WorldWideScience

Sample records for gelina target development

  1. Development of a Secondary Neutron Fluence Standard at GELINA

    International Nuclear Information System (INIS)

    Heyse, Jan; Eykens, Roger; Moens, Andre; Plompen, Arjan J.M.; Schillebeeckx, Peter; Wynants, Ruud; Anastasiou, Maria

    2013-06-01

    The MetroFission project, a Joint Research Project within the European Metrology Research Program, aims at addressing a number of metrological problems involved in the design of proposed Generation IV nuclear reactors. One of the objectives of this multidisciplinary project is the improvement of neutron cross section measurement techniques in order to arrive at uncertainties as required for the design and safety assessment of new generation power plants and fuel cycles. This objective is in line with the 'Uncertainty and target accuracy assessment for innovative systems using recent covariance data evaluations' published by a working party of the OECD Nuclear Energy Agency in 2008. These requests are often very challenging, being at or beyond the state-of-the-art in neutron measurements, which is set by self-normalizing methods and the neutron data standards used at laboratories where the data are measured. A secondary neutron fluence standard has been developed and calibrated at the neutron time-of-flight facility GELINA of the JRC's Institute for Reference Materials and Measurements (IRMM). It consists of a flux monitor, a reference ionization chamber containing a 10 B layer and a 235 U layer, and a parallel plate ionization chamber with 8 well characterized 235 U deposits. These devices are used to determine the neutron fluence, based on the well-known neutron induced fission reaction on 235 U. All deposits have been prepared and characterized at the IRMM target preparation lab. The secondary fluence standard at the GELINA facility can be used for reliable determination of the efficiency of fluence measurement devices used in neutron data measurements at IRMM and elsewhere. It is an essential tool to reliably calibrate fluence normalization devices used in neutron time-of-flight cross section measurements. (authors)

  2. On the feasibility to perform integral transmission experiments in the GELINA target hall at IRMM

    Science.gov (United States)

    Leconte, Pierre; Jean, Cyrille De Saint; Geslot, Benoit; Plompen, Arjan; Belloni, Francesca; Nyman, Markus

    2017-09-01

    Shielding experiments are relevant to validate elastic and inelastic scattering cross sections in the fast energy range. In this paper, we are focusing on the possibility to use the pulsed white neutron time-of-flight facility GELINA to perform this kind of measurement. Several issues need to be addressed: neutron source intensity, room return effect, distance of the materials to be irradiated from the source, and the sensitivity of various reaction rate distributions through the material to different input cross sections. MCNP6 and TRIPOLI4 calculations of the outgoing neutron spectrum are compared, based on electron/positron/gamma/neutron simulations. A first guess of an integral transmission experiment through a 238U slab is considered. It shows that a 10 cm thickness of uranium is sufficient to reach a high sensitivity to the 238U inelastic scattering cross section in the [2-5 MeV] energy range, with small contributions from elastic and fission cross sections. This experiment would contribute to reduce the uncertainty on this nuclear data, which has a significant impact on the power distribution in large commercial reactors. Other materials that would be relevant for the ASTRID 4th generation prototype reactor are also tested, showing that a sufficient sensitivity to nuclear data would be obtained by using a 50 to 100cm thick slab of side 60x60cm. This study concludes on the feasibility and interest of such experiments in the target hall of the GELINA facility.

  3. Inelastic neutron scattering with GAINS at GELINA: An overview of the last decade

    Science.gov (United States)

    Borcea, Catalin; Dessagne, Philippe; Kerveno, Maëlle; Mihailescu, Cristian; Nankov, Nikolay; Negret, Alexandru; Nyman, Markus; Olacel, Adina; Oláh, Laszlo; Plompen, Arjan; Rouki, Chariklia; Rudolf, Gerard

    2017-09-01

    GAINS is an array of HPGe detectors installed at the GELINA neutron source of Joint Research Center, Geel, Belgium. It served to measure the cross section for (n,n'γ) reactions on many isotopes. The paper presents the experimental setup and reviews the main results obtained in the last decade

  4. LA CONFIGURACIÓN DEL SIGLO XXI EN LA POÉTICA DE DANA GELINAS

    Directory of Open Access Journals (Sweden)

    GLORIA VERGARA

    2013-05-01

    Full Text Available In this article we will study the poetry of Dana Gelinas, highlighting the strategies to representing the contemporary world. This Mexican poetess sees humans as entranced in front of windows or powerlessin the social struggle. Dana Gelinas’ poetry is naked and strong like the desert. Her verse come without much of preamble to define the image of the 21st century.

