduce the amount of duplicate work, help manage efficiently the growing lines of existing codes, and render codes inter-comparison much easier. A recent and important activity of the Subgroup A has therefore been to develop the framework and the first bricks of the ModLib library, which is constituted of mostly independent pieces of codes written in Fortran 90 (and above) to be used in existing and future nuclear reaction codes. Significant progresses in the development of ModLib have been made during the past year. Several physics modules have been added to the library, and a few more have been planned in detail for the coming year.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

J. Carmack; L. Braase; F. Goldner

The mission of the Advanced Fuels Campaign (AFC) is to perform Research, Development, and Demonstration (RD&D) activities for advanced fuel forms (including cladding) to enhance the performance and safety of the nation’s current and future reactors, enhance proliferation resistance of nuclear fuel, effectively utilize nuclear energy resources, and address the longer-term waste management challenges. This includes development of a state of the art Research and Development (R&D) infrastructure to support the use of a “goal oriented science based approach.” AFC uses a “goal oriented, science based approach” aimed at a fundamental understanding of fuel and cladding fabrication methods and performancemore » under irradiation, enabling the pursuit of multiple fuel forms for future fuel cycle options. This approach includes fundamental experiments, theory, and advanced modeling and simulation. One of the most challenging aspects of AFC is the management, integration, and coordination of major R&D activities across multiple organizations. AFC interfaces and collaborates with Fuel Cycle Technologies (FCT) campaigns, universities, industry, various DOE programs and laboratories, federal agencies (e.g., Nuclear Regulatory Commission [NRC]), and international organizations. Key challenges are the development of fuel technologies to enable major increases in fuel performance (safety, reliability, power and burnup) beyond current technologies, and development of characterization methods and predictive fuel performance models to enable more efficient development and licensing of advanced fuels. Challenged with the research and development of fuels for two different reactor technology platforms, AFC targeted transmutation fuel development and focused ceramic fuel development for Advanced LWR Fuels.« less

Development of a fiber-guided laser ultrasonic system resilient to high temperature and gamma radiation for nuclear power plant pipe monitoring

NASA Astrophysics Data System (ADS)

Yang, Jinyeol; Lee, Hyeonseok; Lim, Hyung Jin; Kim, Nakhyeon; Yeo, Hwasoo; Sohn, Hoon

2013-08-01

This study develops an embeddable optical fiber-guided laser ultrasonic system for structural health monitoring (SHM) of pipelines exposed to high temperature and gamma radiation inside nuclear power plants (NPPs). Recently, noncontact laser ultrasonics is gaining popularity among the SHM community because of its advantageous characteristics such as (a) scanning capability, (b) immunity against electromagnetic interference (EMI) and (c) applicability to high-temperature surfaces. However, its application to NPP pipelines has been hampered because pipes inside NPPs are often covered by insulators and/or target surfaces are not easily accessible. To overcome this problem, this study designs embeddable optical fibers and fixtures so that laser beams used for ultrasonic inspection can be transmitted between the laser sources and the target pipe. For guided-wave generation, an Nd:Yag pulsed laser coupled with an optical fiber is used. A high-power pulsed laser beam is guided through the optical fiber onto a target structure. Based on the principle of laser interferometry, the corresponding response is measured using a different type of laser beam guided by another optical fiber. All devices are especially designed to sustain high temperature and gamma radiation. The robustness/resilience of the proposed measurement system installed on a stainless steel pipe specimen has been experimentally verified by exposing the specimen to high temperature of up to 350 °C and optical fibers to gamma radiation of up to 125 kGy (20 kGy h-1).

Who Did It? Using International Forensics to Detect and Deter Nuclear Terrorism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dunlop, W H; Smith, H P

On February 2, the ''New York Times'' reported that the Pentagon has formed a nuclear forensics team tasked with identifying the terrorist attackers should the United States be hit with a nuclear bomb. Adapting nuclear technology to the forensics of exploded nuclear weapons is an old but rapidly evolving field. It dates back to at least 1949, when analysis of airborne debris, retrieved at high altitude off the coast of China, convinced President Harry Truman that the Soviet Union had exploded a nuclear device on the steppes of central Asia. The technology is neither new nor has it been particularlymore » secret, but the formation of a national nuclear forensics team was newsworthy and a useful development. An international team, however, would be even better. Although Washington has naturally focused on preventing a nuclear terrorism attack in the United States, a U.S. city is not necessarily the most likely target for nuclear terrorists. It is doubtful that a terrorist organization would be able to acquire a U.S. nuclear device and even more doubtful that it would acquire one on U.S. soil. Accordingly, if a terrorist organization does get its hands on a fission device, it is likely that it will do so on foreign territory. At that point, the terrorists will have an enormously valuable political weapon in their hands and will be loath to risk losing that asset. Given the risks associated with getting the device into the United States, the rational choice would be to deploy the device abroad against much softer targets. For Islamist terrorists, a major ''Christian'' capital such as London, Rome, or Moscow might offer a more suitable target. Among these, Moscow perhaps presents the most compelling case for international cooperation on post-detonation nuclear forensics. Russia has the largest stockpile of poorly secured nuclear devices in the world. It also has porous borders and poor internal security, and it continues to be a potential source of contraband nuclear material and weapons, despite the best efforts of the Cooperative Threat Reduction (CTR) program. If terrorists obtained the nuclear material in Russia and set Moscow as their target, they would not have to risk transporting the weapon, stolen or makeshift, across international borders. Attacks by Chechen terrorists in Beslan and the Dubrovka Theater in Moscow offer ample proof that a willingness to commit mass murder for fanatical reasons rests within Russian borders, and a foreign source of operatives, particularly from the neighboring Islamic states to the south, is by no means inconceivable. Moscow is also a predominantly Christian city where local authorities routinely discriminate against Muslim minorities. Furthermore, extremists might conclude that a nuclear blast in Moscow could inflict damage well beyond those directly stemming from the attack. The Soviet generation that came to power during the Cold War retained a memory of the United States as an ally in the Great Patriotic War. The present Russian generation has no such remembrance but seems to have retained the animosities and suspicions that were a part of the nuclear standoff. Hence, nuclear terrorists may well believe that they could cause another East-West cold war or even encourage Russia to retaliate against the United States. After all, the sinking of the Kursk was believed by some influential Russians to be the result of American action. How much more likely would be such a view if the Kremlin were destroyed? As long as the world is filled with suspicion and conflict, such reactions are to be expected and, more importantly, anticipated. One has only to remember the early reactions and suspicions in the United States following the 1996 TWA Flight 800 airline disaster. Because the United States is the technological leader in nuclear forensics, its capability will certainly be offered and probably demanded no matter what foreign city is subjected to the devastation of a nuclear explosion. The entire world, not just Americans, will live in fear of a second or third nuclear explosion, and forensics could play a vital role in removing or at least narrowing that fear. Because of such worldwide dread, there will be an international aspect to nuclear forensics regardless of where the explosion takes place. It would be better to be prepared in advance for such contingencies than to delve into the arcane world of nuclear weapons and radiochemistry on the fly.« less

Development of an Efficient Meso- scale Multi-phase Flow Solver in Nuclear Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Taehun

2015-10-20

The proposed research aims at formulating a predictive high-order Lattice Boltzmann Equation for multi-phase flows relevant to nuclear energy related application - namely, saturated and sub-cooled boiling in reactors, and liquid- liquid mixing and extraction for fuel cycle separation. An efficient flow solver will be developed based on the Finite Element based Lattice Boltzmann Method (FE- LBM), accounting for phase-change heat transfer and capable of treating multiple phases over length scales from the submicron to the meter. A thermal LBM will be developed in order to handle adjustable Prandtl number, arbitrary specific heat ratio, a wide range of temperature variations,more » better numerical stability during liquid-vapor phase change, and full thermo-hydrodynamic consistency. Two-phase FE-LBM will be extended to liquid–liquid–gas multi-phase flows for application to high-fidelity simulations building up from the meso-scale up to the equipment sub-component scale. While several relevant applications exist, the initial applications for demonstration of the efficient methods to be developed as part of this project include numerical investigations of Critical Heat Flux (CHF) phenomena in nuclear reactor fuel bundles, and liquid-liquid mixing and interfacial area generation for liquid-liquid separations. In addition, targeted experiments will be conducted for validation of this advanced multi-phase model.« less

Managing terrorism or accidental nuclear errors, preparing for iodine-131 emergencies: a comprehensive review.

PubMed

Braverman, Eric R; Blum, Kenneth; Loeffke, Bernard; Baker, Robert; Kreuk, Florian; Yang, Samantha Peiling; Hurley, James R

2014-04-15

Chernobyl demonstrated that iodine-131 (131I) released in a nuclear accident can cause malignant thyroid nodules to develop in children within a 300 mile radius of the incident. Timely potassium iodide (KI) administration can prevent the development of thyroid cancer and the American Thyroid Association (ATA) and a number of United States governmental agencies recommend KI prophylaxis. Current pre-distribution of KI by the United States government and other governments with nuclear reactors is probably ineffective. Thus we undertook a thorough scientific review, regarding emergency response to 131I exposures. We propose: (1) pre-distribution of KI to at risk populations; (2) prompt administration, within 2 hours of the incident; (3) utilization of a lowest effective KI dose; (4) distribution extension to at least 300 miles from the epicenter of a potential nuclear incident; (5) education of the public about dietary iodide sources; (6) continued post-hoc analysis of the long-term impact of nuclear accidents; and (7) support for global iodine sufficiency programs. Approximately two billion people are at risk for iodine deficiency disorder (IDD), the world's leading cause of preventable brain damage. Iodide deficient individuals are at greater risk of developing thyroid cancer after 131I exposure. There are virtually no studies of KI prophylaxis in infants, children and adolescents, our target population. Because of their sensitivity to these side effects, we have suggested that we should extrapolate from the lowest effective adult dose, 15-30 mg or 1-2 mg per 10 pounds for children. We encourage global health agencies (private and governmental) to consider these critical recommendations.

Exploring Pandora's Box: Potential and Pitfalls of Low Coverage Genome Surveys for Evolutionary Biology

PubMed Central

Leese, Florian; Mayer, Christoph; Agrawal, Shobhit; Dambach, Johannes; Dietz, Lars; Doemel, Jana S.; Goodall-Copstake, William P.; Held, Christoph; Jackson, Jennifer A.; Lampert, Kathrin P.; Linse, Katrin; Macher, Jan N.; Nolzen, Jennifer; Raupach, Michael J.; Rivera, Nicole T.; Schubart, Christoph D.; Striewski, Sebastian; Tollrian, Ralph; Sands, Chester J.

2012-01-01

High throughput sequencing technologies are revolutionizing genetic research. With this “rise of the machines”, genomic sequences can be obtained even for unknown genomes within a short time and for reasonable costs. This has enabled evolutionary biologists studying genetically unexplored species to identify molecular markers or genomic regions of interest (e.g. micro- and minisatellites, mitochondrial and nuclear genes) by sequencing only a fraction of the genome. However, when using such datasets from non-model species, it is possible that DNA from non-target contaminant species such as bacteria, viruses, fungi, or other eukaryotic organisms may complicate the interpretation of the results. In this study we analysed 14 genomic pyrosequencing libraries of aquatic non-model taxa from four major evolutionary lineages. We quantified the amount of suitable micro- and minisatellites, mitochondrial genomes, known nuclear genes and transposable elements and searched for contamination from various sources using bioinformatic approaches. Our results show that in all sequence libraries with estimated coverage of about 0.02–25%, many appropriate micro- and minisatellites, mitochondrial gene sequences and nuclear genes from different KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways could be identified and characterized. These can serve as markers for phylogenetic and population genetic analyses. A central finding of our study is that several genomic libraries suffered from different biases owing to non-target DNA or mobile elements. In particular, viruses, bacteria or eukaryote endosymbionts contributed significantly (up to 10%) to some of the libraries analysed. If not identified as such, genetic markers developed from high-throughput sequencing data for non-model organisms may bias evolutionary studies or fail completely in experimental tests. In conclusion, our study demonstrates the enormous potential of low-coverage genome survey sequences and suggests bioinformatic analysis workflows. The results also advise a more sophisticated filtering for problematic sequences and non-target genome sequences prior to developing markers. PMID:23185309

Direct production of 99mTc using a small medical cyclotron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lapi, Suzanne

This project describes an investigation towards the production of 99mTc with a small medical cyclotron. This endeavor addresses the current urgent problem of availability of 99mTc due to the ongoing production reactor failures and the upcoming Canadian reactor shut down. Currently, 99mTc is produced via nuclear fission using highly enriched uranium which is a concern due to nuclear proliferation risks. In addition to this, the United States is dependent solely on currently unreliable foreign sources of this important medical isotope. Clearly, a need exists to probe alternative production routes of 99mTc. In the first year, this project measured cross-sections andmore » production yields of potential pathways to 99mTc and associated radionuclidic impurities produced via these pathways using a small 15 MeV medical cyclotron. During the second and third years target systems for the production of 99mTc via the most promising reaction routes were developed and separation techniques for the isolation of 99mTc from the irradiated target material will be investigated. Systems for the recycling of the enriched target isotopes as well as automated target processing systems were examined in years four and five. This project has the potential to alleviate some of the current crisis in the medical community by developing a technique to produce 99mTc on location at a university hospital. This technology will be applicable at many other sites in the United States as many other similar, low energy (<20 MeV) cyclotrons (currently used for a few hours per day for the production of [ 18F]fluorodeoxyglucose) are available for production of 99mTc though this method, thus leading to job creation and preservation.« less

Peroxisome proliferator-activated receptors for hypertension

PubMed Central

Usuda, Daisuke; Kanda, Tsugiyasu

2014-01-01

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases. PMID:25228953

Target-fueled nuclear reactor for medical isotope production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coats, Richard L.; Parma, Edward J.

A small, low-enriched, passively safe, low-power nuclear reactor comprises a core of target and fuel pins that can be processed to produce the medical isotope .sup.99Mo and other fission product isotopes. The fuel for the reactor and the targets for the .sup.99Mo production are the same. The fuel can be low enriched uranium oxide, enriched to less than 20% .sup.235U. The reactor power level can be 1 to 2 MW. The reactor is passively safe and maintains negative reactivity coefficients. The total radionuclide inventory in the reactor core is minimized since the fuel/target pins are removed and processed after 7more » to 21 days.« less

Measurement of high energy neutrons via Lu(n,xn) reactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henry, E.A.; Becker, J.A.; Archer, D.E.

High energy neutrons can be assayed by the use of the nuclear diagnostic material lutetium. We are measuring the (n,xn) cross sections for natural lutetium in order to develop it as a detector material. We are applying lutetium to diagnose the high energy neutrons produced in test target/blanket systems appropriate for the Accelerator Production of Tritium Project. 3 refs., 5 figs., 1 tab.

Boron Neutron Capture Therapy for Malignant Brain Tumors

PubMed Central

MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

Boron Neutron Capture Therapy for Malignant Brain Tumors.

PubMed

Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji

2016-07-15

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.

Poster - 03: How to manage a nuclear medicine PET-CT for radiation oncology patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinse, Martin; Létourneau, Étienne; Duplan, Danny

Purpose: Development of an adapted multidisciplinary procedure designed to optimize the clinical workflow between radiation therapy (RT) and nuclear medicine (NM) for a PET-CT located in the NM department. Methods : The radiation oncologist (RO) prescribes the PET-CT exam and the clinical RT therapist gives all the necessary information to the patient prior to the exam. The immobilization accessories are prepared in the RT department. The RT and NM therapists work together for radiotracer injection, patient positioning and scan acquisition. The nuclear medicine physician (NMP) will study the images, draw Biological Target Volumes (BTVs) and produce a full exam report.more » Results : All tasks related to a planning PET-CT are done within 48 hours from the request by the RO to the reception of the images with the NMP contours and report. Conclusions : By developing a complete procedure collectively between the RT and NM departments, the patient benefits of a quick access to a RT planning PET-CT exam including the active involvement of every medical practitioners in these fields.« less

Momentum distributions of isotopes produced by fragmentation of relativistic C-12 and O-16 projectiles

NASA Technical Reports Server (NTRS)

Greiner, D. E.; Lindstrom, P. J.; Heckman, H. H.; Cork, B.; Bieser, F. S.

1975-01-01

The fragment momentum distributions in the projectile rest frame are, typically, Gaussian shaped, narrow, consistent with isotropy, depend on fragment and projectile, and have no significant correlation with target mass or beam energy. The nuclear temperature is inferred from the momentum distributions of the fragments and is approximately equal to the projectile nuclear binding energy, indicative of small energy transfer between target and fragment.

Proteomics Analysis of Nucleolar SUMO-1 Target Proteins upon Proteasome Inhibition*

PubMed Central

Matafora, Vittoria; D'Amato, Alfonsina; Mori, Silvia; Blasi, Francesco; Bachi, Angela

2009-01-01

Many cellular processes are regulated by the coordination of several post-translational modifications that allow a very fine modulation of substrates. Recently it has been reported that there is a relationship between sumoylation and ubiquitination. Here we propose that the nucleolus is the key organelle in which SUMO-1 conjugates accumulate in response to proteasome inhibition. We demonstrated that, upon proteasome inhibition, the SUMO-1 nuclear dot localization is redirected to nucleolar structures. To better understand this process we investigated, by quantitative proteomics, the effect of proteasome activity on endogenous nucleolar SUMO-1 targets. 193 potential SUMO-1 substrates were identified, and interestingly in several purified SUMO-1 conjugates ubiquitin chains were found to be present, confirming the coordination of these two modifications. 23 SUMO-1 targets were confirmed by an in vitro sumoylation reaction performed on nuclear substrates. They belong to protein families such as small nuclear ribonucleoproteins, heterogeneous nuclear ribonucleoproteins, ribosomal proteins, histones, RNA-binding proteins, and transcription factor regulators. Among these, histone H1, histone H3, and p160 Myb-binding protein 1A were further characterized as novel SUMO-1 substrates. The analysis of the nature of the SUMO-1 targets identified in this study strongly indicates that sumoylation, acting in coordination with the ubiquitin-proteasome system, regulates the maintenance of nucleolar integrity. PMID:19596686

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, G.N.; Postol, T.A.

Long-range nuclear-armed cruise missiles are highly accurate and are capable of reaching most targets within the United States and the Commonwealth of Independent States (CIS) from launch points beyond their borders. Neither the United States nor the CIS has air surveillance systems capable of providing reliable warning against cruise missiles. Thus it is possible that a small-scale cruise missile attack could go entirely undetected until the nuclear weapons arrived over their targets. Such an attack could destroy the other country's entire strategic bomber force on the ground and severely damage its strategic command and control system, perhaps to the pointmore » of endangering the ability of its ICBM force to be launched on warning. This capability makes long-range nuclear cruise missiles potentially one of the most destabilizing of all nuclear weapons.« less

Systems and methods for managing shared-path instrumentation and irradiation targets in a nuclear reactor

DOEpatents

Heinold, Mark R.; Berger, John F.; Loper, Milton H.; Runkle, Gary A.