  5. Experiments at the GELINA facility for the validation of the self-indication neutron resonance densitometry technique

    Directory of Open Access Journals (Sweden)

    Rossa Riccardo

    2017-01-01

    Full Text Available Self-Indication Neutron Resonance Densitometry (SINRD is a passive non-destructive method that is being investigated to quantify the 239Pu content in a spent fuel assembly. The technique relies on the energy dependence of total cross sections for neutron induced reaction. The cross sections show resonance structures that can be used to quantify the presence of materials in objects, e.g. the total cross-section of 239Pu shows a strong resonance close to 0.3 eV. This resonance will cause a reduction of the number of neutrons emitted from spent fuel when 239Pu is present. Hence such a reduction can be used to quantify the amount of 239Pu present in the fuel. A neutron detector with a high sensitivity to neutrons in this energy region is used to enhance the sensitivity to 239Pu. This principle is similar to self-indication cross section measurements. An appropriate detector can be realized by surrounding a 239Pu-loaded fission chamber with appropriate neutron absorbing material. In this contribution experiments performed at the GELINA time-of-flight facility of the JRC at Geel (Belgium to validate the simulations are discussed. The results confirm that the strongest sensitivity to the target material was achieved with the self-indication technique, highlighting the importance of using a 239Pu fission chamber for the SINRD measurements.

  6. Investigations for the use of the fast digitizers with C6D6 detectors for radiative capture measurements at GELINA

    International Nuclear Information System (INIS)

    Mihailescu, L.C.; Borella, A.; Massimi, C.; Schillebeeckx, P.

    2009-01-01

    The relatively long dead time in conventional data acquisition systems that provide simultaneously the pulse height and the time information for the detected events hinders cross-section measurements with high count rates. This is the case for capture cross-section measurements at the time-of-flight facility GELINA using high radioactive samples or thick samples of materials having strong resonances. Either the high average count rate (e.g. due to the radioactivity of the sample) or the high instantaneous count rate for strong resonances results in a large dead time correction. One solution to reduce the impact of the dead time is the use of a data acquisition system based on fast digitizers. The performances of two commercial digitizers (CAEN N172B and Acqiris DC282), coupled to a C 6 D 6 scintillator, have been tested in terms of pulse height linearity and resolution, dead time and time resolution. The signal processing was done on-line obtaining simultaneously the pulse height and time information for each detected event. With both digitizers a comparable pulse height linearity and resolution has been obtained as with a conventional system. The total dead time of both digital systems is at least a factor 5 shorter than the one for the conventional system. The main difference in performance between the two digitizers is the time resolution. For a relatively large scintillator, a time resolution of about 2 ns has been achieved with the DC282 module and the conventional system while the time resolution was limited to 15 ns with the CAEN N1728B module. For most nuclei a 15 ns time resolution is sufficient to perform resonance shape analysis. Therefore, the CAEN N1728B module can be used for the majority of capture cross-section measurements at GELINA. However, for nuclei with low level density, for which the resolved resonance region extends to the keV-region, a better time resolution is required and the Acqiris DC282 module has to be used.

  7. Determination of the resonance parameters for 232Th from high resolution transmission and capture measurements at GELINA

    International Nuclear Information System (INIS)

    Brusegan, A.; Schillebeeckx, P.; Lobo, G.; Borella, A.; Volev, K.; Janeva, N.