2015-12-29

Systems and methods permit discriminate access to nuclear reactors. Systems provide penetration pathways to irradiation target loading and offloading systems, instrumentation systems, and other external systems at desired times, while limiting such access during undesired times. Systems use selection mechanisms that can be strategically positioned for space sharing to connect only desired systems to a reactor. Selection mechanisms include distinct paths, forks, diverters, turntables, and other types of selectors. Management methods with such systems permits use of the nuclear reactor and penetration pathways between different systems and functions, simultaneously and at only distinct desired times. Existing TIP drives and other known instrumentation and plant systems are useable with access management systems and methods, which can be used in any nuclear plant with access restrictions.

Mabs monograph, air blast instrumentation, 1943-1993 measurement techniques and instrumentation. Volume 1. The nuclear era. 1945-1963. Technical report, 17 September 1992-31 May 1994

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reisler, R.E.; Keefer, J.H.; Ethridge, N.H.

1995-03-01

Blast wave measurement techniques and instrumentation developed by Military Applications of Blast Simulators (MABS) participating countries to study blast phenomena during the nuclear era are summarized. Passive and active gages both mechanical self-recording and electronic systems deployed on kiloton and megaton explosive tests during the period 1945-1963 are presented. The country and the year the gage was introduced are included with the description. References are also provided. Volume 2 covers measurement techniques and instrumentation for the period 1959-1993 and Volume 3 covers structural target and gage calibration from 1943 to 1993.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akerib, DS; Alsum, S; Araújo, HM

The LUX experiment has performed searches for dark matter particles scattering elastically on xenon nuclei, leading to stringent upper limits on the nuclear scattering cross sections for dark matter. Here, for results derived frommore » $${1.4}\\times 10^{4}\\;\\mathrm{kg\\,days}$$ of target exposure in 2013, details of the calibration, event-reconstruction, modeling, and statistical tests that underlie the results are presented. Detector performance is characterized, including measured efficiencies, stability of response, position resolution, and discrimination between electron- and nuclear-recoil populations. Models are developed for the drift field, optical properties, background populations, the electron- and nuclear-recoil responses, and the absolute rate of low-energy background events. Innovations in the analysis include in situ measurement of the photomultipliers' response to xenon scintillation photons, verification of fiducial mass with a low-energy internal calibration source, and new empirical models for low-energy signal yield based on large-sample, in situ calibrations.« less

Analysis system of submicron particle tracks in the fine-grained nuclear emulsion by a combination of hard x-ray and optical microscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naka, T., E-mail: naka@flab.phys.nagoya-u.ac.jp; Institute for Advanced Research, Nagoya University, Aichi 464-8602; Asada, T.

Analyses of nuclear emulsion detectors that can detect and identify charged particles or radiation as tracks have typically utilized optical microscope systems because the targets have lengths from several μm to more than 1000 μm. For recent new nuclear emulsion detectors that can detect tracks of submicron length or less, the current readout systems are insufficient due to their poor resolution. In this study, we developed a new system and method using an optical microscope system for rough candidate selection and the hard X-ray microscope system at SPring-8 for high-precision analysis with a resolution of better than 70 nm resolution.more » Furthermore, we demonstrated the analysis of submicron-length tracks with a matching efficiency of more than 99% and position accuracy of better than 5 μm. This system is now running semi-automatically.« less

The Therapeutic Role of Xenobiotic Nuclear Receptors against Metabolic Syndrome.

PubMed

Pu, Shuqi; Wu, Xiaojie; Yang, Xiaoying; Zhang, Yunzhan; Dai, Yunkai; Zhang, Yueling; Wu, Xiaoting; Liu, Yan; Cui, Xiaona; Jin, Haiyong; Cao, Jianhong; Li, Ruliu; Cai, Jiazhong; Cao, Qizhi; Hu, Ling; Gao, Yong

2018-06-10

Xenobiotic nuclear receptors (XNRs) are nuclear receptors that characterized by coordinately regulating the expression of genes encoding drug-metabolizing enzymes and transporters to essentially eliminate and detoxify xenobiotics and endobiotics from the body, including the peroxisome proliferator-activated receptor (PPAR), the farnesoid X receptor (FXR), the liver X receptor (LXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Heretofore, increasing evidences have suggested that these five XNRs are not only involved in the regulation of xeno-/endo-biotics detoxication but also the development of human diseases, such as cancer, obesity and diabetes. PPAR, FXR, LXR, PXR and CAR, as the receptors for numerous natural or synthetic compounds may be the most effective therapeutic targets in the treatment of metabolic diseases. In this review, we will focus on these five XNRs and their recently discovered functions in diabetes and its complications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Calibration, event reconstruction, data analysis, and limit calculation for the LUX dark matter experiment

NASA Astrophysics Data System (ADS)

Akerib, D. S.; Alsum, S.; Araújo, H. M.; Bai, X.; Bailey, A. J.; Balajthy, J.; Beltrame, P.; Bernard, E. P.; Bernstein, A.; Biesiadzinski, T. P.; Boulton, E. M.; Brás, P.; Byram, D.; Cahn, S. B.; Carmona-Benitez, M. C.; Chan, C.; Currie, A.; Cutter, J. E.; Davison, T. J. R.; Dobi, A.; Dobson, J. E. Y.; Druszkiewicz, E.; Edwards, B. N.; Faham, C. H.; Fallon, S. R.; Fan, A.; Fiorucci, S.; Gaitskell, R. J.; Gehman, V. M.; Genovesi, J.; Ghag, C.; Gilchriese, M. G. D.; Hall, C. R.; Hanhardt, M.; Haselschwardt, S. J.; Hertel, S. A.; Hogan, D. P.; Horn, M.; Huang, D. Q.; Ignarra, C. M.; Jacobsen, R. G.; Ji, W.; Kamdin, K.; Kazkaz, K.; Khaitan, D.; Knoche, R.; Larsen, N. A.; Lee, C.; Lenardo, B. G.; Lesko, K. T.; Lindote, A.; Lopes, M. I.; Manalaysay, A.; Mannino, R. L.; Marzioni, M. F.; McKinsey, D. N.; Mei, D.-M.; Mock, J.; Moongweluwan, M.; Morad, J. A.; Murphy, A. St. J.; Nehrkorn, C.; Nelson, H. N.; Neves, F.; O'Sullivan, K.; Oliver-Mallory, K. C.; Palladino, K. J.; Pease, E. K.; Reichhart, L.; Rhyne, C.; Shaw, S.; Shutt, T. A.; Silva, C.; Solmaz, M.; Solovov, V. N.; Sorensen, P.; Sumner, T. J.; Szydagis, M.; Taylor, D. J.; Taylor, W. C.; Tennyson, B. P.; Terman, P. A.; Tiedt, D. R.; To, W. H.; Tripathi, M.; Tvrznikova, L.; Uvarov, S.; Velan, V.; Verbus, J. R.; Webb, R. C.; White, J. T.; Whitis, T. J.; Witherell, M. S.; Wolfs, F. L. H.; Xu, J.; Yazdani, K.; Young, S. K.; Zhang, C.; LUX Collaboration

2018-05-01

The LUX experiment has performed searches for dark-matter particles scattering elastically on xenon nuclei, leading to stringent upper limits on the nuclear scattering cross sections for dark matter. Here, for results derived from 1.4 ×104 kg days of target exposure in 2013, details of the calibration, event-reconstruction, modeling, and statistical tests that underlie the results are presented. Detector performance is characterized, including measured efficiencies, stability of response, position resolution, and discrimination between electron- and nuclear-recoil populations. Models are developed for the drift field, optical properties, background populations, the electron- and nuclear-recoil responses, and the absolute rate of low-energy background events. Innovations in the analysis include in situ measurement of the photomultipliers' response to xenon scintillation photons, verification of fiducial mass with a low-energy internal calibration source, and new empirical models for low-energy signal yield based on large-sample, in situ calibrations.

Nuclear weapons at 70: reflections on the context and legacy of the Manhattan Project

NASA Astrophysics Data System (ADS)

Reed, B. Cameron

2015-08-01

August 2015 marks the 70th anniversary of the atomic bombings of Hiroshima and Nagasaki. These bombs, the products of the United States Army’s Manhattan Project, helped to end World War II and had enormous long-term effects on global political strategies by setting the stage for the Cold War and nuclear proliferation. This article explores the context and legacy of the Manhattan Project. The state of the war in the summer of 1945 is described, as are how the target cities came to be chosen, deliberations surrounding whether the bombs should be used directly or demonstrated first, and the long-term effects of the Project on individual scientists, the relationship between scientists and society, the subsequent development of nuclear arsenals around the world, and the current status of these arsenals and how they might evolve in the future.

Application for internal dosimetry using biokinetic distribution of photons based on nuclear medicine images*

PubMed Central

Leal Neto, Viriato; Vieira, José Wilson; Lima, Fernando Roberto de Andrade

2014-01-01

Objective This article presents a way to obtain estimates of dose in patients submitted to radiotherapy with basis on the analysis of regions of interest on nuclear medicine images. Materials and Methods A software called DoRadIo (Dosimetria das Radiações Ionizantes [Ionizing Radiation Dosimetry]) was developed to receive information about source organs and target organs, generating graphical and numerical results. The nuclear medicine images utilized in the present study were obtained from catalogs provided by medical physicists. The simulations were performed with computational exposure models consisting of voxel phantoms coupled with the Monte Carlo EGSnrc code. The software was developed with the Microsoft Visual Studio 2010 Service Pack and the project template Windows Presentation Foundation for C# programming language. Results With the mentioned tools, the authors obtained the file for optimization of Monte Carlo simulations using the EGSnrc; organization and compaction of dosimetry results with all radioactive sources; selection of regions of interest; evaluation of grayscale intensity in regions of interest; the file of weighted sources; and, finally, all the charts and numerical results. Conclusion The user interface may be adapted for use in clinical nuclear medicine as a computer-aided tool to estimate the administered activity. PMID:25741101

Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy.

PubMed

Yang, Yuhui; Karakhanova, Svetlana; Hartwig, Werner; D'Haese, Jan G; Philippov, Pavel P; Werner, Jens; Bazhin, Alexandr V

2016-12-01

Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Extension of the BRYNTRN code to monoenergetic light ion beams

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Wilson, John W.; Badavi, Francis F.

1994-01-01

A monoenergetic version of the BRYNTRN transport code is extended to beam transport of light ions (H-2, H-3, He-3, and He-4) in shielding materials (thick targets). The redistribution of energy in nuclear reactions is included in transport solutions that use nuclear fragmentation models. We also consider an equilibrium target-fragment spectrum for nuclei with mass number greater than four to include target fragmentation effects in the linear energy transfer (LET) spectrum. Illustrative results for water and aluminum shielding, including energy and LET spectra, are discussed for high-energy beams of H-2 and He-4.

Nuclear Deterrence in Cyber-ia: Challenges and Controversies

DTIC Science & Technology

2016-09-01

acceptance of possible opponents. In short, the task of managing a nuclear crisis demands clear thinking and good information. But the employment of...economy, and social infrastructure. (Stuxnet was an exceptional, purpose-built destroyer of targeted nuclear facilities.) Failure of deterrence can...lead to historically unprecedented and socially catastrophic damage even in the case of a “limited” nuclear war by Cold War standards. 58 | Air

Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939.

PubMed

Yang, Jun; Liu, Yan; Wang, Bing; Lan, Hongzhen; Liu, Ying; Chen, Fei; Zhang, Ju; Luo, Jian

2017-09-07

Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies. Previously, we found that p27kip1 nuclear-cytoplasmic translocation confers proliferation potential to cholangiocarcinoma cell line QBC939 and this process is mediated by crm-1. However, no other post-transcriptional regulation was found in this process including sumoylation in cholangiocarcinoma. In this study, we explored the role of sumoylation in the nuclear-cytoplasmic translocation of p27kip1 and its involvement of QBC939 cells' proliferation. First, we identified K73 as the sumoylation site in p27kip1. By utilizing plasmid flag-p27kip1, HA-RanBP2, GST-RanBP2 and His-p27kip1 and immunoprecipitation assay, we validated that p27kip1 can serve as the sumoylation target of RanBP2 in QBC939. Furthermore, we confirmed crm-1's role in promoting nuclear-cytoplasmic translocation of p27kip1 and found that RanBP2's function relies on crm-1. However, K73R mutated p27kip1 can't be identified by crm-1 or RanBP2 in p27kip1 translocation process, suggesting sumoylation of p27kip1 via K73 site is necessary in this process by RanBP2 and crm-1. Phenotypically, the overexpression of either RanBP2 or crm-1 can partially rescue the anti-proliferative effect brought by p27kip1 overexpression in both the MTS and EdU assay. For the first time, we identified and validated the K73 sumoylation site in p27kip1, which is critical to RanBP2 and crm-1 in p27kip1 nuclear-cytoplasmic translocation process. Taken together, targeted inhibition of sumoylation of p27kip1 may serve as a potentially potent therapeutic target in the eradication of cholangiocarcinoma development and relapses.

Nuclear Diagnostics at the National Ignition Facility, 2013-2015

NASA Astrophysics Data System (ADS)

Yeamans, C. B.; Cassata, W. S.; Church, J. A.; Fittinghoff, D. N.; Gatu Johnson, M.; Gharibyan, N.; Határik, R.; Sayre, D. B.; Sio, H. W.; Bionta, R. M.; Bleuel, D. L.; Caggiano, J. A.; Cerjan, C. J.; Cooper, G. W.; Eckart, M. J.; Edwards, E. R.; Faye, S. A.; Forrest, C. J.; Frenje, J. A.; Glebov, V. Yu; Grant, P. M.; Grim, G. P.; Hartouni, E. P.; Herrmann, H. W.; Kilkenny, J. D.; Knauer, J. P.; Mackinnon, A. J.; Merrill, F. E.; Moody, K. J.; Moran, M. J.; Petrasso, R. D.; Phillips, T. W.; Rinderknecht, H. G.; Schneider, D. H. G.; Sepke, S. M.; Shaughnessy, D. A.; Stoeffl, W.; Velsko, C. A.; Volegov, P.

2016-05-01

The National Ignition Facility (NIF) relies on a suite of nuclear diagnostics to measure the neutronic output of experiments. Neutron time-of-flight (NTOF) and neutron activation diagnostics (NAD) provide performance metrics of absolute neutron yield and neutron spectral content: spectral width and non-thermal content, from which implosion physical quantities of temperature and scattering mass are inferred. Spatially-distributed flange- mounted NADs (FNAD) measure, with nearly identical systematic uncertainties, primary DT neutron emission to infer a whole-sky neutron field. An automated FNAD system is being developed. A magnetic recoil spectrometer (MRS) shares few systematics with comparable NTOF and NAD devices, and as such is deployed for independent measurement of the primary neutronic quantities. The gas-Cherenkov Gamma Reaction History (GRH) instrument records four energy channels of time-resolved gamma emission to measure nuclear bang time and burn width, as well as to infer carbon areal density in experiments utilizing plastic or diamond capsules. A neutron imaging system (NIS) takes two images of the neutron source, typically gated to create coregistered 13-15 MeV primary and 6-12 MeV downscattered images. The radiochemical analysis of gaseous samples (RAGS) instrument pumps target chamber gas to a chemical reaction and fractionation system configured with gamma counters, allowing measurement of radionuclides with half-lives as short as 8 seconds. Solid radiochemistry collectors (SRC) with backing NAD foils collect target debris, where activated materials from the target assembly are used as indicators of neutron spectrum content, and also serve as the primary diagnostic for nuclear forensic science experiments. Particle time-of-flight (PTOF) measures compression-bang time using DT- or DD-neutrons, as well as shock bang-time using D3He-protons for implosions with lower x-ray background. In concert, these diagnostics serve to measure the basic and advanced quantities required to understand NIF experimental results.

Polymeric micelles as a diagnostic tool for image-guided drug delivery and radiotherapy of HER2 overexpressing breast cancer

NASA Astrophysics Data System (ADS)

Hoang, Nu Bryan

Block copolymer micelles have emerged as a viable formulation strategy with several drugs relying on this technology in clinical evaluation. To date, information on the tumor penetration and intratumoral distribution of block copolymer micelles (BCM) has been quite limited. Thus, there is impetus to develop a radiolabeled formulation that can be used to gain invaluable insight into the intratumoral distribution of the BCMs. This information could then be used to direct formulation strategies as a means to optimize treatment outcomes. This thesis describes the synthesis and characterization of a targeted block copolymer micelle system based on poly(ethylene glycol)-block -poly(epsilon-caprolactone) labeled with the radionuclide Indium-111 (111In). The incorporation of the imageable component, 111In permits pursuit of image-guided drug delivery for real-time monitoring of tumor localization and intratumoral distribution. Intracellular trafficking of drugs and therapies such as Auger electron emitting radionuclides to perinuclear and nuclear regions of cells is critical to realizing their full therapeutic potential. HER2 specific antibodies (trastuzumab fab fragments) and nuclear localization signal peptides were conjugated to the surface of the BCMs to direct uptake in HER2 expressing cells and subsequent localization in the cell nucleus. Cell uptake was HER2 density dependent, confirming receptor-mediated internalization of the BCMs. Importantly, conjugation of NLS resulted in a significant increase in nuclear uptake of the radionuclide 111In. Successful nuclear targeting was shown to improve the antiproliferative effect of the Auger electrons. In addition, a significant radiation enhancement effect was observed by concurrent delivery of low-dose MTX and 111In in all breast cancer cell lines evaluated. Imaging enabled the accurate quantification of the specific tumor uptake of the micelles and visualization of their degree of tumor penetration in relation to microvessel density. Ultimately, the 111In-micelles could be used for such diverse applications as detection of malignancies, molecular characterization of tumors, improved therapy guidance and targeted anti-cancer treatment.

A Monte Carlo study of macroscopic and microscopic dose descriptors for kilovoltage cellular dosimetry

NASA Astrophysics Data System (ADS)

Oliver, P. A. K.; Thomson, Rowan M.

2017-02-01

This work investigates how doses to cellular targets depend on cell morphology, as well as relations between cellular doses and doses to bulk tissues and water. Multicellular models of five healthy and cancerous soft tissues are developed based on typical values of cell compartment sizes, elemental compositions and number densities found in the literature. Cells are modelled as two concentric spheres with nucleus and cytoplasm compartments. Monte Carlo simulations are used to calculate the absorbed dose to the nucleus and cytoplasm for incident photon energies of 20-370 keV, relevant for brachytherapy, diagnostic radiology, and out-of-field radiation in higher-energy external beam radiotherapy. Simulations involving cell clusters, single cells and single nuclear cavities are carried out for cell radii between 5 and 10~μ m, and nuclear radii between 2 and 9~μ m. Seven nucleus and cytoplasm elemental compositions representative of animal cells are considered. The presence of a cytoplasm, extracellular matrix and surrounding cells can affect the nuclear dose by up to 13 % . Differences in cell and nucleus size can affect dose to the nucleus (cytoplasm) of the central cell in a cluster of 13 cells by up to 13 % (8 % ). Furthermore, the results of this study demonstrate that neither water nor bulk tissue are reliable substitutes for subcellular targets for incident photon energies  <50 keV: nuclear (cytoplasm) doses differ from dose-to-medium by up to 32 % (18 % ), and from dose-to-water by up to 21 % (8 % ). The largest differences between dose descriptors are seen for the lowest incident photon energies; differences are less than 3 % for energies ≥slant 90 keV. The sensitivity of results with regard to the parameters of the microscopic tissue structure model and cell model geometry, and the importance of the nucleus and cytoplasm as targets for radiation-induced cell death emphasize the importance of accurate models for cellular dosimetry studies.