    2003-01-01

    To deduce the resonance parameters for 232 Th in the resolved resonance region, high resolution transmission and capture measurements are being performed. The measurements are performed at the Time-Of-Flight facility GELINA. A comparison of experimental data resulting from capture (top) and transmission (bottom) are shown. The transmission measurements are performed at a 50 m flight path. The neutron are detected with a 0.25' thick lithium glass (NE912) placed in an Al sphere and viewed by a 5' EMI KQB photomultiplier orthogonal to the neutron beam axis. The injection of a stabilised light pulse in the detector during the measurements provided an efficient tool to control to better than 1% the gain of the entire electronics. The experimental set-up includes a sample-changer, placed at 23 m from the neutron source, which is driven by the acquisition system. The determination of the flight path length, was based on transmission of the 6.673 eV resonance of 238 U. We summarise, for the different energy regions of interest, the scheduled measurement conditions: the operation frequency of the accelerator and the target thickness. A simultaneous analysis of the data using REFIT will result in the resonance parameters from 0 to 4 keV. We show the result of a resonance shape analysis for the resonances at 21.8 and 23.5 eV. The resulting resonance parameters are important for the energy calibration and normalisation of the capture measurements in both the resolved and unresolved resonance region. The capture measurements are completed and were performed at a 60 m flight path. The sample consisted of a metallic natural thorium disc of 8 cm diameter and 1.0 mm thick, corresponding to a thickness of 3.176 10 -3 at/b. The neutron flux was measured with an ionisation chamber loaded with three back-to-back layers of about 40 μg/cm 2 10 B. The gamma rays, originating from the 232 Th(n,γ) reaction, were detected by four C 6 D 6 -based liquid scintillators (NE230) placed

  8. Results of Time-of-Flight Neutron Capture Measurements of 176,177,178,179 Hf-enriched and nat Hf samples at 10 m, 30 m and 60 m stations of GELINA

    International Nuclear Information System (INIS)

    Ware, T.C.; Dean, C.J.; Borella, A.; Kopecky, S.; Moens, A.; Schillebeeckx, P.; Janeva, N.; Moxon, M.C.

    2014-04-01

    Neutron capture measurements have been performed at the time-offlight facility GELINA to determine neutron resonance parameters for 174,176,177,178,179,180 Hf. In total, 16 distinct experiments were conducted at the 12 m, 28 m and 58 m capture stations using C 6 D 6 detectors with a moderated neutron beam and the accelerator operating at 50 Hz or 800 Hz. Measurements were performed with nat Hf metallic samples and oxide samples enriched in 176 Hf, 177 Hf, 178 Hf and 179 Hf. This report describes the experimental details required to deliver the experimental capture yields to the EXFOR data library which is maintained by the Nuclear Energy Agency of the OECD and the Nuclear Data Section of the IAEA. The experimental conditions and data reduction procedures are described. In addition, the full covariance information based on the AGS concept is given, such that resonance parameters together with their covariances can be derived in a least squares adjustment to the data. (author)

  9. Development of distributed target

    CERN Document Server

    Yu Hai Jun; Li Qin; Zhou Fu Xin; Shi Jin Shui; Ma Bing; Chen Nan; Jing Xiao Bing

    2002-01-01

    Linear introduction accelerator is expected to generate small diameter X-ray spots with high intensity. The interaction of the electron beam with plasmas generated at the X-ray converter will make the spot on target increase with time and debase the X-ray dose and the imaging resolving power. A distributed target is developed which has about 24 pieces of thin 0.05 mm tantalum films distributed over 1 cm. due to the structure adoption, the distributed target material over a large volume decreases the energy deposition per unit volume and hence reduces the temperature of target surface, then reduces the initial plasma formalizing and its expansion velocity. The comparison and analysis with two kinds of target structures are presented using numerical calculation and experiments, the results show the X-ray dose and normalized angle distribution of the two is basically the same, while the surface of the distributed target is not destroyed like the previous block target

  10. Targets development at Sandia National Laboratories

    International Nuclear Information System (INIS)

    Smith, M.L.; Hebron, D.; Derzon, M.; Olson, R.; Alberts, T.

    1997-01-01

    For many years, Sandia National Laboratories under contract to the Department of Energy has produced targets designed to understand complex ion beam and z-pinch plasma physics. This poster focuses on the features of target designs that make them suitable for Z-pinch plasma physics applications. Precision diagnostic targets will prove critical in understanding the plasma physics model needed for future ion beam and z-pinch design. Targets are designed to meet specific physics needs; in this case the authors have fabricated targets to maximize information about the end-on versus side-on x-ray emission and z-pinch hohlraum development. In this poster, they describe the fabrication and characterization techniques. They include discussion of current targets under development as well as target fabrication capabilities. Advanced target designs are fabricated by Sandia National Laboratories in cooperation with General Atomics of San Diego, CA and W.J. Schafer Associates, Inc. of Livermore, CA

  11. Developing conservation targets in social-ecological systems

    Directory of Open Access Journals (Sweden)

    Phillip S. Levin

    2015-12-01

    Full Text Available The development of targets is foundational in conservation. Although progress has been made in setting targets, the diverse linkages among ecological and social components make target setting for coupled social-ecological systems extremely challenging. Developing integrated social-ecological targets is difficult because it forces policy makers to consider how management actions propagate throughout social-ecological systems, and because ultimately it is society, not scientists, that defines targets. We developed an interdisciplinary approach for identifying management targets and illustrate this approach using an example motivated by Puget Sound, USA. Our approach blends ecological modeling with empirical social science to articulate trade-offs and reveal societal preferences for different social-ecological states. The framework aims to place information in the hands of decision makers and promote discussion in the appropriate forums. Our ultimate objective is to encourage the informed participation of citizens in the development of social-ecological targets that reflect their values while also protecting key ecosystem attributes.

  12. Development of annular targets for 99Mo production

    International Nuclear Information System (INIS)

    Conner, C.; Lewandowski, E.F.; Snelgrove, J.L.; Liberatore, M.W.; Walker, D.E.; Wiencek, T.C.; McGann, D.J.; Hofman, G.L.; Vandegrift, G.F.

    1999-01-01

    During 1999, significant progress was made in the development of a low-enriched uranium (LEU) target for production of 99 Mo. Successful conversion requires an inexpensive, reliable target. To keep the target geometry the same when changing from high-enriched uranium (HEU) to LEU targets, a denser form of uranium is required in order to increase the amount of uranium per target by a factor of approximately five. Targets containing LEU in the form of a metal foil are being developed for producing 99 Mo from the fissioning of 235 U. A new annular target was developed this year, and seven targets were irradiated in the Indonesian RSG-GAS reactor. Results of development of this annular target and its performance during irradiation are described. (author)

  13. Development of IFE target systems on the NIF

    International Nuclear Information System (INIS)

    Schultz, K.R.; Fagaly, R.L.; Bernat, T.; Meier, W.; Petzoldt, R.; Foreman, L.

    1995-01-01

    The Target Systems session of the Workshop on NIF Experiments for IFE developed a list of critical issues for inertial fusion energy (IFE) target systems, and considered the potential of the National Ignition Facility (NIF) to help in the resolution of these issues and in the development of IFE target systems. This paper describes the IFE Target System issues, categorized into target fabrication issues and target transport issues, describes potential NIF IFE target systems experiments, considers the impact of these experiments on the NIF and discusses the development required before these experiments could be done. Most target systems issues must be resolved by development in the laboratory, not in the NIF, and some must be resolved before the NIF can be successful. However, experiments done in the NIF could play a valuable role in developing target systems for IFE. These experiments should have modest impact on the basic design of the NIF, but could require several hundred dedicated, high yield shots

  14. Development of targeted radiotherapy systems

    International Nuclear Information System (INIS)

    Ferro, Guillermina; Villarreal, Jose E.; Garcia, Laura; Tendilla, Jose I.; Paredes, Lydia; Murphy, Consuelo A.; Pedraza, Martha

    2001-01-01

    Conventional or external beam radiotherapy, has been a viable alternative for cancer treatment. Although this technique is effective, its use is limited if the patient has multiple malignant lesions (metastases). An alternative approach is based on the design of radiopharmaceuticals that, to be administered in the patient, are directed specifically toward the target cell producing a selective radiation delivery. This treatment is known as targeted radiotherapy. We have summarized and discussed some results related to our investigations on the development of targeted radiotherapy systems, including aspects of internal dosimetry

  15. APT target-blanket fabrication development

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, D.L.

    1997-06-13

    Concepts for producing tritium in an accelerator were translated into hardware for engineering studies of tritium generation, heat transfer, and effects of proton-neutron flux on materials. Small-scale target- blanket assemblies were fabricated and material samples prepared for these performance tests. Blanket assemblies utilize composite aluminum-lead modules, the two primary materials of the blanket. Several approaches are being investigated to produce large-scale assemblies, developing fabrication and assembly methods for their commercial manufacture. Small-scale target-blanket assemblies, designed and fabricated at the Savannah River Site, were place in Los Alamos Neutron Science Center (LANSCE) for irradiation. They were subjected to neutron flux for nine months during 1996-97. Coincident with this test was the development of production methods for large- scale modules. Increasing module size presented challenges that required new methods to be developed for fabrication and assembly. After development, these methods were demonstrated by fabricating and assembling two production-scale modules.