Optimal Fragmentation and Dispersion of Hazardous Near-Earth Objects

NASA Technical Reports Server (NTRS)

Wie, Bong

2012-01-01

The complex problem of protecting the Earth from the possibility of a catastrophic impact by a hazardous near-Earth object (NEO) has been recently reassessed in [1]. In a letter on NEOs from the White House Office of Science and Technology Policy (OSTP) to the U.S. Senate and Congress in 2010, the White House OSTP strongly recommended that NASA take the lead in conducting research activities for NEO detection, characterization, and deflection technologies. Furthermore, President Obama's new National Space Policy specifically directs NASA to "pursue capabilities, in cooperation with other departments, agencies, and commercial partners, to detect, track, catalog, and characterize NEOs to reduce the risk of harm to humans from an unexpected impact on our planet." The Planetary Defense Task Force of the NASA Advisory Council also recommended that the NASA Office of the Chief Technologist (OCT) begin efforts to investigate asteroid deflection techniques. With national interest growing in the United States, the NEO threat detection and mitigation problem was recently identified as one of NASA's Space Technology Grand Challenges. An innovative solution to NASA's NEO Impact Threat Mitigation Grand Challenge problem was developed through a NIAC Phase I study (9/16/11 - 9/15/12), and it will be further investigated for a NIAC Phase II study (9/10/12 - 9/9/14). Various NEO deflection technologies, including nuclear explosions, kinetic impactors, and slow-pull gravity tractors, have been proposed and examined during the past two decades. Still, there is no consensus on how to reliably deflect or disrupt hazardous NEOs in a timely manner. It is expected that the most probable mission scenarios will have a mission lead time much shorter than 10 years, so the use of nuclear explosives becomes the most feasible method for planetary defense. Direct intercept missions with a short warning time will result in arrival closing velocities of 10-30 kilometers per second with respect to the target asteroid. Given such a large arrival delta V requirement, a rendezvous mission to the target asteroid is infeasible with existing launch vehicles. Furthermore, state-of-the-art penetrating subsurface nuclear explosion technology limits the penetrator's impact velocity to less than approximately 300 meters per second because higher impact velocities prematurely destroy the nuclear fuzing mechanisms. Therefore, significant advances in hypervelocity nuclear interceptor/ penetrator technology must be achieved to enable a last-minute nuclear disruption mission with intercept velocities as high as 30 kilometers per second. Consequently, a HAIV (Hypervelocity Asteroid Intercept Vehicle) mission architecture (Figure 1.1), which blends a hypervelocity kinetic impactor with a subsurface nuclear explosion for optimal fragmentation and dispersion of hazardous NEOs, has been developed through a Phase I study, and it will be further developed and validated through a Phase II study.

Targeted estrogen delivery reverses the metabolic syndrome

PubMed Central

Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

2013-01-01

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

Target fragmentation in radiobiology

NASA Technical Reports Server (NTRS)

Wilson, John W.; Cucinotta, Francis A.; Shinn, Judy L.; Townsend, Lawrence W.

1993-01-01

Nuclear reactions in biological systems produce low-energy fragments of the target nuclei seen as local high events of linear energy transfer (LET). A nuclear-reaction formalism is used to evaluate the nuclear-induced fields within biosystems and their effects within several biological models. On the basis of direct ionization interaction, one anticipates high-energy protons to have a quality factor and relative biological effectiveness (RBE) of unity. Target fragmentation contributions raise the effective quality factor of 10 GeV protons to 3.3 in reasonable agreement with RBE values for induced micronuclei in bean sprouts. Application of the Katz model indicates that the relative increase in RBE with decreasing exposure observed in cell survival experiments with 160 MeV protons is related solely to target fragmentation events. Target fragment contributions to lens opacity given an RBE of 1.4 for 2 GeV protons in agreement with the work of Lett and Cox. Predictions are made for the effective RBE for Harderian gland tumors induced by high-energy protons. An exposure model for lifetime cancer risk is derived from NCRP 98 risk tables, and protraction effects are examined for proton and helium ion exposures. The implications of dose rate enhancement effects on space radiation protection are considered.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niu, Mingshan; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu

Constitutive NF-κB activation is required for survival of activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). However, current NF-κB targeting strategies lack cancer cell specificity. Here, we identified a novel inhibitor, piperlongumine, features direct binding to NF-κB p65 subunit and suppression of p65 nuclear import. This was accompanied by NF-κB reporter activity suppression and NF-κB target gene downregulation. Moreover, mutation of Cys{sup 38} to Ser in p65 abolished this effect of piperlongumine on inhibition of p65 nuclear import. Furthermore, we show that piperlongumine selectively inhibited proliferation and induced apoptosis of ABC-DLBCL cells. Most notably, it has beenmore » reported that piperlongumine did not affect normal cells even at high doses and was nontoxic to animals. Hence, our current study provides new insight into piperlongumine's mechanism of action and novel approach to ABC-DLBCL target therapy. - Highlights: • Current NF-κB targeting strategies lack cancer cell specificity. • Piperlongumine inhibits NF-κB p65 subunit nuclear import via directly binding to p65. • Piperlongumine selectively inhibits proliferation of ABC-DLBCL cells. • This study provides a novel approach to ABC-DLBCL target therapy.« less

The RIB production target for the SPES project

NASA Astrophysics Data System (ADS)

Monetti, Alberto; Andrighetto, Alberto; Petrovich, Carlo; Manzolaro, Mattia; Corradetti, Stefano; Scarpa, Daniele; Rossetto, Francesco; Martinez Dominguez, Fernando; Vasquez, Jesus; Rossignoli, Massimo; Calderolla, Michele; Silingardi, Roberto; Mozzi, Aldo; Borgna, Francesca; Vivian, Gianluca; Boratto, Enrico; Ballan, Michele; Prete, Gianfranco; Meneghetti, Giovanni

2015-10-01

Facilities making use of the Isotope Separator On-Line (ISOL) method for the production of Radioactive Ion Beams (RIB) attract interest because they can be used for nuclear structure and reaction studies, astrophysics research and interdisciplinary applications. The ISOL technique is based on the fast release of the nuclear reaction products from the chosen target material together with their ionization into short-lived nuclei beams. Within this context, the SPES (Selective Production of Exotic Species) facility is now under construction in Italy at INFN-LNL (Istituto Nazionale di Fisica Nucleare — Laboratori Nazionali di Legnaro). The SPES facility will produce RIBs mainly from n-rich isotopes obtained by a 40 MeV cyclotron proton beam (200 μA) directly impinging on a uranium carbide multi-foil fission target. The aim of this work is to describe and update, from a comprehensive point of view, the most important results obtained by the analysis of the on-line behavior of the SPES production target assembly. In particular an improved target configuration has been studied by comparing different codes and physics models: the thermal analyses and the isotope production are re-evaluated. Then some consequent radioprotection aspects, which are essential for the installation and operation of the facility, are presented.

Preparation and characterisation of isotopically enriched Ta2O5 targets for nuclear astrophysics studies

NASA Astrophysics Data System (ADS)

Caciolli, A.; Scott, D. A.; Di Leva, A.; Formicola, A.; Aliotta, M.; Anders, M.; Bellini, A.; Bemmerer, D.; Broggini, C.; Campeggio, M.; Corvisiero, P.; Depalo, R.; Elekes, Z.; Fülöp, Zs.; Gervino, G.; Guglielmetti, A.; Gustavino, C.; Gyürky, Gy.; Imbriani, G.; Junker, M.; Marta, M.; Menegazzo, R.; Napolitani, E.; Prati, P.; Rigato, V.; Roca, V.; Rolfs, C.; Rossi Alvarez, C.; Somorjai, E.; Salvo, C.; Straniero, O.; Strieder, F.; Szücs, T.; Terrasi, F.; Trautvetter, H. P.; Trezzi, D.

2012-10-01

The direct measurement of reaction cross-sections at astrophysical energies often requires the use of solid targets of known thickness, isotopic composition, and stoichiometry that are able to withstand high beam currents for extended periods of time. Here, we report on the production and characterisation of isotopically enriched Ta2O5 targets for the study of proton-induced reactions at the Laboratory for Underground Nuclear Astrophysics facility of the Laboratori Nazionali del Gran Sasso. The targets were prepared by anodisation of tantalum backings in enriched water (up to 66% in 17O and up to 96% in 18O. Special care was devoted to minimising the presence of any contaminants that could induce unwanted background reactions with the beam in the energy region of astrophysical interest. Results from target characterisation measurements are reported, and the conclusions for proton capture measurements with these targets are drawn.

Fabrication of 121Sb isotopic targets for the study of nuclear high spin features

NASA Astrophysics Data System (ADS)

Devi, K. Rojeeta; Kumar, Suresh; Kumar, Neeraj; Abhilash, S. R.; Kabiraj, D.

2018-06-01

Isotopic 121Sb targets with 197Au backing have been prepared by Physical Vapor Deposition (PVD) method using the diffusion pump based coating unit at target laboratory, Inter University Accelerator Centre (IUAC), New Delhi, India. The target thickness was measured by stylus profilo-meter and the purity of the targets was investigated by Energy Dispersive X-ray Analysis (EDXA). One of these targets has been used in an experiment which was performed at IUAC for nuclear structure study through fusion evaporation reaction. The excitation function of the 121Sb(12C, yxnγ) reaction has been performed for energies 58 to 70 MeV in steps of 4 MeV. The experimental results were compared with the calculations of statistical models : PACE4 and CASCADE. The methods adopted to achieve best quality foils and good deposition efficiency are reported in this paper.

The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior

PubMed Central

Jessen, Heather M.; Kolodkin, Mira H.; Bychowski, Meaghan E.; Auger, Catherine J.; Auger, Anthony P.

2010-01-01

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females. PMID:20051490

The nuclear receptor corepressor has organizational effects within the developing amygdala on juvenile social play and anxiety-like behavior.

PubMed

Jessen, Heather M; Kolodkin, Mira H; Bychowski, Meaghan E; Auger, Catherine J; Auger, Anthony P

2010-03-01

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.

The unified database for the fixed target experiment BM@N

NASA Astrophysics Data System (ADS)

Gertsenberger, K. V.

2016-09-01

The article describes the developed database designed as comprehensive data storage of the fixed target experiment BM@N [1] at Joint Institute for Nuclear Research (JINR) in Dubna. The structure and purposes of the BM@N facility will be briefly presented. The scheme of the unified database and its parameters will be described in detail. The use of the BM@N database implemented on the PostgreSQL database management system (DBMS) allows one to provide user access to the actual information of the experiment. Also the interfaces developed for the access to the database will be presented. One was implemented as the set of C++ classes to access the data without SQL statements, the other-Web-interface being available on the Web page of the BM@N experiment.

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis.

PubMed

He, Hongliang; Yuan, Quan; Bie, Jinghua; Wallace, Ryan L; Yannie, Paul J; Wang, Jing; Lancina, Michael G; Zolotarskaya, Olga Yu; Korzun, William; Yang, Hu; Ghosh, Shobha

2018-03-01

Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR-/- mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque burden. Copyright © 2017 Elsevier Inc. All rights reserved.

Topics in nuclear chromodynamics: Color transparency and hadronization in the nucleus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brodsky, S.J.

1988-03-01

The nucleus plays two complimentary roles in quantum chromodynamics: (1) A nuclear target can be used as a control medium or background field to modify or probe quark and gluon subprocesses. Some novel examples are color transparency, the predicted transparency of the nucleus to hadrons participating in high momentum transfer exclusive reactions, and formation zone phenomena, the absence of hard, collinear, target-induced radiation by a quark or gluon interacting in a high momentum transfer inclusive reaction if its energy is large compared to a scale proportional to the length of the target. (Soft radiation and elastic initial state interactions inmore » the nucleus still occur.) Coalescence with co-moving spectators is discussed as a mechanism which can lead to increased open charm hadroproduction, but which also suppresses forward charmonium production (relative to lepton pairs) in heavy ion collisions. Also discussed are some novel features of nuclear diffractive amplitudes--high energy hadronic or electromagnetic reactions which leave the entire nucleus intact and give nonadditive contributions to the nuclear structure function at low /kappa cur//sub Bj/. (2) Conversely, the nucleus can be studied as a QCD structure. At short distances, nuclear wave functions and nuclear interactions necessarily involve hidden color, degrees of freedom orthogonal to the channels described by the usual nucleon or isobar degrees of freedom. At asymptotic momentum transfer, the deuteron form factor and distribution amplitude are rigorously calculable. One can also derive new types of testable scaling laws for exclusive nuclear amplitudes in terms of the reduced amplitude formalism.« less

Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

PubMed Central

Heerma van Voss, Marise R; Vesuna, Farhad; Bol, Guus M; Meeldijk, Jan; Raman, Ana; Offerhaus, G Johan; Buerger, Horst; Patel, Arvind H; van der Wall, Elsken; van Diest, Paul J; Raman, Venu

2017-01-01

Purpose DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Methods Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. Results DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Conclusion Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types. PMID:28761359

Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer.

PubMed

Heerma van Voss, Marise R; Vesuna, Farhad; Bol, Guus M; Meeldijk, Jan; Raman, Ana; Offerhaus, G Johan; Buerger, Horst; Patel, Arvind H; van der Wall, Elsken; van Diest, Paul J; Raman, Venu

2017-01-01

DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P <0.001) and breast cancer (HR 2.39, P =0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P =0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types.

Strategic policy and process: An assessment of the evolution of American nuclear strategy, its determinants, and its implications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lehman, C.M.

1993-01-01

This dissertation examines the evolution of American strategic nuclear policy with particular emphasis on the substantial change in nuclear doctrine which occurred during the first and second Administrations of President Richard M. Nixon. The dissertation argues that this period saw the emergence of a new and substantially different strategic nuclear policy which changed fundamentally the basis upon which America's nuclear deterrence rested. It argues, further, that this policy has remained largely unchanged through the course of five succeeding administrations. The dissertation describes and analyzes the evolution of the defense policy formulation process of the United States government from the yearsmore » of the Truman Administration to the Bush Administration. Primary attention is directed towards identifying the specific policies of each Administration highlighting the factors which appear to have been the most significant in prompting changes in American strategic nuclear policy. An in-depth examination of strategic nuclear policy formulation and implementation is provided for the period of the Nixon Administration. The Administration's policies are analyzed and the full constellation of forces that brought about a major adjustment in the strategic nuclear policy of the Unites States are identified and analyzed. Particular emphasis is placed on tracking and assessing the role that Congress has played in the development of nuclear policy before, during, and after Nixon years. Specific attention is directed to defining the [open quotes]determinants[close quotes] of strategic nuclear policy and to a careful delineation of the dangers associated with a divergence between public policy pronouncements an the actual employment or targeting practices governing the potential use of nuclear weapons. A final section draws conclusions and postulates several basic guidelines for the formulation of future US strategic nuclear policy.« less

Multi-layered nanoparticles for penetrating the endosome and nuclear membrane via a step-wise membrane fusion process.

PubMed

Akita, Hidetaka; Kudo, Asako; Minoura, Arisa; Yamaguti, Masaya; Khalil, Ikramy A; Moriguchi, Rumiko; Masuda, Tomoya; Danev, Radostin; Nagayama, Kuniaki; Kogure, Kentaro; Harashima, Hideyoshi

2009-05-01

Efficient targeting of DNA to the nucleus is a prerequisite for effective gene therapy. The gene-delivery vehicle must penetrate through the plasma membrane, and the DNA-impermeable double-membraned nuclear envelope, and deposit its DNA cargo in a form ready for transcription. Here we introduce a concept for overcoming intracellular membrane barriers that involves step-wise membrane fusion. To achieve this, a nanotechnology was developed that creates a multi-layered nanoparticle, which we refer to as a Tetra-lamellar Multi-functional Envelope-type Nano Device (T-MEND). The critical structural elements of the T-MEND are a DNA-polycation condensed core coated with two nuclear membrane-fusogenic inner envelopes and two endosome-fusogenic outer envelopes, which are shed in stepwise fashion. A double-lamellar membrane structure is required for nuclear delivery via the stepwise fusion of double layered nuclear membrane structure. Intracellular membrane fusions to endosomes and nuclear membranes were verified by spectral imaging of fluorescence resonance energy transfer (FRET) between donor and acceptor fluorophores that had been dually labeled on the liposome surface. Coating the core with the minimum number of nucleus-fusogenic lipid envelopes (i.e., 2) is essential to facilitate transcription. As a result, the T-MEND achieves dramatic levels of transgene expression in non-dividing cells.

Molecular-genetic imaging based on reporter gene expression.

PubMed

Kang, Joo Hyun; Chung, June-Key

2008-06-01

Molecular imaging includes proteomic, metabolic, cellular biologic process, and genetic imaging. In a narrow sense, molecular imaging means genetic imaging and can be called molecular-genetic imaging. Imaging reporter genes play a leading role in molecular-genetic imaging. There are 3 major methods of molecular-genetic imaging, based on optical, MRI, and nuclear medicine modalities. For each of these modalities, various reporter genes and probes have been developed, and these have resulted in successful transitions from bench to bedside applications. Each of these imaging modalities has its unique advantages and disadvantages. Fluorescent and bioluminescent optical imaging modalities are simple, less expensive, more convenient, and more user friendly than other imaging modalities. Another advantage, especially of bioluminescence imaging, is its ability to detect low levels of gene expression. MRI has the advantage of high spatial resolution, whereas nuclear medicine methods are highly sensitive and allow data from small-animal imaging studies to be translated to clinical practice. Moreover, multimodality imaging reporter genes will allow us to choose the imaging technologies that are most appropriate for the biologic problem at hand and facilitate the clinical application of reporter gene technologies. Reporter genes can be used to visualize the levels of expression of particular exogenous and endogenous genes and several intracellular biologic phenomena, including specific signal transduction pathways, nuclear receptor activities, and protein-protein interactions. This technique provides a straightforward means of monitoring tumor mass and can visualize the in vivo distributions of target cells, such as immune cells and stem cells. Molecular imaging has gradually evolved into an important tool for drug discovery and development, and transgenic mice with an imaging reporter gene can be useful during drug and stem cell therapy development. Moreover, instrumentation improvements, the identification of novel targets and genes, and imaging probe developments suggest that molecular-genetic imaging is likely to play an increasingly important role in the diagnosis and therapy of cancer.

Development of a Time-Resolved Fluorescence Resonance Energy Transfer Ultrahigh-Throughput Screening Assay for Targeting the NSD3 and MYC Interaction. | Office of Cancer Genomics

Cancer.gov

Epigenetic modulators play critical roles in reprogramming of cellular functions, emerging as a new class of promising therapeutic targets. Nuclear receptor binding SET domain protein 3 (NSD3) is a member of the lysine methyltransferase family. Interestingly, the short isoform of NSD3 without the methyltransferase fragment, NSD3S, exhibits oncogenic activity in a wide range of cancers. We recently showed that NSD3S interacts with MYC, a central regulator of tumorigenesis, suggesting a mechanism by which NSD3S regulates cell proliferation through engaging MYC.

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology.