  16. Development of RI Target Production Technology

    International Nuclear Information System (INIS)

    Jeong, Do Young; Ko, Kwang Hoon; Kim, Cheol Jung; Kim, Taek Soo; Rho, Si Pyo; Park, Hyun Min; Lim, Gwon; Cha, Yong Ho; Han, Jae Min

    2010-04-01

    This project was accomplished with an aim of productive technical development on the 'enriched target' which is used essentially in radioisotope production. The research was advanced systematically with target production pilot system configuration and core technical development. We composed Yb-176 productive pilot system which equip the chemical purification technique of medical treatment level and proved its capability. Possibilities to separate Zn-67 by the method of using the polarizing light in principle and to separate Zn-70 by the method of using the double optical pumping in theory were also proved. RI target production technologies are recognized excessively with monopolistic techniques of part atomic energy advanced nations such as Russia and US and they are come, but we prepared the opportunity will be able to complete a full cycle of like (RI material production -> RI target production -> RI application) with this project accomplishment. When considering only the direct demand of stable isotope which is used in various industrial, we forecast with the fact that RI target markets will become larger with the approximately 5 billion dollars in 2020 and this technology will contribute in the domestic rising industry creation with high value added

  17. Target developments program to prepare LMJ campaigns

    Energy Technology Data Exchange (ETDEWEB)

    Collier, R; Bachelet, F; Botrel, R; Breton, O; Chicanne, C; Dauteuil, C H; Durut, F; Fleury, E; Guillot, L; Hermerel, C; Jeannot, L; Legaie, O; Legay, G; Martin, M; Reneaume, B; Theobald, M; Vincent-Viry, O, E-mail: remy.collier@cea.f [Commissariat a l' Energie Atomique, Direction des Applications Militaires, Valduc, F-21120 Is-sur-Tille (France)

    2010-08-01

    To carry out laser plasma experiments on CEA laser facilities, a R and D program was set up and is still under way to deliver complex targets. For a decade, specific developments are also dedicated to 'Ligne d'Integration Laser' (LIL) in France and Omega facilities (USA). To prepare the targets intended for the first experiments on the Laser 'Megajoule' (LMJ) facility, new developments are required, such as cocktail hohlraum fabrication, gas barrier coating and foam shells developments. For fusion experiments on LMJ, an important program is also under way to elaborate the Cryogenic Target Assembly (CTA), to fill and transport the CTA and to study the conformation process of the DT layer.

  18. Experimental methods in radioactive ion-beam target/ion source development and characterization

    International Nuclear Information System (INIS)

    Welton, R.F.; Alton, G.D.; Cui, B.; Murray, S.N.

    1998-01-01

    We have developed off-line experimental techniques and apparatuses that permit direct measurement of effusive-flow delay times and ionization efficiencies for nearly any chemically reactive element in high-temperature target/ion sources (TIS) commonly used for on-line radioactive ion-beam (RIB) generation. The apparatuses include a hot Ta valve for effusive-flow delay-time measurements, a cooled molecular injection system for determination of ionization efficiencies, and a gas flow measurement/control system for introducing very low, well-defined molecular flows into the TIS. Measurements are performed on a test stand using molecular feed compounds containing stable complements of the radioactive nuclei of interest delivered to the TIS at flow rates commensurate with on-line RIB generation. In this article, the general techniques are described and effusive-flow delay times and ionization efficiency measurements are reported for fluorine in an electron-beam plasma target/ion source developed for RIB generation and operated in both positive- and negative-ion extraction modes. copyright 1998 American Institute of Physics

  19. A High Resolution Spallation Driven Facility at the CERN-PS to Measure Neutron Cross Sections in the Interval from 1 eV to 250 MeV a Relative Performance Assessment

    CERN Document Server

    Rubbia, Carlo; Bouvet-Bensimon, D; Buono, S; Cappi, R; Cennini, P; Gelès, C; Goulas, I; Kadi, Y; Pavlopoulos, P; Revol, Jean Pierre Charles; Tzima, A; Vlachoudis, V

    1998-01-01

    In the proposed facility with 24 GeV PS beam on a Lead target, the number of produced neutrons exceeds 760 per proton. In comparison, with a LINAC (GELINA) one currently obtains only about 0.05 neutrons per electron of about 100 MeV. An additional factor of 2.5 for the CERN facility is due to the strong, forward peaking of the neutron flux, arising from the high proton energy and corresponding longitudinal boost. This huge factor in neutron yield per incident particle, namely 2.5 x 760/0.05 = 3.8 x 10^4, is only partially off-set by the higher, time averaged current of the LINAC e.g. 100 mA vs . 2 mA of the CERN-PS. Therefore the useful, initial neutron rate at the CERN facility is about three orders of magnitude larger than in the most performing electron LINAC’s, GELINA in Belgium and ORELLA in the US. The time duration of the PS pulse is presently Deltat|_r.m.s.=13.5 ns and we believe it could be reduced to Deltat|_r.m.s.= 6.75 ns. The electron LINAC has much shorter pulses Deltat| _r.m.s.= 1 ns, to which...

  20. Spallation neutron source target station design, development, and commissioning

    Energy Technology Data Exchange (ETDEWEB)

    Haines, J.R., E-mail: hainesjr@ornl.gov; McManamy, T.J.; Gabriel, T.A.; Battle, R.E.; Chipley, K.K.; Crabtree, J.A.; Jacobs, L.L.; Lousteau, D.C.; Rennich, M.J.; Riemer, B.W.

    2014-11-11

    The spallation neutron source target station is designed to safely, reliably, and efficiently convert a 1 GeV beam of protons to a high flux of about 1 meV neutrons that are available at 24 neutron scattering instrument beam lines. Research and development findings, design requirements, design description, initial checkout testing, and results from early operation with beam are discussed for each of the primary target subsystems, including the mercury target, neutron moderators and reflector, surrounding vessels and shielding, utilities, remote handling equipment, and instrumentation and controls. Future plans for the mercury target development program are also briefly discussed.

  1. Development of the jet-target system of the MAGIX experiment

    Energy Technology Data Exchange (ETDEWEB)

    Stephan, Aulenbacher [Institut fuer Kernphysik, JGU, Mainz (Germany); Collaboration: Magix/MESA-Collaboration

    2016-07-01

    Since the new accelerator MESA which will be built up in Mainz in the next years operates at low Energies (100 MeV), but at high beam currents (1 mA), a thin windowless target is required. Therefore the MAGIX collaboration is developing a Jet-Target. This target blasts a Gas-Jet perpendicular to the beam through the scattering chamber of MAGIX. This talk is about the development of this Target System.

  2. Technologies using accelerator-driven targets under development at BNL

    International Nuclear Information System (INIS)

    Van Tuyle, G.J.

    1994-01-01

    Recent development work conducted at Brookhaven National Laboratory on technologies which use particle accelerator-driven targets is summarized. These efforts include development of the Spallation-Induced Lithium Conversion (SILC) Target for the Accelerator Production of Tritium (APT), the Accelerator-Driven Assembly for Plutonium Transformation (ADAPT) Target for the Accelerator-Based Conversion (ABC) of excess weapons plutonium. The PHOENIX Concept for the accelerator-driven transmutation of minor actinides and fission products from the waste stream of commercial nuclear power plants, and other potential applications

  3. [The development of novel tumor targeting delivery strategy].

    Science.gov (United States)

    Gao, Hui-le; Jiang, Xin-guo

    2016-02-01

    Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor

  4. Advanced laser fusion target fabrication research and development proposal

    International Nuclear Information System (INIS)

    Stupin, D.M.; Fries, R.J.

    1979-05-01

    A research and development program is described that will enable the fabrication of 10 6 targets/day for a laser fusion prototype power reactor in 2007. We give personnel and cost estimates for a generalized laser fusion target that requires the development of several new technologies. The total cost of the program between 1979 and 2007 is $362 million in today's dollars

  5. Development of uranium metal targets for 99Mo production

    International Nuclear Information System (INIS)

    Wiencek, T.C.; Hofman, G.L.