PubMed

Krasniqi, Ahmet; D'Huyvetter, Matthias; Devoogdt, Nick; Frejd, Fredrik Y; Sörensen, Jens; Orlova, Anna; Keyaerts, Marleen; Tolmachev, Vladimir

2018-06-01

Imaging of expression of therapeutic targets may enable stratification of patients for targeted treatments. The use of small radiolabeled probes based on the heavy-chain variable region of heavy-chain-only immunoglobulins or nonimmunoglobulin scaffolds permits rapid localization of radiotracers in tumors and rapid clearance from normal tissues. This makes high-contrast imaging possible on the day of injection. This mini review focuses on small proteins for radionuclide-based imaging that would allow same-day imaging, with the emphasis on clinical applications and promising preclinical developments within the field of oncology. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Radiobromine production, isolation and radiosynthesis for the development of a novel prostate cancer radiotherapeutic agent

NASA Astrophysics Data System (ADS)

Ellison, Paul A.; Graves, Stephen A.; Murali, Dhanabalan; De Jesus, Onofre T.; Barnhart, Todd E.; Thomadsen, Bruce R.; Speer, Tod; Nickles, Robert J.

2017-05-01

The radioactive isotopes of bromine accessible with low energy medical cyclotrons have unique potential for diagnostic and radiotherapeutic nuclear medicine applications. These include bromine-76 (t1/2 = 16 h) for positron emission tomography and bromine-77 (t1/2 = 57 h) for Auger radionuclide therapy. Methods are presented to synthesize NiSe discs from elemental starting materials for proton irradiation in a 4π water cooling target configuration. Radiobromide was isolated from the irradiated NiSe material by dry distillation and used to radiolabel 7α-BrDHT for investigation as an Androgen-receptor-targeted theranostic radiopharmaceutical.

Coherent dissociation of relativistic {sup 9}C nuclei in nuclear track emulsion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krivenkov, D. O.; Artemenkov, D. A.; Bradnova, V.

2010-04-30

For the first time nuclear track emulsion is exposed to relativistic {sup 9}C nuclei. A systematic pattern of the distributions of charge combinations of fragments in the peripheral interactions of {sup 9}C nuclei in a nuclear track emulsion has been obtained. The main conclusion is that the contribution of the channel {sup 9}C->{sup 8}B+p and {sup 9}C->{sup 7}Be+2p is most important in events that do not involve the production of target-nucleus fragments or mesons (coherent dissociation). It can be concluded that in the peripheral {sup 9}C dissociation the picture hitherto obtained for {sup 8}B and {sup 7}Be with the additionmore » of one or two protons, respectively, is reproduced. Three coherent dissociation events {sup 9}C->3{sup 3}He accompanied by neither target fragments of the nucleus target nor charged mesons are identified.« less

Aptamer-Mediated Codelivery of Doxorubicin and NF-κB Decoy Enhances Chemosensitivity of Pancreatic Tumor Cells

PubMed Central

Porciani, David; Tedeschi, Lorena; Marchetti, Laura; Citti, Lorenzo; Piazza, Vincenzo; Beltram, Fabio; Signore, Giovanni

2015-01-01

Aptamers able to bind efficiently cell-surface receptors differentially expressed in tumor and in healthy cells are emerging as powerful tools to perform targeted anticancer therapy. Here, we present a novel oligonucleotide chimera, composed by an RNA aptamer and a DNA decoy. Our assembly is able to (i) target tumor cells via an antitransferrin receptor RNA aptamer and (ii) perform selective codelivery of a chemotherapeutic drug (Doxorubicin) and of an inhibitor of a cell-survival factor, the nuclear factor κB decoy oligonucleotide. Both payloads are released under conditions found in endolysosomal compartments (low pH and reductive environment). Targeting and cytotoxicity of the oligonucleotidic chimera were assessed by confocal microscopy, cell viability, and Western blot analysis. These data indicated that the nuclear factor κB decoy does inhibit nuclear factor κB activity and ultimately leads to an increased therapeutic efficacy of Doxorubicin selectively in tumor cells. PMID:25919089

Cytomegalovirus recruitment of cellular kinases to dissolve the nuclear lamina.

PubMed

Muranyi, Walter; Haas, Jürgen; Wagner, Markus; Krohne, Georg; Koszinowski, Ulrich H

2002-08-02

The passage of large-sized herpesviral capsids through the nuclear lamina and the inner nuclear membrane to leave the nucleus requires a dissolution of the nuclear lamina. Here, we report on the functions of M50/p35, a beta-herpesviral protein of murine cytomegalovirus. M50/p35 inserts into the inner nuclear membrane and is aggregated by a second viral protein, M53/p38, to form the capsid docking site. M50/p35 recruits the cellular protein kinase C for phosphorylation and dissolution of the nuclear lamina, suggesting that herpesviruses target a critical element of nuclear architecture.

Functionalized PEI Nanoparticles For Delivery Of IGF-1R-Targeted siRNA's to UPAR-Expressing Tumors In Vitro And In Vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giblin, Michael F

2012-12-14

This proposal addressed the use of imaging technologies to develop therapeutic nanoparticle constructs which could reduce expression of molecules within the cancer cell important in tumor progression. The proposal described new labeling techniques that would result in therapeutic constructs which could be tracked both within targeted cells individually as well as within the individuals being treated. Representing a new generation of dual-labeled in vivo imaging agent, the constructs envisioned here would allow microPET imaging of targeted receptor expression as well as fluorescent imaging of silencing complexes targeting IGF-1R mRNA's. As such, this proposal was highly relevant to the Office ofmore » Biological and Environmental Research (BER) goals of facilitating improvements in radiotracer design in order to solve critical problems in biology and nuclear medicine.« less

Cellular and molecular mechanisms of HIV-1 integration targeting.

PubMed

Engelman, Alan N; Singh, Parmit K

2018-07-01

Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co-activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus-host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors.

Targeted Nuclear Imaging Probes for Cardiac Amyloidosis.

PubMed

Bravo, Paco E; Dorbala, Sharmila

2017-07-01

The aim of the present manuscript is to review the latest advancements of radionuclide molecular imaging in the diagnosis and prognosis of individuals with cardiac amyloidosis. 99m Technetium labeled bone tracer scintigraphy had been known to image cardiac amyloidosis, since the 1980s; over the past decade, bone scintigraphy has been revived specifically to diagnose transthyretin cardiac amyloidosis. 18 F labeled and 11 C labeled amyloid binding radiotracers developed for imaging Alzheimer's disease, have been repurposed since 2013, to image light chain and transthyretin cardiac amyloidosis. 99m Technetium bone scintigraphy for transthyretin cardiac amyloidosis, and amyloid binding targeted PET imaging for light chain and transthyretin cardiac amyloidosis, are emerging as highly accurate methods. Targeted radionuclide imaging may soon replace endomyocardial biopsy in the evaluation of patients with suspected cardiac amyloidosis. Further research is warranted on the role of targeted imaging to quantify cardiac amyloidosis and to guide therapy.

Radioisotope Electric Propulsion for Fast Outer Planetary Orbiters

NASA Technical Reports Server (NTRS)

Oleson, Steven; Benson, Scott; Gefert, Leon; Patterson, Michael; Schreiber, Jeffrey

2002-01-01

Recent interest in outer planetary targets by the Office of Space Science has spurred the search for technology options to enable relatively quick missions to outer planetary targets. Several options are being explored including solar electric propelled stages combined with aerocapture at the target and nuclear electric propulsion. Another option uses radioisotope powered electric thrusters to reach the outer planets. Past work looked at using this technology to provide faster flybys. A better use for this technology is for outer planet orbiters. Combined with medium class launch vehicles and a new direct trajectory these small, sub-kilowatt ion thrusters and Stirling radioisotope generators were found to allow missions as fast as 5 to 12 years for objects from Saturn to Pluto, respectively. Key to the development is light spacecraft and science payload technologies.

Genetic transformation protocols using zygotic embryos as explants: an overview.

PubMed

Tahir, Muhammad; Waraich, Ejaz A; Stasolla, Claudio

2011-01-01

Genetic transformation of plants is an innovative research tool which has practical significance for the development of new and improved genotypes or cultivars. However, stable introduction of genes of interest into nuclear genomes depends on several factors such as the choice of target tissue, the method of DNA delivery in the target tissue, and the appropriate method to select the transformed plants. Mature or immature zygotic embryos have been a popular choice as explant or target tissue for genetic transformation in both angiosperms and gymnosperms. As a result, considerable protocols have emerged in the literature which have been optimized for various plant species in terms of transformation methods and selection procedures for transformed plants. This article summarizes the recent advances in plant transformation using zygotic embryos as explants.

Thin-thick hydrogen target for nuclear physics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gheller, J.-M.; Juster, F.-P.; Authelet, G.

In spectroscopic studies of unstable nuclei, hydrogen targets are of key importance. The CHyMENE Project aims to provide to the nuclear physics community a thin and pure solid windowless hydrogen or deuterium target. CHyMENE project must respond to this request for the production of solid Hydrogen. The solid hydrogen target is produced in a continuous flow (1 cm/s) by an extrusion technique (developed with the PELIN laboratory) in a vacuum chamber. The shape of the target is determined by the design of the nozzle at the extrusion process. For the purpose, the choice is a rectangular shape with a widthmore » of 10 mm and a thickness in the range of 30-50 microns necessary for the physics objectives. The cryostat is equipped with a GM Cryocooler with sufficient power for the solidification of the hydrogen in the lower portion of the extruder. In the higher part of the cryostat, the hydrogen gas is first liquefied and partially solidified. It is then compressed at 100 bars in the cooled extruder before expulsion of the film through the nozzle at the center of the reaction vacuum chamber. After the previous step, the solid hydrogen ribbon falls by gravity into a dedicated chamber where it sublimes and the gas is pumped and evacuated in a exhaust line. This paper deals with the design of the cryostat with its equipment, with the sizing of the thermal bridge (Aluminum and copper), with the results regarding the contact resistance as well as with the vacuum computations of the reaction and recovery hydrogen gas chambers.« less

Russian University Education in Nuclear Safeguards and Security

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duncan, Cristen L.; Kryuchkov, Eduard F.; Geraskin, Nikolay I.

2009-03-15

As safeguards and security (S&S) systems are installed and upgraded in nuclear facilities throughout Russia, it becomes increasingly important to develop mechanisms for educating future Russian nuclear scientists and engineers in the technologies and methodologies of physical protection (PP) and nuclear material control and accounting (MC&A). As part of the U.S. Department of Energy’s (DOE) program to secure nuclear materials in Russia, the Education Project supports technical S&S degree programs at key Russian universities and nonproliferation education initiatives throughout the Russian Federation that are necessary to achieve the overall objective of fostering qualified and vigilant Russian S&S personnel. The Educationmore » Project supports major educational degree programs at the Moscow Engineering Physics Institute (MEPhI) and Tomsk Polytechnic University (TPU). The S&S Graduate Program is available only at MEPhI and is the world’s first S&S degree program. Ten classes of students have graduated with a total of 79 Masters Degrees as of early 2009. At least 84% of the graduates over the ten years are still working in the S&S field. Most work at government agencies or research organizations, and some are pursuing their PhD. A 5½ year Engineering Degree Program (EDP) in S&S is currently under development at MEPhI and TPU. The EDP is more tailored to the needs of nuclear facilities. The program’s first students (14) graduated from MEPhI in February 2007. Similar-sized classes are graduating from MEPhI each February. All of the EDP graduates are working in the S&S field, many at nuclear facilities. TPU also established an EDP and graduated its first class of approximately 18 students in February 2009. For each of these degree programs, the American project team works with MEPhI and TPU to develop appropriate curriculum, identify and acquire various training aids, develop and publish textbooks, and strengthen instructor skills. The project has also supported the instruction of policy-oriented nonproliferation courses at various Russian universities. These courses are targeted towards future workers in the nuclear field to help build an effective nonproliferation awareness within the nuclear complex. A long-range goal of this project is to assist the educational programs at MEPhI and TPU in becoming self-sustainable and therefore able to maintain the three degree programs without DOE support. This paper describes current development of these education programs and new initiatives. The paper also describes general nonproliferation education activities supported by DOE that complement the more technical S&S degree programs.« less

MICROMEGAS calibration for ACTAR TPC

NASA Astrophysics Data System (ADS)

Mauss, B.; Roger, T.; Pancin, J.; Damoy, S.; Grinyer, G. F.

2018-02-01

Active targets, such as the ACtive TARget and Time Projection Chamber (ACTAR TPC) being developed at GANIL, are detection systems that operate on the basis of a time projection chamber but where the filling gas also serves as a thick target for nuclear reactions. In nuclear physics experiments, the energy resolution is of primary importance to identify the reaction products and to precisely reconstruct level schemes of nuclei. These measurements are based on the energy deposited on a pixelated pad plane. A MICROMEGAS detector is used in ACTAR TPC for the ionization electron collection and amplification, and it is a major contributor to the energy dispersion through, for example, inhomogeneities of the amplification gap. A variation of one percent in the gap can lead to an amplitude variation of more than two percent which is of the same order as the resolution obtained with an energy deposition of 5 MeV. One way to calibrate the pad plane is through the use of a two dimensional source scanning table. It is used to calibrate the gain inhomogeneities and, using MAGBOLTZ calculations, deduce the corresponding gap variations. The inverse of this method would allow the relative gain variations to be calculated for the different gas mixtures and pressures used in experiments with ACTAR TPC.

High energy primary knock-on process in metal deuterium systems initiated by bombardment with noble gas ions

NASA Astrophysics Data System (ADS)

Gann, V. V.; Tolstolutskaya, G. D.

2008-08-01

An experimental study confirms the possibility of nuclear fusion reactions initiating in metal-deuterium targets by bombarding them with ions that are not the reagents of the fusion reaction, in particular, with noble gas ions. The yields of (d,d) and (d,t) reactions were measured as functions of energy (0.4-3.2 MeV) and mass of incident ions (He +, Ne +, Ar +, Kr + and Xe +). Irradiation by heavy ions produced a number of energetic deuterium atoms in the deuteride and deuterium + tritium metal targets. At ion energies of ˜0.1-1 MeV the d-d reaction yields are relatively high. A model of nuclear fusion reaction cross-sections in atomic collision cascades initiated by noble gas ion beam in metal-deuterium target is developed. The method for calculation tritium or deuterium recoil fluxes and the yield of d-d fusion reaction in subsequent collisions was proposed. It was shown that D(d,p)t and D(t,n) 4He reactions mainly occur in energy region of the recoiled D-atom from 10 keV to 250 keV. The calculated probabilities of d-d and d-t fusion reactions were found to be in a good agreement with the experimental data.

Abundant off-target edits from site-directed RNA editing can be reduced by nuclear localization of the editing enzyme.

PubMed

Vallecillo-Viejo, Isabel C; Liscovitch-Brauer, Noa; Montiel-Gonzalez, Maria Fernanda; Eisenberg, Eli; Rosenthal, Joshua J C

2018-01-02

Site-directed RNA editing (SDRE) is a general strategy for making targeted base changes in RNA molecules. Although the approach is relatively new, several groups, including our own, have been working on its development. The basic strategy has been to couple the catalytic domain of an adenosine (A) to inosine (I) RNA editing enzyme to a guide RNA that is used for targeting. Although highly efficient on-target editing has been reported, off-target events have not been rigorously quantified. In this report we target premature termination codons (PTCs) in messages encoding both a fluorescent reporter protein and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein transiently transfected into human epithelial cells. We demonstrate that while on-target editing is efficient, off-target editing is extensive, both within the targeted message and across the entire transcriptome of the transfected cells. By redirecting the editing enzymes from the cytoplasm to the nucleus, off-target editing is reduced without compromising the on-target editing efficiency. The addition of the E488Q mutation to the editing enzymes, a common strategy for increasing on-target editing efficiency, causes a tremendous increase in off-target editing. These results underscore the need to reduce promiscuity in current approaches to SDRE.

Mechanism of Dual Targeting of the Phytochrome Signaling Component HEMERA/pTAC12 to Plastids and the Nucleus.

PubMed

Nevarez, P Andrew; Qiu, Yongjian; Inoue, Hitoshi; Yoo, Chan Yul; Benfey, Philip N; Schnell, Danny J; Chen, Meng

2017-04-01

HEMERA (HMR) is a nuclear and plastidial dual-targeted protein. While it functions in the nucleus as a transcriptional coactivator in phytochrome signaling to regulate a distinct set of light-responsive, growth-relevant genes, in plastids it is known as pTAC12, which associates with the plastid-encoded RNA polymerase, and is essential for inducing the plastomic photosynthetic genes and initiating chloroplast biogenesis. However, the mechanism of targeting HMR to the nucleus and plastids is still poorly understood. Here, we show that HMR can be directly imported into chloroplasts through a transit peptide residing in the N-terminal 50 amino acids. Upon cleavage of the transit peptide and additional proteolytic processing, mature HMR, which begins from Lys-58, retains its biochemical properties in phytochrome signaling. Unexpectedly, expression of mature HMR failed to rescue not only the plastidial but also the nuclear defects of the hmr mutant. This is because the predicted nuclear localization signals of HMR are nonfunctional, and therefore mature HMR is unable to accumulate in either plastids or the nucleus. Surprisingly, fusing the transit peptide of the small subunit of Rubisco with mature HMR rescues both its plastidial and nuclear localization and functions. These results, combined with the observation that the nuclear form of HMR has the same reduced molecular mass as plastidial HMR, support a retrograde protein translocation mechanism in which HMR is targeted first to plastids, processed to the mature form, and then relocated to the nucleus. © 2017 American Society of Plant Biologists. All Rights Reserved.

Theater Land Attack Cruise Missile Defense: Guarding the Back Door

DTIC Science & Technology

1999-06-01

employ radio command, laser, anti- radiation homing, or electro-optical guidance systems. TASMs will benefit from the same technological developments...mile-range Al-Husayn missile within range of all major Israeli cities, and its nuclear facilities in the Negev desert. The existence of these sites...solutions (“engage on remote”), or simply launch missiles without radiating , and allow the AFCR to guide the missiles to the target

Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

PubMed Central

Zhu, Jun; Koken, Marcel H. M.; Quignon, Frédérique; Chelbi-Alix, Mounira K.; Degos, Laurent; Wang, Zhen Yi; Chen, Zhu; de Thé, Hugues

1997-01-01

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins. PMID:9108090

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma.

PubMed

Sundaram, Gopinath M; Veera Bramhachari, Pallaval

2017-06-01

Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with non-coding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma.

Development of an inertial confinement fusion platform to study charged-particle-producing nuclear reactions relevant to nuclear astrophysics

DOE PAGES

Gatu Johnson, M.; Zylstra, A. B.; Bacher, A.; ...

2017-03-28

Here, this paper describes the development of a platform to study astrophysically relevant nuclear reactions using inertial-confinement fusion implosions on the OMEGA and National Ignition Facility laser facilities, with a particular focus on optimizing the implosions to study charged-particle- producing reactions. Primary requirements on the platform are high yield, for high statistics in the fusion product measurements, combined with low areal density, to allow the charged fusion products to escape. This is optimally achieved with direct-drive exploding pusher implosions using thin-glass-shell capsules. Mitigation strategies to eliminate a possible target sheath potential which would accelerate the emitted ions are discussed. Themore » potential impact of kinetic effects on the implosions is also considered. The platform is initially employed to study the complementary T(t,2n)α, T( 3He,np)α and 3He( 3He,2p)α reactions. Proof-of-principle results from the first experiments demonstrating the ability to accurately measure the energy and yields of charged particles are presented. Lessons learned from these experiments will be used in studies of other reactions. Ultimately, the goals are to explore thermonuclear reaction rates and fundamental nuclear physics in stellarlike plasma environments, and to push this new frontier of nuclear astrophysics into unique regimes not reachable through existing platforms, with thermal ion velocity distributions, plasma screening, and low reactant energies.« less

Development of an inertial confinement fusion platform to study charged-particle-producing nuclear reactions relevant to nuclear astrophysics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gatu Johnson, M.; Zylstra, A. B.; Bacher, A.