    1993-10-01

    A substantial amount of high enriched uranium (HEU) is used for the production of medical-grade 99 Mo. Promising methods of producing irradiation targets are being developed and may lead to the reduction or elimination of this HEU use. To substitute low enriched uranium (LEU) for HEU in the production of 99 Mo, the target material may be changed to uranium metal foil. Methods of fabrication are being developed to simplify assembly and disassembly of the targets. Removal of the uranium foil after irradiation without dissolution of the cladding is a primary goal in order to reduce the amount of liquid radioactive waste material produced in the process. Proof-of-concept targets have been fabricated. Destructive testing indicates that acceptable contact between the uranium foil and the cladding can be achieved. Thermal annealing tests, which simulate the cladding/uranium diffusion conditions during irradiation, are underway. Plans are being made to irradiate test targets

  6. Low enrichment Mo-99 target development program at ANSTO

    International Nuclear Information System (INIS)

    Donlevy, Therese M.; Anderson, Peter J.; Beattie, David; Braddock, Ben; Fulton, Scott; Godfrey, Robert; Law, Russell; McNiven, Scott; Sirkka, Pertti; Storr, Greg; Wassink, David; Wong, Alan; Yeoh, Guan

    2002-01-01

    The Australian Nuclear Science and Technology Organisation (ANSTO, formerly AAEC) has been producing fission product Mo-99 in HIFAR, from the irradiation of Low Enrichment Uranium (LEU) UO 2 targets, for nearly thirty years. Over this period, the U-235 enrichment has been increased in stages, from natural to 1.8% to 2.2%. The decision to provide Australia with a replacement research reactor (RRR) for HIFAR has created an ideal opportunity to review and improve the current Mo-99 production process from target design through to chemical processing and waste management options. ANSTO has entered into a collaboration with Argonne National Laboratory (RERTR) to develop a target using uranium metal foil with U-235 enrichment of less than 20% The initial focus has been to demonstrate use of LEU foil targets in HIFAR, using existing irradiation methodology. The current effort focussed on designing a target assembly with optimised thermohydraulic characteristics to accommodate larger LEU foils to meet Mo-99 production needs. The ultimate goal is to produce an LEU target suitable for use in the Replacement Research Reactor when it is commissioned in 2005. This paper reports our activities on: - The regulatory approval processes required in order to undertake irradiation of this new target; -Supporting calculations (neutronics, computational fluid dynamics) for safety submission; - Design challenges and changes to prototype irradiation; - Trial irradiation of LEU foil target in HIFAR; - Future target and rig development program at ANSTO. (author)

  7. Multi-target drugs: the trend of drug research and development.

    Science.gov (United States)

    Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

    2012-01-01

    Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

  8. Applying cognitive training to target executive functions during early development.

    Science.gov (United States)

    Wass, Sam V

    2015-01-01

    Developmental psychopathology is increasingly recognizing the importance of distinguishing causal processes (i.e., the mechanisms that cause a disease) from developmental outcomes (i.e., the symptoms of the disorder as it is eventually diagnosed). Targeting causal processes early in disordered development may be more effective than waiting until outcomes are established and then trying to reverse the pathogenic process. In this review, I evaluate evidence suggesting that neural and behavioral plasticity may be greatest at very early stages of development. I also describe correlational evidence suggesting that, across a number of conditions, early emerging individual differences in attentional control and working memory may play a role in mediating later-developing differences in academic and other forms of learning. I review the currently small number of studies that applied direct and indirect cognitive training targeted at young individuals and discuss methodological challenges associated with targeting this age group. I also discuss a number of ways in which early, targeted cognitive training may be used to help us understand the developmental mechanisms subserving typical and atypical cognitive development.

  9. Radioactive target and source development at Argonne National Laboratory

    International Nuclear Information System (INIS)

    Greene, J.P.; Ahmad, I.; Thomas, G.E.

    1992-01-01

    An increased demand for low-level radioactive targets has created the need for a laboratory dedicated to the production of these foils. A description is given of the radioactive target produced as well as source development work being performed at the Physics Division target facility of Argonne National Laboratory (ANL). Highlights include equipment used and the techniques employed. In addition, some examples of recent source preparation are given as well as work currently in progress

  10. Software for a measuring facility for activation analysis

    International Nuclear Information System (INIS)

    De Keyser, A.; De Roost, E.