Here, this paper describes the development of a platform to study astrophysically relevant nuclear reactions using inertial-confinement fusion implosions on the OMEGA and National Ignition Facility laser facilities, with a particular focus on optimizing the implosions to study charged-particle- producing reactions. Primary requirements on the platform are high yield, for high statistics in the fusion product measurements, combined with low areal density, to allow the charged fusion products to escape. This is optimally achieved with direct-drive exploding pusher implosions using thin-glass-shell capsules. Mitigation strategies to eliminate a possible target sheath potential which would accelerate the emitted ions are discussed. Themore » potential impact of kinetic effects on the implosions is also considered. The platform is initially employed to study the complementary T(t,2n)α, T( 3He,np)α and 3He( 3He,2p)α reactions. Proof-of-principle results from the first experiments demonstrating the ability to accurately measure the energy and yields of charged particles are presented. Lessons learned from these experiments will be used in studies of other reactions. Ultimately, the goals are to explore thermonuclear reaction rates and fundamental nuclear physics in stellarlike plasma environments, and to push this new frontier of nuclear astrophysics into unique regimes not reachable through existing platforms, with thermal ion velocity distributions, plasma screening, and low reactant energies.« less

Investigations into Alternative Desorption Agents for Amidoxime-Based Polymeric Uranium Adsorbents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill, Gary A.; Kuo, Li-Jung; Strivens, Jonathan E.

2015-06-01

Amidoxime-based polymeric braid adsorbents that can extract uranium (U) from seawater are being developed to provide a sustainable supply of fuel for nuclear reactors. A critical step in the development of the technology is to develop elution procedures to selectively remove U from the adsorbents and to do so in a manner that allows the adsorbent material to be reused. This study investigates use of high concentrations of bicarbonate along with targeted chelating agents as an alternative means to the mild acid elution procedures currently in use for selectively eluting uranium from amidoxime-based polymeric adsorbents.

JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimoto, Arata, E-mail: anishimo@yamaguchi-u.ac.jp; Kugimiya, Naruji; Hosoyama, Toru

2013-08-30

Highlights: •JAB1 interacted with unphosphorylated STAT3 in the nucleus. •JAB1 knockdown tended to increase nuclear STAT3 expression. •JAB1 knockdown significantly decreased unphosphorylated STAT3 DNA-binding activity. •JAB1 knockdown significantly decreased MDR1, NANOG, and VEGF expressions. •Nuclear JAB1, but not nuclear STAT3, correlated with STAT3 DNA-binding activity. -- Abstract: Recent studies have revealed that unphosphorylated STAT3 forms a dimer, translocates to the nucleus, binds to the STAT3 binding site, and activates the transcription of STAT3 target genes, thereby playing an important role in oncogenesis in addition to phosphorylated STAT3. Among signaling steps of unphosphorylated STAT3, nuclear translocation and target DNA-binding are themore » critical steps for its activation. Therefore, elucidating the regulatory mechanism of these signaling steps of unphosphorylated STAT3 is a potential step in the discovery of a novel cancer drug. However, the mechanism of unphosphorylated STAT3 binding to the promoter of target genes remains unclear. In this study, we focused on Jun activation domain-binding protein 1 (JAB1) as a candidate protein that regulates unphosphorylated STAT3 DNA-binding activity. Initially, we observed that both unphosphorylated STAT3 and JAB1 existed in the nucleus of human colon cancer cell line COLO205 at the basal state (no cytokine stimulation). On the other hand, phosphorylated STAT3 did not exist in the nucleus of COLO205 cells at the basal state. Immunoprecipitation using nuclear extract of COLO205 cells revealed that JAB1 interacted with unphosphorylated STAT3. To investigate the effect of JAB1 on unphosphorylated STAT3 activity, RNAi studies were performed. Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA-binding activity. Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target genes. Furthermore, the expression level of nuclear JAB1, but not nuclear STAT3, correlated with unphosphorylated STAT3 DNA-binding activity between COLO205 and LoVo cells. Taken together, these results suggest that nuclear JAB1 positively regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cell line COLO205.« less

Diffusion and retention are major determinants of protein targeting to the inner nuclear membrane

PubMed Central

Ungricht, Rosemarie; Klann, Michael; Horvath, Peter

2015-01-01

Newly synthesized membrane proteins are constantly sorted from the endoplasmic reticulum (ER) to various membranous compartments. How proteins specifically enrich at the inner nuclear membrane (INM) is not well understood. We have established a visual in vitro assay to measure kinetics and investigate requirements of protein targeting to the INM. Using human LBR, SUN2, and LAP2β as model substrates, we show that INM targeting is energy-dependent but distinct from import of soluble cargo. Accumulation of proteins at the INM relies on both a highly interconnected ER network, which is affected by energy depletion, and an efficient immobilization step at the INM. Nucleoporin depletions suggest that translocation through nuclear pore complexes (NPCs) is rate-limiting and restricted by the central NPC scaffold. Our experimental data combined with mathematical modeling support a diffusion-retention–based mechanism of INM targeting. We experimentally confirmed the sufficiency of diffusion and retention using an artificial reporter lacking natural sorting signals that recapitulates the energy dependence of the process in vivo. PMID:26056139

Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models

PubMed Central

Yokoi, Fumiaki; Dang, Mai T.; Zhou, Tong; Li, Yuqing

2012-01-01

DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ɛ-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ɛ-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ɛ-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ɛ-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients. PMID:22080833

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehmood, Rashid; Yasuhara, Noriko; Oe, Souichi

The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand themore » nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.« less

Nuclear Medicine in the Philippines: A Glance at the Past, a Gaze at the Present, and a Glimpse of the Future

PubMed Central

Bautista, Patricia A.; Luis, Teofilo O.L. San

2016-01-01

While the introduction of radioactive tracers in the study of metabolic pathways has been well-documented in clinical thyroidology as early as 1924, the widespread utilization in other clinical specialties has been hampered by slow developments in radiation-detecting devices and in the production of appropriate radiopharmaceuticals, in addition to the morbid fear of radiation. In the Philippines, the first radioisotope laboratory was established in 1956. Ten years later, the Philippine Society of Nuclear Medicine was formed. Through the years, challenges were overcome, foundations were laid down, growth was encouraged, friendships with other organizations were built, adjustments were made, and rules were enforced. To date, there are approximately 58 nuclear medicine centers randomly distributed from north to south of the Philippines, 7 accredited nuclear medicine training institutions, 95 board-certified nuclear medicine physicians (a few of whom are also internationally recognized), and a regionally-indexed Philippine Journal of Nuclear Medicine. Qualifying examinations for technologists were also recently instated. International relations are constantly strengthened by sending trainees abroad and accepting foreign trainees here, as well as participating in conferences and other endeavors. While the cost of putting up nuclear medicine centers in the Philippines is still prohibitive, it should not pose too much of a constraint as there are foreign and local parties willing to help. With appropriate instrumentation, targeting radiopharmaceuticals and trained human resources, nuclear medicine can indeed contribute much to health care delivery. PMID:27408901

Cross-sections of residual nuclei from deuteron irradiation of thin thorium target at energy 7 GeV

NASA Astrophysics Data System (ADS)

Vespalec, Radek; Adam, Jindrich; Baldin, Anton Alexandrovich; Khushvaktov, Jurabek; Solnyshkin, Alexander Alexandrovich; Tsoupko-Sitnikov, Vsevolod Mikhailovich; Tyutyunikov, Sergey Ivanovich; Vrzalova, Jitka; Zavorka, Lukas; Zeman, Miroslav

2017-09-01

The residual nuclei yields are of great importance for the estimation of basic radiation-technology characteristics (like a total target activity, production of long-lived nuclides etc.) of accelerator driven systems planned for transmutation of spent nuclear fuel and for a design of radioisotopes production facilities. Experimental data are also essential for validation of nuclear codes describing various stages of a spallation reaction. Therefore, the main aim of this work is to add new experimental data in energy region of relativistic deuterons, as similar data are missing in nuclear databases. The sample made of thin natural thorium foil was irradiated at JINR Nuclotron accelerator with a deuteron beam of the total kinetic energy 7 GeV. Integral number of deuterons was determined with the use of aluminum activation detectors. Products of deuteron induced spallation reaction were qualified and quantified by means of gamma-ray spectroscopy method. Several important spectroscopic corrections were applied to obtain results of high accuracy. Experimental cumulative and independent cross-sections were determined for more than 80 isotopes including meta-stable isomers. The total uncertainty of results rarely exceeded 9%. Experimental results were compared with MCNP6.1 Monte-Carlo code predictions. Generally, experimental and calculated cross-sections are in a reasonably good agreement, with the exception of a few light isotopes in a fragmentation region, where the calculations are highly under-estimated. Measured data will be useful for future development of high-energy nuclear codes. After completion, final data will be added into the EXFOR database.

SRF selectively controls tip cell invasive behavior in angiogenesis.

PubMed

Franco, Claudio A; Blanc, Jocelyne; Parlakian, Ara; Blanco, Raquel; Aspalter, Irene M; Kazakova, Natalia; Diguet, Nicolas; Mylonas, Elena; Gao-Li, Jacqueline; Vaahtokari, Anne; Penard-Lacronique, Virgine; Fruttiger, Markus; Rosewell, Ian; Mericskay, Mathias; Gerhardt, Holger; Li, Zhenlin

2013-06-01

Efficient angiogenic sprouting is essential for embryonic, postnatal and tumor development. Serum response factor (SRF) is known to be important for embryonic vascular development. Here, we studied the effect of inducible endothelial-specific deletion of Srf in postnatal and adult mice. We find that endothelial SRF activity is vital for postnatal growth and survival, and is equally required for developmental and pathological angiogenesis, including during tumor growth. Our results demonstrate that SRF is selectively required for endothelial filopodia formation and cell contractility during sprouting angiogenesis, but seems dispensable for vascular remodeling. At the molecular level, we observe that vascular endothelial growth factor A induces nuclear accumulation of myocardin-related transcription factors (MRTFs) and regulates MRTF/SRF-dependent target genes including Myl9, which is important for endothelial cell migration in vitro. We conclude that SRF has a unique function in regulating migratory tip cell behavior during sprouting angiogenesis. We hypothesize that targeting the SRF pathway could provide an opportunity to selectively target tip cell filopodia-driven angiogenesis to restrict tumor growth.

Benchmark Report on Key Outage Attributes: An Analysis of Outage Improvement Opportunities and Priorities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Germain, Shawn St.; Farris, Ronald

2014-09-01

Advanced Outage Control Center (AOCC), is a multi-year pilot project targeted at Nuclear Power Plant (NPP) outage improvement. The purpose of this pilot project is to improve management of NPP outages through the development of an AOCC that is specifically designed to maximize the usefulness of communication and collaboration technologies for outage coordination and problem resolution activities. This report documents the results of a benchmarking effort to evaluate the transferability of technologies demonstrated at Idaho National Laboratory and the primary pilot project partner, Palo Verde Nuclear Generating Station. The initial assumption for this pilot project was that NPPs generally domore » not take advantage of advanced technology to support outage management activities. Several researchers involved in this pilot project have commercial NPP experience and believed that very little technology has been applied towards outage communication and collaboration. To verify that the technology options researched and demonstrated through this pilot project would in fact have broad application for the US commercial nuclear fleet, and to look for additional outage management best practices, LWRS program researchers visited several additional nuclear facilities.« less

3D reconstruction of nuclear reactions using GEM TPC with planar readout

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bihałowicz, Jan Stefan

2015-02-24

The research program of the Extreme Light Infrastructure – Nuclear Physics (ELI-NP) laboratory under construction in Magurele, Romania facilities the need of developing a gaseous active-target detector providing 3D reconstruction of charged products of nuclear reactions induced by gamma beam. The monoenergetic, high-energy (E{sub γ} > 19 MeV) gamma beam of intensity 10{sup 13}γ/s allows studying nuclear reactions in astrophysics. A Time Projection Chamber with crossed strip readout (eTPC) is proposed as one of the imaging detectors. The special feature of the readout electrode structure is a 2D reconstruction based on the information read out simultaneously from three arrays ofmore » strips that form virtual pixels. It is expected to reach similar spatial resolution as for pixel readout at largely reduced cost of electronics. The paper presents the current progress and first results of the small scale prototype TPC which is a one of implementation steps towards eTPC detector proposed in the Technical Design Report of Charged Particles Detection at ELI-NP.« less

Analysis of Nuclear Lifetimes Using the Gamma-ray Induced Doppler Shift Attenuation Method

NASA Astrophysics Data System (ADS)

Crespi, F. C. L.

2018-05-01

Lifetime measurements allow extraction of fundamental information on the nature of the excited states of a nuclear system. Since nuclear lifetimes cover many orders of magnitude, a number of experimental techniques and detection setups have been developed depending on the range of the lifetime of interest. The Gamma-ray Induced Doppler Shift Attenuation (GRIDSA) Method presented here is applied to the measurement of very short lifetimes, in the femtosecond range. It allows determining the nuclear lifetime by measuring the Doppler shift of a gamma ray emitted from the state of interest, in different directions with respect to a coincident preceding gamma ray, populating the same state and inducing a recoil of the nucleus in the target material with velocities of the order of 104-105 m/s. We realized an experiment in order to test the GRIDSA technique for the measurement of fs lifetimes after (n,γ) reactions. The measurement was performed at the Institut Laue-Langevin (ILL) with the 8 Ge-clover detectors of the FIPPS array. Preliminary results are discussed.

Immediate effects of the Fukushima nuclear power plant disaster on depressive symptoms among mothers with infants: a prefectural-wide cross-sectional study from the Fukushima Health Management Survey.

PubMed

Goto, Aya; Bromet, Evelyn J; Fujimori, Kenya

2015-03-26

Mothers of young children are at high-risk for developing adverse mental health effects following a nuclear accident. Using the Japanese pregnancy registration system, the prefecture of Fukushima launched a population-based survey of women who were pregnant at the time of the Fukushima nuclear accident in order to assess their and their newborns' health. In this paper, we focus on the results of a screen for depressive symptoms among new mothers and its association with geographical region and interruption of obstetrical care after the Fukushima nuclear accident, which occurred after the Great East Japan Earthquake on March 11, 2011. The survey targeted women who lived in Fukushima prefecture and who had registered their pregnancies between August 1, 2010 and July 31, 2011. Among the 16,001 women targeted, 9,321 returned the questionnaires (response proportion = 58.3%) and data from 8,196 women with singleton live births were analyzed. The main outcome measure was a standard two-item depression screen. Regional radiation levels were determined from the prefecture's periodical reports, and interruption in obstetrical care after the Fukushima nuclear accident was determined from mothers' individual responses to the questionnaire. Among the 8,196 women, 2,262 (28%) screened positive for depressive symptoms. After adjusting for maternal and infant characteristics, both mothers in Soso, the region in which the nuclear power plant is located, and mothers that had changed obstetrical care facilities were significantly more likely to screen positive for depression. In contrast, mothers in Iwaki and Aizu, regions with relatively low radiation levels, were significantly less likely to screen positive for depression. Our findings suggest that improving mental health support for mothers with infants should be a high priority in the acute phase of nuclear disaster response. We further recommend that in the strategic provisioning of parental support, close attention should be paid to regional variations in negative mental health consequences, particularly to those who experienced an interruption in their obstetrical care.

rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development.

PubMed

Gates, Julie; Lam, Geanette; Ortiz, José A; Losson, Régine; Thummel, Carl S

2004-01-01

Pulses of the steroid hormone ecdysone trigger the major developmental transitions in Drosophila, including molting and puparium formation. The ecdysone signal is transduced by the EcR/USP nuclear receptor heterodimer that binds to specific response elements in the genome and directly regulates target gene transcription. We describe a novel nuclear receptor interacting protein encoded by rigor mortis (rig) that is required for ecdysone responses during larval development. rig mutants display defects in molting, delayed larval development, larval lethality, duplicated mouth parts, and defects in puparium formation--phenotypes that resemble those seen in EcR, usp, E75A and betaFTZ-F1 mutants. Although the expression of these nuclear receptor genes is essentially normal in rig mutant larvae, the ecdysone-triggered switch in E74 isoform expression is defective. rig encodes a protein with multiple WD-40 repeats and an LXXLL motif, sequences that act as specific protein-protein interaction domains. Consistent with the presence of these elements and the lethal phenotypes of rig mutants, Rig protein interacts with several Drosophila nuclear receptors in GST pull-down experiments, including EcR, USP, DHR3, SVP and betaFTZ-F1. The ligand binding domain of betaFTZ-F1 is sufficient for this interaction, which can occur in an AF-2-independent manner. Antibody stains reveal that Rig protein is present in the brain and imaginal discs of second and third instar larvae, where it is restricted to the cytoplasm. In larval salivary gland and midgut cells, however, Rig shuttles between the cytoplasm and nucleus in a spatially and temporally regulated manner, at times that correlate with the major lethal phase of rig mutants and major switches in ecdysone-regulated gene expression. Taken together, these data indicate that rig exerts essential functions during larval development through gene-specific effects on ecdysone-regulated transcription, most likely as a cofactor for one or more nuclear receptors. Furthermore, the dynamic intracellular redistribution of Rig protein suggests that it may act to refine spatial and temporal responses to ecdysone during development.

The Future of Air Power in the Aftermath of the Gulf War

DTIC Science & Technology

1992-07-01

strategic-nuclear capabilities, for which the deterrence of direct nuclear attack against the United States itself was always a lesser-included case of a...conflicts, when there are only low-value, low-contrast targets in most cases . In regard to the 20 US MILITARY STRATEGY geographic setting, the attack...navigated over their intended targets to drop laser-guided glide bombs within three feet of the aim points, with the concurrent filming of the attack

01-ERD-111 - The Development of Synthetic High Affinity Ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perkins, J; Balhorn, R; Cosman, M

2004-02-05

The aim of this project was to develop Synthetic High-Affinity Ligands (SHALs), which bind with high affinity and specificity to proteins of interest for national security and cancer therapy applications. The aim of producing synthetic ligands for sensory devices as an alternative to antibody-based detection assays and therapeutic agents is to overcome the drawbacks associated with antibody-based in next-generation sensors and systems. The focus area of the project was the chemical synthesis of the SHALs. The project concentrated on two different protein targets. (a) The C fragment of tetanus and botulinum toxin, potential biowarfare agents. A SHAL for tetanus ormore » botulinum toxin would be incorporated into a sensory device for the toxins. (b) HLA-DR10, a protein found in high abundance on the surface of Non-Hodgkins Lymphoma. A SHAL specific to a tumor marker, labeled with a radionuclide, would enable the targeted delivery of radiation therapy to metastatic disease. The technical approach used to develop a SHAL for each protein target will be described in more detail below. However, in general, the development of a SHAL requires a combination of computational modeling techniques, modern nuclear magnetic resonance spectroscopy (NMR) and synthetic chemistry.« less

Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

PubMed

Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

2015-01-01

The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Managing Terrorism or Accidental Nuclear Errors, Preparing for Iodine-131 Emergencies: A Comprehensive Review

PubMed Central

Braverman, Eric R.; Blum, Kenneth; Loeffke, Bernard; Baker, Robert; Kreuk, Florian; Yang, Samantha Peiling; Hurley, James R.

2014-01-01

Chernobyl demonstrated that iodine-131 (131I) released in a nuclear accident can cause malignant thyroid nodules to develop in children within a 300 mile radius of the incident. Timely potassium iodide (KI) administration can prevent the development of thyroid cancer and the American Thyroid Association (ATA) and a number of United States governmental agencies recommend KI prophylaxis. Current pre-distribution of KI by the United States government and other governments with nuclear reactors is probably ineffective. Thus we undertook a thorough scientific review, regarding emergency response to 131I exposures. We propose: (1) pre-distribution of KI to at risk populations; (2) prompt administration, within 2 hours of the incident; (3) utilization of a lowest effective KI dose; (4) distribution extension to at least 300 miles from the epicenter of a potential nuclear incident; (5) education of the public about dietary iodide sources; (6) continued post-hoc analysis of the long-term impact of nuclear accidents; and (7) support for global iodine sufficiency programs. Approximately two billion people are at risk for iodine deficiency disorder (IDD), the world’s leading cause of preventable brain damage. Iodide deficient individuals are at greater risk of developing thyroid cancer after 131I exposure. There are virtually no studies of KI prophylaxis in infants, children and adolescents, our target population. Because of their sensitivity to these side effects, we have suggested that we should extrapolate from the lowest effective adult dose, 15–30 mg or 1–2 mg per 10 pounds for children. We encourage global health agencies (private and governmental) to consider these critical recommendations. PMID:24739768

Focus small to find big - the microbeam story.

PubMed

Wu, Jinhua; Hei, Tom K

2017-08-29

Even though the first ultraviolet microbeam was described by S. Tschachotin back in 1912, the development of sophisticated micro-irradiation facilities only began to flourish in the late 1980s. In this article, we highlight significant microbeam experiments, describe the latest microbeam irradiator configurations and critical discoveries made by using the microbeam apparatus. Modern radiological microbeams facilities are capable of producing a beam size of a few micrometers, or even tens of nanometers in size, and can deposit radiation with high precision within a cellular target. In the past three decades, a variety of microbeams has been developed to deliver a range of radiations including charged particles, X-rays, and electrons. Despite the original intention for their development to measure the effects of a single radiation track, the ability to target radiation with microbeams at sub-cellular targets has been extensively used to investigate radiation-induced biological responses within cells. Studies conducted using microbeams to target specific cells in a tissue have elucidated bystander responses, and further studies have shown reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in the process. The radiation-induced abscopal effect, which has a profound impact on cancer radiotherapy, further reaffirmed the importance of bystander effects. Finally, by targeting sub-cellular compartments with a microbeam, we have reported cytoplasmic-specific biological responses. Despite the common dogma that nuclear DNA is the primary target for radiation-induced cell death and carcinogenesis, studies conducted using microbeam suggested that targeted cytoplasmic irradiation induces mitochondrial dysfunction, cellular stress, and genomic instability. A more recent development in microbeam technology includes application of mouse models to visualize in vivo DNA double-strand breaks. Microbeams are making important contributions towards our understanding of radiation responses in cells and tissue models.

Manipulating the NF-κB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions.

PubMed

Ortega, Ryan A; Barham, Whitney; Sharman, Kavya; Tikhomirov, Oleg; Giorgio, Todd D; Yull, Fiona E

2016-01-01

Tumor-associated macrophages (TAMs) are critically important in the context of solid tumor progression. Counterintuitively, these host immune cells can often support tumor cells along the path from primary tumor to metastatic colonization and growth. Thus, the ability to transform protumor TAMs into antitumor, immune-reactive macrophages would have significant therapeutic potential. However, in order to achieve these effects, two major hurdles would need to be overcome: development of a methodology to specifically target macrophages and increased knowledge of the optimal targets for cell-signaling modulation. This study addresses both of these obstacles and furthers the development of a therapeutic agent based on this strategy. Using ex vivo macrophages in culture, the efficacy of mannosylated nanoparticles to deliver small interfering RNA specifically to TAMs and modify signaling pathways is characterized. Then, selective small interfering RNA delivery is tested for the ability to inhibit gene targets within the canonical or alternative nuclear factor-kappaB pathways and result in antitumor phenotypes. Results confirm that the mannosylated nanoparticle approach can be used to modulate signaling within macrophages. We also identify appropriate gene targets in critical regulatory pathways. These findings represent an important advance toward the development of a novel cancer therapy that would minimize side effects because of the targeted nature of the intervention and that has rapid translational potential.

Cross section measurement of alpha particle induced nuclear reactions on natural cadmium up to 52MeV.

PubMed

Ditrói, F; Takács, S; Haba, H; Komori, Y; Aikawa, M

2016-12-01

Cross sections of alpha particle induced nuclear reactions have been measured on thin natural cadmium targets foils in the energy range from 11 to 51.2MeV. This work was a part of our systematic study on excitation functions of light ion induced nuclear reactions on different target materials. Regarding the cross sections, the alpha induced reactions are not deeply enough investigated. Some of the produced isotopes are of medical interest, others have application in research and industry. The radioisotope 117m Sn is a very important theranostic (therapeutic + diagnostic) radioisotope, so special care was taken to the results for that isotope. The well-established stacked foil technique followed by gamma-spectrometry with HPGe gamma spectrometers were used. The target and monitor foils in the stack were commercial high purity metal foils. From the irradiated targets 117m Sn, 113 Sn, 110 Sn, 117m,g In, 116m In, 115m In, 114m In, 113m In, 111 In, 110m,g In, 109m In, 108m,g In, 115g Cd and 111m Cd were identified and their excitation functions were derived. The results were compared with the data of the previous measurements from the literature and with the results of the theoretical nuclear reaction model code calculations TALYS 1.8 (TENDL-2015) and EMPIRE 3.2 (Malta). From the cross section curves thick target yields were calculated and compared with the available literature data. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nuclear autophagy: An evolutionarily conserved mechanism of nuclear degradation in the cytoplasm.

PubMed

Luo, Majing; Zhao, Xueya; Song, Ying; Cheng, Hanhua; Zhou, Rongjia

2016-11-01

Macroautophagy/autophagy is a catabolic process that is essential for cellular homeostasis. Studies on autophagic degradation of cytoplasmic components have generated interest in nuclear autophagy. Although its mechanisms and roles have remained elusive, tremendous progress has been made toward understanding nuclear autophagy. Nuclear autophagy is evolutionarily conserved in eukaryotes that may target various nuclear components through a series of processes, including nuclear sensing, nuclear export, autophagic substrate encapsulation and autophagic degradation in the cytoplasm. However, the molecular processes and regulatory mechanisms involved in nuclear autophagy remain largely unknown. Numerous studies have highlighted the importance of nuclear autophagy in physiological and pathological processes such as cancer. This review focuses on current advances in nuclear autophagy and provides a summary of its research history and landmark discoveries to offer new perspectives.

New approach to description of (d,xn) spectra at energies below 50 MeV in Monte Carlo simulation by intra-nuclear cascade code with Distorted Wave Born Approximation

NASA Astrophysics Data System (ADS)

Hashimoto, S.; Iwamoto, Y.; Sato, T.; Niita, K.; Boudard, A.; Cugnon, J.; David, J.-C.; Leray, S.; Mancusi, D.

2014-08-01

A new approach to describing neutron spectra of deuteron-induced reactions in the Monte Carlo simulation for particle transport has been developed by combining the Intra-Nuclear Cascade of Liège (INCL) and the Distorted Wave Born Approximation (DWBA) calculation. We incorporated this combined method into the Particle and Heavy Ion Transport code System (PHITS) and applied it to estimate (d,xn) spectra on natLi, 9Be, and natC targets at incident energies ranging from 10 to 40 MeV. Double differential cross sections obtained by INCL and DWBA successfully reproduced broad peaks and discrete peaks, respectively, at the same energies as those observed in experimental data. Furthermore, an excellent agreement was observed between experimental data and PHITS-derived results using the combined method in thick target neutron yields over a wide range of neutron emission angles in the reactions. We also applied the new method to estimate (d,xp) spectra in the reactions, and discussed the validity for the proton emission spectra.

Creating genetically modified pigs by using nuclear transfer

PubMed Central

Lai, Liangxue; Prather, Randall S

2003-01-01

Nuclear transfer (NT) is a procedure by which genetically identical individuals can be created. The technology of pig somatic NT, including in vitro maturation of oocytes, isolation and treatment of donor cells, artificial activation of reconstructed oocytes, embryo culture and embryo transfer, has been intensively studied in recent years, resulting in birth of cloned pigs in many labs. While it provides an efficient method for producing transgenic pigs, more importantly, it is the only way to produce gene-targeted pigs. So far pig cloning has been successfully used to produce transgenic pigs expressing the green fluorescence protein, expand transgenic pig groups and create gene targeted pigs which are deficient of alpha-1,3-galactosyltransferase. The production of pigs with genetic modification by NT is now in the transition from investigation to practical use. Although the efficiency of somatic cell NT in pig, when measured as development to term as a proportion of oocytes used, is not high, it is anticipated that the ability of making specific modifications to the swine genome will result in this technology having a large impact not only on medicine but also on agriculture. PMID:14613542

Testing quantum chromodynamics in electroproduction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brodsky, S.J.

1987-05-01

The exclusive channels in electroproduction are discussed. The study of color transparency, the formation zone, and other novel aspects of QCD by measuring exclusive reactions inside nuclear targets is covered. Diffractive electroproduction channels are discussed, and exclusive nuclear processes in QCD are examined. Non-additivity of nuclear structure functions (EMC effect) is also discussed, as well as jet coalescence in electroproduction. (LEW)

Parallel computation of multigroup reactivity coefficient using iterative method

NASA Astrophysics Data System (ADS)

Susmikanti, Mike; Dewayatna, Winter

2013-09-01

One of the research activities to support the commercial radioisotope production program is a safety research target irradiation FPM (Fission Product Molybdenum). FPM targets form a tube made of stainless steel in which the nuclear degrees of superimposed high-enriched uranium. FPM irradiation tube is intended to obtain fission. The fission material widely used in the form of kits in the world of nuclear medicine. Irradiation FPM tube reactor core would interfere with performance. One of the disorders comes from changes in flux or reactivity. It is necessary to study a method for calculating safety terrace ongoing configuration changes during the life of the reactor, making the code faster became an absolute necessity. Neutron safety margin for the research reactor can be reused without modification to the calculation of the reactivity of the reactor, so that is an advantage of using perturbation method. The criticality and flux in multigroup diffusion model was calculate at various irradiation positions in some uranium content. This model has a complex computation. Several parallel algorithms with iterative method have been developed for the sparse and big matrix solution. The Black-Red Gauss Seidel Iteration and the power iteration parallel method can be used to solve multigroup diffusion equation system and calculated the criticality and reactivity coeficient. This research was developed code for reactivity calculation which used one of safety analysis with parallel processing. It can be done more quickly and efficiently by utilizing the parallel processing in the multicore computer. This code was applied for the safety limits calculation of irradiated targets FPM with increment Uranium.

Actinide targets for fundamental research in nuclear physics

NASA Astrophysics Data System (ADS)

Eberhardt, K.; Düllmann, Ch. E.; Haas, R.; Mokry, Ch.; Runke, J.; Thörle-Pospiech, P.; Trautmann, N.

2018-05-01

Thin actinide layers deposited on various substrates are widely used as calibration sources in nuclear spectroscopy. Other applications include fundamental research in nuclear chemistry and -physics, e.g., the chemical and physical properties of super-heavy elements (SHE, Z > 103) or nuclear reaction studies with heavy ions. For the design of future nuclear reactors like fast-fission reactors and accelerator-driven systems for transmutation of nuclear waste, precise data for neutron absorption as well as neutron-induced fission cross section data for 242Pu with neutrons of different energies are of particular importance, requiring suitable Pu-targets. Another application includes studies of nuclear transitions in 229Th harvested as α-decay recoil product from a thin layer of its 233U precursor. For this, a thin and very smooth layer of 233U is used. We report here on the production of actinide layers mostly obtained by Molecular Plating (MP). MP is currently the only fabrication method in cases where the desired actinide material is available only in very limited amounts or possesses a high specific activity. Here, deposition is performed from organic solution applying a current density of 1-2 mA/cm2. Under these conditions target thicknesses of 500-1000 μg/cm2 are possible applying a single deposition step with deposition yields approaching 100 %. For yield determination α-particle spectroscopy, γ-spectroscopy and Neutron Activation Analysis is routinely used. Layer homogeneity is checked with Radiographic Imaging. As an alternative technique to MP the production of thin lanthanide and actinide layers by the so-called "Drop on Demand"-technique applied e.g., in ink-jet printing is currently under investigation.

Analysis of the initiation of nuclear pore assembly by ectopically targeting nucleoporins to chromatin

PubMed Central

Schwartz, Michal; Travesa, Anna; Martell, Steven W; Forbes, Douglass J

2015-01-01

Nuclear pore complexes (NPCs) form the gateway to the nucleus, mediating virtually all nucleocytoplasmic trafficking. Assembly of a nuclear pore complex requires the organization of many soluble sub-complexes into a final massive structure embedded in the nuclear envelope. By use of a LacI/LacO reporter system, we were able to assess nucleoporin (Nup) interactions, show that they occur with a high level of specificity, and identify nucleoporins sufficient for initiation of the complex process of NPC assembly in vivo. Eleven nucleoporins from different sub-complexes were fused to LacI-CFP and transfected separately into a human cell line containing a stably integrated LacO DNA array. The LacI-Nup fusion proteins, which bound to the array, were examined for their ability to recruit endogenous nucleoporins to the intranuclear LacO site. Many could recruit nucleoporins of the same sub-complex and a number could also recruit other sub-complexes. Strikingly, Nup133 and Nup107 of the Nup107/160 subcomplex and Nup153 and Nup50 of the nuclear pore basket recruited a near full complement of nucleoporins to the LacO array. Furthermore, Nup133 and Nup153 efficiently targeted the LacO array to the nuclear periphery. Our data support a hierarchical, seeded assembly pathway and identify Nup133 and Nup153 as effective “seeds” for NPC assembly. In addition, we show that this system can be applied to functional studies of individual nucleoporin domains as well as to specific nucleoporin disease mutations. We find that the R391H cardiac arrhythmia/sudden death mutation of Nup155 prevents both its subcomplex assembly and nuclear rim targeting of the LacO array. PMID:25602437

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donangelo, R.J.

An integral representation for the classical limit of the quantum mechanical S-matrix is developed and applied to heavy-ion Coulomb excitation and Coulomb-nuclear interference. The method combines the quantum principle of superposition with exact classical dynamics to describe the projectile-target system. A detailed consideration of the classical trajectories and of the dimensionless parameters that characterize the system is carried out. The results are compared, where possible, to exact quantum mechanical calculations and to conventional semiclassical calculations. It is found that in the case of backscattering the classical limit S-matrix method is able to almost exactly reproduce the quantum-mechanical S-matrix elements, andmore » therefore the transition probabilities, even for projectiles as light as protons. The results also suggest that this approach should be a better approximation for heavy-ion multiple Coulomb excitation than earlier semiclassical methods, due to a more accurate description of the classical orbits in the electromagnetic field of the target nucleus. Calculations using this method indicate that the rotational excitation probabilities in the Coulomb-nuclear interference region should be very sensitive to the details of the potential at the surface of the nucleus, suggesting that heavy-ion rotational excitation could constitute a sensitive probe of the nuclear potential in this region. The application to other problems as well as the present limits of applicability of the formalism are also discussed.« less

Inhibition of IκB Kinase-Nuclear Factor-κB Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin*

PubMed Central

Kasinski, Andrea L.; Du, Yuhong; Thomas, Shala L.; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R.; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P.; Liotta, Dennis; Fu, Haian

2009-01-01

The nuclear factor-κB (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-κB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway through direct action on IκB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-κB, with an IC50 value of 1.3 μM compared with curcumin, with an IC50 value of 13 μM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-α-induced IκB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-α-induced NF-κB signaling by EF24 extends the therapeutic application of EF24 to other NF-κB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis. PMID:18577686

Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin.

PubMed

Kasinski, Andrea L; Du, Yuhong; Thomas, Shala L; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P; Liotta, Dennis; Fu, Haian

2008-09-01

The nuclear factor-kappaB (NF-kappaB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-kappaB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-kappaB signaling pathway through direct action on IkappaB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-kappaB, with an IC(50) value of 1.3 microM compared with curcumin, with an IC(50) value of 13 microM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced IkappaB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-alpha-induced NF-kappaB signaling by EF24 extends the therapeutic application of EF24 to other NF-kappaB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.

PubMed

Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril Ab; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; De Val, Sarah; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

2017-01-31

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.

Particle induced nuclear reaction calculations of Boron target nuclei

NASA Astrophysics Data System (ADS)

Tel, Eyyup; Sahan, Muhittin; Sarpün, Ismail Hakki; Kavun, Yusuf; Gök, Ali Armagan; Poyraz, Meltem

2017-09-01

Boron is usable element in many areas such as health, industry and energy. Especially, Boron neutron capture therapy (BNCT) is one of the medical applications. Boron target is irradiated with low energy thermal neutrons and at the end of reactions alpha particles occur. After this process recoiling lithium-7 nuclei is composed. In this study, charge particle induced nuclear reactions calculations of Boron target nuclei were investigated in the incident proton and alpha energy range of 5-50 MeV. The excitation functions for 10B target nuclei reactions have been calculated by using PCROSS Programming code. The semi-empirical calculations for (p,α) reactions have been done by using cross section formula with new coefficient obtained by Tel et al. The calculated results were compared with the experimental data from the literature.

Cholesterol-modified poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery.

PubMed

Lee, Jeong-Jun; Lee, Song Yi; Park, Ju-Hwan; Kim, Dae-Duk; Cho, Hyun-Jong

2016-07-25

Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance ((1)H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

Fast analysis of radionuclide decay chain migration

NASA Astrophysics Data System (ADS)

Chen, J. S.; Liang, C. P.; Liu, C. W.; Li, L.

2014-12-01

A novel tool for rapidly predicting the long-term plume behavior of an arbitrary length radionuclide decay chain is presented in this study. This fast tool is achieved based on generalized analytical solutions in compact format derived for a set of two-dimensional advection-dispersion equations coupled with sequential first-order decay reactions in groundwater system. The performance of the developed tool is evaluated by a numerical model using a Laplace transform finite difference scheme. The results of performance evaluation indicate that the developed model is robust and accurate. The developed model is then used to fast understand the transport behavior of a four-member radionuclide decay chain. Results show that the plume extents and concentration levels of any target radionuclide are very sensitive to longitudinal, transverse dispersion, decay rate constant and retardation factor. The developed model are useful tools for rapidly assessing the ecological and environmental impact of the accidental radionuclide releases such as the Fukushima nuclear disaster where multiple radionuclides leaked through the reactor, subsequently contaminating the local groundwater and ocean seawater in the vicinity of the nuclear plant.

Mapping the Dynamics of the Glucocorticoid Receptor within the Nuclear Landscape.

PubMed

Stortz, Martin; Presman, Diego M; Bruno, Luciana; Annibale, Paolo; Dansey, Maria V; Burton, Gerardo; Gratton, Enrico; Pecci, Adali; Levi, Valeria

2017-07-24

The distribution of the transcription machinery among different sub-nuclear domains raises the question on how the architecture of the nucleus modulates the transcriptional response. Here, we used fluorescence fluctuation analyses to quantitatively explore the organization of the glucocorticoid receptor (GR) in the interphase nucleus of living cells. We found that this ligand-activated transcription factor diffuses within the nucleus and dynamically interacts with bodies enriched in the coregulator NCoA-2, DNA-dependent foci and chromatin targets. The distribution of the receptor among the nuclear compartments depends on NCoA-2 and the conformation of the receptor as assessed with synthetic ligands and GR mutants with impaired transcriptional abilities. Our results suggest that the partition of the receptor in different nuclear reservoirs ultimately regulates the concentration of receptor available for the interaction with specific targets, and thus has an impact on transcription regulation.

RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

PubMed Central

Du, Jun; Xu, Ren

2012-01-01

The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR) subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer. PMID:23443091

Neutron source, linear-accelerator fuel enricher and regenerator and associated methods

DOEpatents

Steinberg, Meyer; Powell, James R.; Takahashi, Hiroshi; Grand, Pierre; Kouts, Herbert

1982-01-01

A device for producing fissile material inside of fabricated nuclear elements so that they can be used to produce power in nuclear power reactors. Fuel elements, for example, of a LWR are placed in pressure tubes in a vessel surrounding a liquid lead-bismuth flowing columnar target. A linear-accelerator proton beam enters the side of the vessel and impinges on the dispersed liquid lead-bismuth columns and produces neutrons which radiate through the surrounding pressure tube assembly or blanket containing the nuclear fuel elements. These neutrons are absorbed by the natural fertile uranium-238 elements and are transformed to fissile plutonium-239. The fertile fuel is thus enriched in fissile material to a concentration whereby they can be used in power reactors. After use in the power reactors, dispensed depleted fuel elements can be reinserted into the pressure tubes surrounding the target and the nuclear fuel regenerated for further burning in the power reactor.

A Multi-targeted Approach to Suppress Tumor-Promoting Inflammation

PubMed Central

Samadi, Abbas K.; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Bishayee, Anupam; Lokeshwar, Bal L.; Grue, Brendan; Panis, Carolina; Boosani, Chandra S.; Poudyal, Deepak; Stafforini, Diana M.; Bhakta, Dipita; Niccolai, Elena; Guha, Gunjan; Rupasinghe, H.P. Vasantha; Fujii, Hiromasa; Honoki, Kanya; Mehta, Kapil; Aquilano, Katia; Lowe, Leroy; Hofseth, Lorne J.; Ricciardiello, Luigi; Ciriolo, Maria Rosa; Singh, Neetu; Whelan, Richard L.; Chaturvedi, Rupesh; Ashraf, S. Salman; Kumara, HMC Shantha; Nowsheen, Somaira; Mohammed, Sulma I.; Helferich, William G.; Yang, Xujuan

2015-01-01

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-kappaB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes. PMID:25951989

Nuclear Excitation by Electronic Transition of U-235

NASA Astrophysics Data System (ADS)

Chodash, Perry

2017-01-01

Nuclear excitation by electronic transition (NEET) is a rare nuclear excitation that is theorized to exist in numerous isotopes. NEET is the inverse of bound internal conversion and occurs when an electronic transition couples to a nuclear transition causing the nucleus to enter an excited state. This process can only occur for isotopes with low-lying nuclear levels due to the requirement that the electronic and nuclear transitions have similar energies. One of the candidate isotopes for NEET, 235U, has been studied several times over the past 40 years and NEET of 235U has never been conclusively observed. These past experiments generated conflicting results with some experiments claiming to observe NEET of 235U and others setting limits for the NEET rate. If NEET of 235U were to occur, the uranium would be excited to its first excited nuclear state. The first excited nuclear state in 235U is only 76 eV, the second lowest known nuclear state. Additionally, the 76 eV state is a nuclear isomer that decays by internal conversion with a half-life of 26 minutes. In order to measure whether NEET occurs in 235U and at what rate, a uranium plasma was required. The plasma was generated using a Q-switched Nd:YAG laser outputting 789 mJ pulses of 1064 nm light. The laser light was focused onto uranium targets generating an intensity on target of order 1012 W/cm2. The resulting plasma was captured on a catcher plate and electrons emitted from the catcher plate were accelerated and focused onto a microchannel plate detector. Measurements performed using a variety of uranium targets spanning depleted uranium up to 99.4% enriched uranium did not observe a 26 minute decay. An upper limit for the NEET rate of 235U was determined. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. The U.S. DHS, UC Berkeley, the NNIS fellowship and the NSSC further supported this work.

Targeting of the Nuclear Receptor Coactivator Isoform DELTA3AIB1 in Breast Cancer

DTIC Science & Technology

2007-03-01

lab showed that the downregulation of overall levels of AIB1 plus ∆3AIB1, using a regulatable AIB1 directed ribozyme , resulted in reduced tumor...overall levels of AIB1 plus ∆3AIB1, using a regulatable AIB1 directed ribozyme , resulted in reduced tumor growth in vivo. Overall, these data indicate a...Reiter R, Powers C, Wellstein A, Riegel AT. Ribozyme targeting shows that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen

Calculation of (n,α) reaction cross sections by using some Skyrme force parameters for Potassium (41K) target nuclei

NASA Astrophysics Data System (ADS)

Tel, Eyyup; Sahan, Muhittin; Alkanli, Hasancan; Sahan, Halide; Yigit, Mustafa

2017-09-01

In this study, the (n,α) nuclear reaction cross section was calculated for 41K target nuclei for neutron and proton density parameters using SKa, SKb, SLy5, and SLy6 Skyrme force. Theoretical cross section for the (n,α) nuclear reaction was obtained using a formula constituted by Tel et al. (2008). Results are compared with experimental data from EXFOR. The calculated results from formula was found in a close agreement with experimental data.

Nuclear subsurface explosion modeling and hydrodynamic fragmentation simulation of hazardous asteroids

NASA Astrophysics Data System (ADS)

Premaratne, Pavithra Dhanuka

Disruption and fragmentation of an asteroid using nuclear explosive devices (NEDs) is a highly complex yet a practical solution to mitigating the impact threat of asteroids with short warning time. A Hypervelocity Asteroid Intercept Vehicle (HAIV) concept, developed at the Asteroid Deflection Research Center (ADRC), consists of a primary vehicle that acts as kinetic impactor and a secondary vehicle that houses NEDs. The kinetic impactor (lead vehicle) strikes the asteroid creating a crater. The secondary vehicle will immediately enter the crater and detonate its nuclear payload creating a blast wave powerful enough to fragment the asteroid. The nuclear subsurface explosion modeling and hydrodynamic simulation has been a challenging research goal that paves the way an array of mission critical information. A mesh-free hydrodynamic simulation method, Smoothed Particle Hydrodynamics (SPH) was utilized to obtain both qualitative and quantitative solutions for explosion efficiency. Commercial fluid dynamics packages such as AUTODYN along with the in-house GPU accelerated SPH algorithms were used to validate and optimize high-energy explosion dynamics for a variety of test cases. Energy coupling from the NED to the target body was also examined to determine the effectiveness of nuclear subsurface explosions. Success of a disruption mission also depends on the survivability of the nuclear payload when the secondary vehicle approaches the newly formed crater at a velocity of 10 km/s or higher. The vehicle may come into contact with debris ejecting the crater which required the conceptual development of a Whipple shield. As the vehicle closes on the crater, its skin may also experience extreme temperatures due to heat radiated from the crater bottom. In order to address this thermal problem, a simple metallic thermal shield design was implemented utilizing a radiative heat transfer algorithm and nodal solutions obtained from hydrodynamic simulations.

Short Distance of Nuclei - Mining the Wealth of Existing Jefferson Lab Data - Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weinstein, Lawrence; Kuhn, Sebastian

Over the last fifteen years of operation, the Jefferson Lab CLAS Collaboration has performed many experiments using nuclear targets. Because the CLAS detector has a very large acceptance and because it used a very open (i.e., nonspecific) trigger, there is a vast amount of data on many different reaction channels yet to be analyzed. The goal of the Jefferson Lab Nuclear Data Mining grant was to (1) collect the data from nuclear target experiments using the CLAS detector, (2) collect the associated cuts and corrections used to analyze that data, (3) provide non-expert users with a software environment for easymore » analysis of the data, and (4) to search for interesting reaction signatures in the data. We formed the Jefferson Lab Nuclear Data Mining collaboration under the auspices of this grant. The collaboration successfully carried out all of our goals. Dr. Gavalian, the data mining scientist, created a remarkably user-friendly web-based interface to enable easy analysis of the nuclear-target data by non-experts. Data from many of the CLAS nuclear target experiments has been made available on servers at Old Dominion University. Many of the associated cuts and corrections have been incorporated into the data mining software. The data mining collaboration was extraordinarily successful in finding interesting reaction signatures in the data. Our paper Momentum sharing in imbalanced Fermi systems was published in Science. Several analyses of CLAS data are continuing and will result in papers after the end of the grant period. We have held several analysis workshops and have given many invited talks at international conferences and workshops related to the data mining initiative. Our initiative to maximize the impact of data collected with CLAS in the 6-GeV era was very successful. During the hiatus between the end of 6-GeV experiments and the beginning of 12-GeV experiments, our collaboration and the physics community at large benefited tremendously from the Jefferson Lab Nuclear Data Mining effort.« less

Electromagnetic Dissociation and Spacecraft Electronics Damage

NASA Technical Reports Server (NTRS)

Norbury, John W.

2016-01-01

When protons or heavy ions from galactic cosmic rays (GCR) or solar particle events (SPE) interact with target nuclei in spacecraft, there can be two different types of interactions. The more familiar strong nuclear interaction often dominates and is responsible for nuclear fragmentation in either the GCR or SPE projectile nucleus or the spacecraft target nucleus. (Of course, the proton does not break up, except possibly to produce pions or other hadrons.) The less familiar, second type of interaction is due to the very strong electromagnetic fields that exist when two charged nuclei pass very close to each other. This process is called electromagnetic dissociation (EMD) and primarily results in the emission of neutrons, protons and light ions (isotopes of hydrogen and helium). The cross section for particle production is approximately defined as the number of particles produced in nucleus-nucleus collisions or other types of reactions. (There are various kinematic and other factors which multiply the particle number to arrive at the cross section.) Strong, nuclear interactions usually dominate the nuclear reactions of most interest that occur between GCR and target nuclei. However, for heavy nuclei (near Fe and beyond) at high energy the EMD cross section can be much larger than the strong nuclear interaction cross section. This paper poses a question: Are there projectile or target nuclei combinations in the interaction of GCR or SPE where the EMD reaction cross section plays a dominant role? If the answer is affirmative, then EMD mechanisms should be an integral part of codes that are used to predict damage to spacecraft electronics. The question can become more fine-tuned and one can ask about total reaction cross sections as compared to double differential cross sections. These issues will be addressed in the present paper.

Extension and applications of switching model: Range theory, multiple scattering model of Goudsmit-Saunderson, and lateral spread treatment of Marwick-Sigmund

NASA Astrophysics Data System (ADS)

Ikegami, Seiji

2017-09-01

The switching model (PSM) developed in the previous paper is extended to obtain an ;extended switching model (ESM). In the ESM, the mixt electronic-and-nuclear energy-loss region, in addition to the electronic and nuclear energy-loss regions in PSM, is taken into account analytically and appropriately. This model is combined with a small-angle multiple scattering range theory considering both nuclear and electronic stopping effects developed by Marwick-Sigmund and Valdes-Arista to formulate a improved range theory. The ESM is also combined with the multiple scattering theory with non-small angle approximation by Goudsmit-Saunderson. Furthermore, we applied ESM to lateral spread model of Marwick-Sigmund. Numerical calculations of the entire distribution functions including one of the mixt region are roughly and approximately possible. However, exact numerical calculation may be impossible. Consequently, several preliminary numerical calculations of the electronic, mixt, and nuclear regions are performed to examine their underlying behavior with respect to the incident energy, the scattering angle, the outgoing projectile intensity, and the target thickness. We show the numerical results not only of PSM and but also of ESM. Both numerical results are shown in the present paper for the first time. Since the theoretical relations are constructed using reduced variables, the calculations are made only on the case of C colliding on C.

Scalable Methods for Uncertainty Quantification, Data Assimilation and Target Accuracy Assessment for Multi-Physics Advanced Simulation of Light Water Reactors

NASA Astrophysics Data System (ADS)

Khuwaileh, Bassam

High fidelity simulation of nuclear reactors entails large scale applications characterized with high dimensionality and tremendous complexity where various physics models are integrated in the form of coupled models (e.g. neutronic with thermal-hydraulic feedback). Each of the coupled modules represents a high fidelity formulation of the first principles governing the physics of interest. Therefore, new developments in high fidelity multi-physics simulation and the corresponding sensitivity/uncertainty quantification analysis are paramount to the development and competitiveness of reactors achieved through enhanced understanding of the design and safety margins. Accordingly, this dissertation introduces efficient and scalable algorithms for performing efficient Uncertainty Quantification (UQ), Data Assimilation (DA) and Target Accuracy Assessment (TAA) for large scale, multi-physics reactor design and safety problems. This dissertation builds upon previous efforts for adaptive core simulation and reduced order modeling algorithms and extends these efforts towards coupled multi-physics models with feedback. The core idea is to recast the reactor physics analysis in terms of reduced order models. This can be achieved via identifying the important/influential degrees of freedom (DoF) via the subspace analysis, such that the required analysis can be recast by considering the important DoF only. In this dissertation, efficient algorithms for lower dimensional subspace construction have been developed for single physics and multi-physics applications with feedback. Then the reduced subspace is used to solve realistic, large scale forward (UQ) and inverse problems (DA and TAA). Once the elite set of DoF is determined, the uncertainty/sensitivity/target accuracy assessment and data assimilation analysis can be performed accurately and efficiently for large scale, high dimensional multi-physics nuclear engineering applications. Hence, in this work a Karhunen-Loeve (KL) based algorithm previously developed to quantify the uncertainty for single physics models is extended for large scale multi-physics coupled problems with feedback effect. Moreover, a non-linear surrogate based UQ approach is developed, used and compared to performance of the KL approach and brute force Monte Carlo (MC) approach. On the other hand, an efficient Data Assimilation (DA) algorithm is developed to assess information about model's parameters: nuclear data cross-sections and thermal-hydraulics parameters. Two improvements are introduced in order to perform DA on the high dimensional problems. First, a goal-oriented surrogate model can be used to replace the original models in the depletion sequence (MPACT -- COBRA-TF - ORIGEN). Second, approximating the complex and high dimensional solution space with a lower dimensional subspace makes the sampling process necessary for DA possible for high dimensional problems. Moreover, safety analysis and design optimization depend on the accurate prediction of various reactor attributes. Predictions can be enhanced by reducing the uncertainty associated with the attributes of interest. Accordingly, an inverse problem can be defined and solved to assess the contributions from sources of uncertainty; and experimental effort can be subsequently directed to further improve the uncertainty associated with these sources. In this dissertation a subspace-based gradient-free and nonlinear algorithm for inverse uncertainty quantification namely the Target Accuracy Assessment (TAA) has been developed and tested. The ideas proposed in this dissertation were first validated using lattice physics applications simulated using SCALE6.1 package (Pressurized Water Reactor (PWR) and Boiling Water Reactor (BWR) lattice models). Ultimately, the algorithms proposed her were applied to perform UQ and DA for assembly level (CASL progression problem number 6) and core wide problems representing Watts Bar Nuclear 1 (WBN1) for cycle 1 of depletion (CASL Progression Problem Number 9) modeled via simulated using VERA-CS which consists of several multi-physics coupled models. The analysis and algorithms developed in this dissertation were encoded and implemented in a newly developed tool kit algorithms for Reduced Order Modeling based Uncertainty/Sensitivity Estimator (ROMUSE).

Cortical Recruitment and Nuclear–Cytoplasmic Shuttling of Scd5p, a Protein Phosphatase-1-targeting Protein Involved in Actin Organization and EndocytosisD⃞

PubMed Central

Chang, Ji Suk; Henry, Kenneth; Geli, María Isabel; Lemmon, Sandra K.

2006-01-01

Scd5p regulates endocytosis and cortical actin organization as a targeting subunit for the Ser/Thr protein phosphatase-1 (PP1) in yeast. To identify localization signals in Scd5p required for cell surface recruitment, visualization of GFP-tagged Scd5 truncations and deletions was performed. Scd5p contains a PP1 binding site, a 3-repeat region of 20 amino acids (3R), and a 9-repeat region of 12 amino acids (9R). We found that the 9R is critical for cortical localization of Scd5p, but cortical recruitment is not essential for Scd5p's function in actin organization and endocytosis. We propose that Scd5p can target PP1 to endocytic factors in the cytoplasm that have been disassembled and/or inactivated by phosphorylation. We also found that Scd5p undergoes nuclear-cytoplasmic shuttling in a Crm1p-dependent manner. Scd5p-ΔCT lacking the 9R region and its nuclear export signal (NES) accumulates in the nucleus, causing cortical actin and endocytic defects. Cytoplasmic localization and function of Scd5p-ΔCT is restored by NES addition. However, removal of Scd5p's nuclear localization signal prevents nuclear entry, but endocytosis and actin organization remain relatively normal. These results indicate that nuclear-cytoplasmic shuttling is not required for regulation of Scd5p's cortical function and suggest that Scd5p has an independent nuclear function. PMID:16251346

Drug target ontology to classify and integrate drug discovery data.

PubMed

Lin, Yu; Mehta, Saurabh; Küçük-McGinty, Hande; Turner, John Paul; Vidovic, Dusica; Forlin, Michele; Koleti, Amar; Nguyen, Dac-Trung; Jensen, Lars Juhl; Guha, Rajarshi; Mathias, Stephen L; Ursu, Oleg; Stathias, Vasileios; Duan, Jianbin; Nabizadeh, Nooshin; Chung, Caty; Mader, Christopher; Visser, Ubbo; Yang, Jeremy J; Bologa, Cristian G; Oprea, Tudor I; Schürer, Stephan C

2017-11-09

One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource.

Nuclear localization signal targeting to macronucleus and micronucleus in binucleated ciliate Tetrahymena thermophila.

PubMed

Iwamoto, Masaaki; Mori, Chie; Osakada, Hiroko; Koujin, Takako; Hiraoka, Yasushi; Haraguchi, Tokuko

2018-06-08

Ciliated protozoa possess two morphologically and functionally distinct nuclei: a macronucleus (MAC) and a micronucleus (MIC). The MAC is transcriptionally active and functions in all cellular events. The MIC is transcriptionally inactive during cell growth, but functions in meiotic events to produce progeny nuclei. Thus, these two nuclei must be distinguished by the nuclear proteins required for their distinct functions during cellular events such as cell proliferation and meiosis. To understand the mechanism of the nuclear transport specific to either MAC or MIC, we identified specific nuclear localization signals (NLSs) in two MAC- and MIC-specific nuclear proteins, macronuclear histone H1 and micronuclear linker histone-like protein (Mlh1), respectively. By expressing GFP-fused fragments of these proteins in Tetrahymena thermophila cells, two distinct regions in macronuclear histone H1 protein were assigned as independent MAC-specific NLSs and two distinct regions in Mlh1 protein were assigned as independent MIC-specific NLSs. These NLSs contain several essential lysine residues responsible for the MAC- and MIC-specific nuclear transport, but neither contains any consensus sequence with known monopartite or bipartite NLSs in other model organisms. Our findings contribute to understanding how specific nuclear targeting is achieved to perform distinct nuclear functions in binucleated ciliates. © 2018 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Search for anomalous C-jets in Chacaltaya emulsion chamber experiment

NASA Technical Reports Server (NTRS)

Kumano, H.

1985-01-01

Anomalous C-jets were measured in Chacaltaya emulsion chamber No.17. Measurement of 150 C-jets nuclear interactions occured in the target layer in the chamber itself with total visible energy greater than 5 TeV was completed. they are recorded in area of 11 sq m, corresponding to 17.1 sq m year exposure. Among them, seven events have no pinaught and two events are peculiar in that three showers out of four show abnormal cascade development. Two show remarkable characteristics indicating that they are coming from exotic interactions in the target layer. Illustrations of these events are presented and the thresholds of this type of event are discussed.

The radioactive beam facility ALTO

NASA Astrophysics Data System (ADS)

Essabaa, Saïd; Barré-Boscher, Nicole; Cheikh Mhamed, Maher; Cottereau, Evelyne; Franchoo, Serge; Ibrahim, Fadi; Lau, Christophe; Roussière, Brigitte; Saïd, Abdelhakim; Tusseau-Nenez, Sandrine; Verney, David

2013-12-01

The Transnational Access facility ALTO (TNA07-ENSAR/FP7) has been commissioned and received from the French safety authorities, the operation license. It is allowed to run at nominal intensity to produce 1011 fissions/s in a thick uranium carbide target by photo-fission using a 10 μA, 50 MeV electron beam. In addition the recent success in operating the selective laser ion source broadens the physics program with neutron-rich nuclear beams possible at this facility installed at IPN Orsay. The facility also aims at being a test bench for the SPIRAL2 project. In that framework an ambitious R&D program on the target ion source system is being developed.

Nuclear Physics with 10 PW laser beams at Extreme Light Infrastructure - Nuclear Physics (ELI-NP)

NASA Astrophysics Data System (ADS)

Zamfir, N. V.

2014-05-01

The field of the uncharted territory of high-intensity laser interaction with matter is confronted with new exotic phenomena and, consequently, opens new research perspectives. The intense laser beams interacting with a gas or solid target generate beams of electrons, protons and ions. These beams can induce nuclear reactions. Electrons also generate ions high-energy photons via bremsstrahlung processes which can also induce nuclear reactions. In this context a new research domain began to form in the last decade or so, namely nuclear physics with high power lasers. The observation of high brilliance proton beams of tens of MeV energy from solid targets has stimulated an intense research activity. The laser-driven particle beams have to compete with conventional nuclear accelerator-generated beams. The ultimate goal is aiming at applications of the laser produced beams in research, technology and medicine. The mechanism responsible for ion acceleration are currently subject of intensive research in many laboratories in the world. The existing results, experimental and theoretical, and their perspectives are reviewed in this article in the context of IZEST and the scientific program of ELI-NP.

CHEMICAL ANALYSIS OF SIMULATED HIGH LEVEL WASTE GLASSES TO SUPPORT SULFATE SOLUBILITY MODELING

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fox, K.; Marra, J.

2014-08-14

The U.S. Department of Energy (DOE), Office of Environmental Management (EM) is sponsoring an international, collaborative project to develop a fundamental model for sulfate solubility in nuclear waste glass. The solubility of sulfate has a significant impact on the achievable waste loading for nuclear waste forms both within the DOE complex and to some extent at U.K. sites. The development of enhanced borosilicate glass compositions with improved sulfate solubility will allow for higher waste loadings and accelerated cleanup missions. Much of the previous work on improving sulfate retention in waste glasses has been done on an empirical basis, making itmore » difficult to apply the findings to future waste compositions despite the large number of glass systems studied. A more fundamental, rather than empirical, model of sulfate solubility in glass, under development at Sheffield Hallam University (SHU), could provide a solution to the issues of sulfate solubility. The model uses the normalized cation field strength index as a function of glass composition to predict sulfate capacity, and has shown early success for some glass systems. The objective of the current scope is to mature the sulfate solubility model to the point where it can be used to guide glass composition development for DOE waste vitrification efforts, allowing for enhanced waste loadings and waste throughput. A series of targeted glass compositions was selected to resolve data gaps in the current model. SHU fabricated these glasses and sent samples to the Savannah River National Laboratory (SRNL) for chemical composition analysis. SHU will use the resulting data to enhance the sulfate solubility model and resolve any deficiencies. In this report, SRNL provides chemical analyses for simulated waste glasses fabricated SHU in support of sulfate solubility model development. A review of the measured compositions revealed that there are issues with the B{sub 2}O{sub 3} and Fe{sub 2}O{sub 3} concentrations missing their targeted values by a significant amount for several of the study glasses. SHU is reviewing the fabrication of these glasses and the chemicals used in batching them to identify the source of these issues. The measured sulfate concentrations were all below their targeted values. This is expected, as the targeted concentrations likely exceeded the solubility limit for sulfate in these glass compositions. Some volatilization of sulfate may also have occurred during fabrication of the glasses. Measurements of the other oxides in the study glasses were reasonably close to their targeted values« less

Development of a Versatile Ultrasonic Internal Pipe/Vessel Component Monitor for In-Service Inspection of Nuclear Reactor Components

DOE Office of Scientific and Technical Information (OSTI.GOV)

Searfass, Clifford T.; Malinowski, Owen M.; Van Velsor, Jason K.

2015-03-22

The stated goal of this work was to develop a versatile system which could accurately measure vessel and valve internal vibrations and cavitation formation under in-service conditions in nuclear power plants, ultrasonically. The developed technology will benefit the nuclear power generation industry by allowing plant operators to monitor valve and vessel internals during operation. This will help reduce planned outages and plant component failures. During the course of this work, Structural Integrity Associates, Inc. gathered information from industry experts that target vibration amplitudes to be detected should be in the range of 0.001-in to 0.005-in (0.025-mm to 0.127-mm) and targetmore » vibration frequency ranges which should be detected were found to be between 0-Hz and 300-Hz. During the performed work, an ultrasonic measuring system was developed which utilized ultrasonic pulse-echo time-of-flight measurements to measure vibration frequency and amplitude. The developed system has been shown to be able to measure vibration amplitudes as low as 0.0008-in (0.020-mm) with vibration frequencies in the range of 17-Hz to 1000-Hz. Therefore, the developed system was able to meet the industry needs for vibration measurement. The developed ultrasonic system was also to be able to measure cavitation formation by monitoring the received ultrasonic time- and frequency-domain signals. This work also demonstrated the survivability of commercially available probes at temperatures up to 300-F for several weeks.« less

HARP targets pion production cross section and yield measurements: Implications for MiniBooNE neutrino flux

NASA Astrophysics Data System (ADS)

Wickremasinghe, Don Athula Abeyarathna

The prediction of the muon neutrino flux from a 71.0 cm long beryllium target for the MiniBooNE experiment is based on a measured pion production cross section which was taken from a short beryllium target (2.0 cm thick - 5% nuclear interaction length) in the Hadron Production (HARP) experiment at CERN. To verify the extrapolation to our longer target, HARP also measured the pion production from 20.0 cm and 40.0 cm beryllium targets. The measured production yields on targets of 50% and 100% nuclear interaction lengths in the kinematic rage of momentum from 0.75 GeV/c to 6.5 GeV/c and the range of angle from 30 mrad to 210 mrad are presented along with an update of the short target cross sections. The best fitted extended Sanford-Wang (SW) model parameterization for updated short beryllium target positive pion production cross section is presented. Yield measurements for all three targets are also compared with that from the Monte Carlo predictions in the MiniBooNE experiment for different SW parameterization. The comparisons of muon neutrino flux predictions for updated SW model is presented.

Iodine Symporter Targeting with 124I/131I Theranostics.

PubMed

Nagarajah, James; Janssen, Marcel; Hetkamp, Philipp; Jentzen, Walter

2017-09-01

Theranostics, a modern approach combining therapeutics and diagnostics, is among the most promising concepts in nuclear medicine for optimizing and individualizing treatments for many cancer entities. Theranostics has been used in clinical routines in nuclear medicine for more than 60 y-as 131 I for diagnostic and therapeutic purposes in thyroid diseases. In this minireview, we provide a survey of the use of 2 different radioiodine isotopes for targeting the sodium-iodine symporter in thyroid cancer and nonthyroidal neoplasms as well as a brief summary of theranostics for neuroendocrine neoplasms and metastatic castration-refractory prostate cancer. In particular, we discuss the role of 124 I-based dosimetry in targeting of the sodium-iodine symporter and describe the clinical application of 124 I dosimetry in a patient who had radioiodine-refractory thyroid cancer and who underwent a redifferentiation treatment with the mitogen-activated extracellular signal-related kinase kinase inhibitor trametinib. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Light vector mesons in the nuclear medium

NASA Astrophysics Data System (ADS)

Wood, M. H.; Nasseripour, R.; Weygand, D. P.; Djalali, C.; Tur, C.; Mosel, U.; Muehlich, P.; Adams, G.; Amaryan, M. J.; Ambrozewicz, P.; Anghinolfi, M.; Asryan, G.; Avakian, H.; Bagdasaryan, H.; Baillie, N.; Ball, J. P.; Baltzell, N. A.; Barrow, S.; Battaglieri, M.; Bedlinskiy, I.; Bektasoglu, M.; Bellis, M.; Benmouna, N.; Berman, B. L.; Biselli, A. S.; Blaszczyk, L.; Bouchigny, S.; Boiarinov, S.; Bradford, R.; Branford, D.; Briscoe, W. J.; Brooks, W. K.; Burkert, V. D.; Butuceanu, C.; Calarco, J. R.; Careccia, S. L.; Carman, D. S.; Carnahan, B.; Casey, L.; Chen, S.; Cheng, L.; Cole, P. L.; Collins, P.; Coltharp, P.; Crabb, D.; Crannell, H.; Crede, V.; Cummings, J. P.; Dashyan, N.; de Vita, R.; de Sanctis, E.; Degtyarenko, P. V.; Denizli, H.; Dennis, L.; Deur, A.; Dharmawardane, K. V.; Dickson, R.; Dodge, G. E.; Doughty, D.; Dugger, M.; Dytman, S.; Dzyubak, O. P.; Egiyan, H.; Egiyan, K. S.; El Fassi, L.; Elouadrhiri, L.; Eugenio, P.; Fedotov, G.; Feldman, G.; Feuerbach, R. J.; Fradi, A.; Funsten, H.; Garçon, M.; Gavalian, G.; Gilfoyle, G. P.; Giovanetti, K. L.; Girod, F. X.; Goetz, J. T.; Gordon, C. I. O.; Gothe, R. W.; Griffioen, K. A.; Guidal, M.; Guler, N.; Guo, L.; Gyurjyan, V.; Hadjidakis, C.; Hafidi, K.; Hakobyan, H.; Hakobyan, R. S.; Hanretty, C.; Hardie, J.; Hassall, N.; Hersman, F. W.; Hicks, K.; Hleiqawi, I.; Holtrop, M.; Hyde-Wright, C. E.; Ilieva, Y.; Ireland, D. G.; Ishkhanov, B. S.; Isupov, E. L.; Ito, M. M.; Jenkins, D.; Jo, H. S.; Johnstone, J. R.; Joo, K.; Juengst, H. G.; Kalantarians, N.; Kellie, J. D.; Khandaker, M.; Khetarpal, P.; Kim, W.; Klein, A.; Klein, F. J.; Klimenko, A. V.; Kossov, M.; Krahn, Z.; Kramer, L. H.; Kubarovsky, V.; Kuhn, J.; Kuhn, S. E.; Kuleshov, S. V.; Lachniet, J.; Laget, J. M.; Langheinrich, J.; Lawrence, D.; Li, Ji; Livingston, K.; Lu, H. Y.; MacCormick, M.; Markov, N.; Mattione, P.; McAleer, S.; McKinnon, B.; McNabb, J. W. C.; Mecking, B. A.; Mehrabyan, S.; Melone, J. J.; Mestayer, M. D.; Meyer, C. A.; Mibe, T.; Mikhailov, K.; Minehart, R.; Mirazita, M.; Miskimen, R.; Mokeev, V.; Moriya, K.; Morrow, S. A.; Moteabbed, M.; Mueller, J.; Munevar, E.; Mutchler, G. S.; Nadel-Turonski, P.; Niccolai, S.; Niculescu, G.; Niculescu, I.; Niczyporuk, B. B.; Niroula, M. R.; Niyazov, R. A.; Nozar, M.; Osipenko, M.; Ostrovidov, A. I.; Park, K.; Pasyuk, E.; Paterson, C.; Pereira, S. Anefalos; Pierce, J.; Pivnyuk, N.; Pocanic, D.; Pogorelko, O.; Pozdniakov, S.; Preedom, B. M.; Price, J. W.; Prok, Y.; Protopopescu, D.; Raue, B. A.; Riccardi, G.; Ricco, G.; Ripani, M.; Ritchie, B. G.; Ronchetti, F.; Rosner, G.; Rossi, P.; Sabatié, F.; Salamanca, J.; Salgado, C.; Santoro, J. P.; Sapunenko, V.; Schumacher, R. A.; Serov, V. S.; Sharabian, Y. G.; Sharov, D.; Shvedunov, N. V.; Smith, E. S.; Smith, L. C.; Sober, D. I.; Sokhan, D.; Stavinsky, A.; Stepanyan, S.; Stepanyan, S. S.; Stokes, B. E.; Stoler, P.; Strakovsky, I. I.; Strauch, S.; Taiuti, M.; Tedeschi, D. J.; Tkabladze, A.; Tkachenko, S.; Todor, L.; Ungaro, M.; Vineyard, M. F.; Vlassov, A. V.; Watts, D. P.; Weinstein, L. B.; Williams, M.; Wolin, E.; Yegneswaran, A.; Zana, L.; Zhang, B.; Zhang, J.; Zhao, B.; Zhao, Z. W.

2008-07-01

The light vector mesons (ρ,ω, and ϕ) were produced in deuterium, carbon, titanium, and iron targets in a search for possible in-medium modifications to the properties of the ρ meson at normal nuclear densities and zero temperature. The vector mesons were detected with the CEBAF Large Acceptance Spectrometer (CLAS) via their decays to e+e-. The rare leptonic decay was chosen to reduce final-state interactions. A combinatorial background was subtracted from the invariant mass spectra using a well-established event-mixing technique. The ρ-meson mass spectrum was extracted after the ω and ϕ signals were removed in a nearly model-independent way. Comparisons were made between the ρ mass spectra from the heavy targets (A>2) with the mass spectrum extracted from the deuterium target. With respect to the ρ-meson mass, we obtain a small shift compatible with zero. Also, we measure widths consistent with standard nuclear many-body effects such as collisional broadening and Fermi motion.

Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat

2012-01-06

Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, wemore » generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.« less

Nuclear physics in particle therapy: a review

NASA Astrophysics Data System (ADS)

Durante, Marco; Paganetti, Harald

2016-09-01

Charged particle therapy has been largely driven and influenced by nuclear physics. The increase in energy deposition density along the ion path in the body allows reducing the dose to normal tissues during radiotherapy compared to photons. Clinical results of particle therapy support the physical rationale for this treatment, but the method remains controversial because of the high cost and of the lack of comparative clinical trials proving the benefit compared to x-rays. Research in applied nuclear physics, including nuclear interactions, dosimetry, image guidance, range verification, novel accelerators and beam delivery technologies, can significantly improve the clinical outcome in particle therapy. Measurements of fragmentation cross-sections, including those for the production of positron-emitting fragments, and attenuation curves are needed for tuning Monte Carlo codes, whose use in clinical environments is rapidly increasing thanks to fast calculation methods. Existing cross sections and codes are indeed not very accurate in the energy and target regions of interest for particle therapy. These measurements are especially urgent for new ions to be used in therapy, such as helium. Furthermore, nuclear physics hardware developments are frequently finding applications in ion therapy due to similar requirements concerning sensors and real-time data processing. In this review we will briefly describe the physics bases, and concentrate on the open issues.

Nuclear physics in particle therapy: a review.

PubMed

Durante, Marco; Paganetti, Harald

2016-09-01

Charged particle therapy has been largely driven and influenced by nuclear physics. The increase in energy deposition density along the ion path in the body allows reducing the dose to normal tissues during radiotherapy compared to photons. Clinical results of particle therapy support the physical rationale for this treatment, but the method remains controversial because of the high cost and of the lack of comparative clinical trials proving the benefit compared to x-rays. Research in applied nuclear physics, including nuclear interactions, dosimetry, image guidance, range verification, novel accelerators and beam delivery technologies, can significantly improve the clinical outcome in particle therapy. Measurements of fragmentation cross-sections, including those for the production of positron-emitting fragments, and attenuation curves are needed for tuning Monte Carlo codes, whose use in clinical environments is rapidly increasing thanks to fast calculation methods. Existing cross sections and codes are indeed not very accurate in the energy and target regions of interest for particle therapy. These measurements are especially urgent for new ions to be used in therapy, such as helium. Furthermore, nuclear physics hardware developments are frequently finding applications in ion therapy due to similar requirements concerning sensors and real-time data processing. In this review we will briefly describe the physics bases, and concentrate on the open issues.

In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saitoh, Noriko; Uchimura, Yasuhiro; The 21st Century Center of Excellence, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811

2006-05-01

SUMO modification plays a critical role in a number of cellular functions including nucleocytoplasmic transport, gene expression, cell cycle and formation of subnuclear structures such as promyelocytic leukemia (PML) bodies. In order to identify the sites where SUMOylation takes place in the cell, we developed an in situ SUMOylation assay using a semi-intact cell system and subsequently combined it with siRNA-based knockdown of nucleoporin RanBP2, also known as Nup358, which is one of the known SUMO E3 proteins. With the in situ SUMOylation assay, we found that both nuclear rim and PML bodies, besides mitotic apparatuses, are major targets formore » active SUMOylation. The ability to analyze possible SUMO conjugation sites would be a valuable tool to investigate where SUMO E3-like activities and/or SUMO substrates exist in the cell. Specific knockdown of RanBP2 completely abolished SUMOylation along the nuclear rim and dislocated RanGAP1 from the nuclear pore complexes. Interestingly, the loss of RanBP2 markedly reduced the number of PML bodies, in contrast to other, normal-appearing nuclear compartments including the nuclear lamina, nucleolus and chromatin, suggesting a novel link between RanBP2 and PML bodies. SUMOylation facilitated by RanBP2 at the nuclear rim may be a key step for the formation of a particular subnuclear organization. Our data imply that SUMO E3 proteins like RanBP2 facilitate spatio-temporal SUMOylation for certain nuclear structure and function.« less