    1985-01-01

    A software package has been developed for an APPLE P.C. The programs are intended to control an automated measuring station for photon activation analysis at GELINA, the linear accelerator of C.B.N.M. at Geel (Belgium). They allow to set-up a measuring scheme, to execute it under computer control, to accumulate and store 2 K-spectra using a built-in ADC and to output the results as listings, plots or evaluated reports

  11. Development of new target concepts for proton beams at CERN/ISOLDE

    CERN Document Server

    Delonca, Melanie; Montavon, Ghislain; Peyraut, Francois

    More and more, the power of primary beam sent onto targets increases until reaching several kiloWatts of magnitude, inducing new problematic and challenges. Consequently, the need of new target design arises and leads to new conceptual design proposal. Amongst them, a concept of Lead Bismuth Eutectic (LBE) loop target making use of an heat exchanger (HEX) and a pump has been proposed during the European project EURISOL Design Study. This concept proposed an improvement in terms of release efficiency of short-lived species by transforming the irradiated liquid into droplets shape. This thesis presents the development of this target design proposal. A prototype target has been developed and will be tested under proton beam at ISOLDE at Cern, Geneva. Several analytical tools for the study of this kind of targets are proposed, taking into account different design parameters. These tools can be applied for other high power target concept and allow an easy dimensioning of this kind of targets. As well, an innovativ...

  12. Formulation and development of colon-targeted mucopenetrating ...

    African Journals Online (AJOL)

    Purpose: To formulation and develop colon-targeted mucopenetrating metronidazole nanoparticles. Methods: Metronidazole-loaded chitosan nanoparticles with a pH-sensitive polymer, hydroxyl propyl methyl cellulose phthalate (HPMCP), were prepared by ionic gelation technique and then coated with Eudragit S100 by ...

  13. Development of a coating technique for inertial confinement fusion plastic targets

    International Nuclear Information System (INIS)

    Kubo, U.; Tsubakihara, H.

    1986-01-01

    Deuterated polystyrene as a target material offers several advantages over other polymers because of the following: (1) it is chemically and physically stable at ordinary conditions, (2) it can be easily formed into spherical shells, and (3) it has a very high fraction of D 2 /H 2 (above approx.99%). As in our previous studies, the fabrication method was basically a utilization of the emulsion technique. This method is well suited to mass-producing the polymer targets without microprocessing techniques. We have developed a fabrication method for single shell targets and an extension of this technique also enables us to fabricate double shell targets. This new method is faster and less labor intensive than previous techniques. The development of ICF experiments requires multilayer structure targets; we have developed, moreover, a new fabrication technique called the multicoating method. The polymer coating can be fabricated by the application of an emulsion technique. On the other hand, with metal coating, a nonelectroplating method was used, and nickel was employed as the coating metal. The thickness of the polymer coating layer can be controlled with the rotational speed of a stirrer in the emulsion. In the case of nickel coating, it is achieved by controlling the plating bath temperature and immersion time during the plating process. The experiment resulted in the development of a new technique for the fabrication of multilayer targets and low density, thick polymer-layer-coated targets

  14. Development of Fission Mo-99 Process for LEU Dispersion Target

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Kon; Lee, Su Seung; Hong, Soon Bog; Jang, Kyung Duk; Park, Ul Jae; Lee, Jun Sig [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    KAERI (Korea Atomic Energy Research Institute) is developing LEU-based fission {sup 99}Mo production process which is connected to the new research reactor (Kijang New Research Reactor, KJRR), which is being constructed in Gijang, Busan, Korea. Historically, the most fission {sup 99}Mo producers have been used highly enriched uranium (HEU) targets so far. However, to reduce the use of HEU in private sector for non-proliferation, {sup 99}Mo producers are forced to convert their HEU-based process to use low enriched uranium (LEU) targets. Economic impact of a target conversion from HEU to LEU is significant. Overall cost for the production of the fission {sup 99}Mo increases significantly with the conversion of fission {sup 99}Mo targets from HEU to LEU. It is not only because the yield of LEU is only 50% of HEU, but also because radioactive waste production increases 200%. On the basis, worldwide efforts on the development of {sup 99}Mo production process that is optimized for the LEU target become an important issue. In this study, fission {sup 99}Mo process with non-irradiated LEU targets was presented except separation and purification steps. Pre- and post-irradiation tests of the fission {sup 99}Mo target will be done in 4th quarter of 2016.

  15. Development of Fission Mo-99 Process for LEU Dispersion Target

    International Nuclear Information System (INIS)

    Lee, Seung Kon; Lee, Su Seung; Hong, Soon Bog; Jang, Kyung Duk; Park, Ul Jae; Lee, Jun Sig

    2016-01-01

    KAERI (Korea Atomic Energy Research Institute) is developing LEU-based fission 99 Mo production process which is connected to the new research reactor (Kijang New Research Reactor, KJRR), which is being constructed in Gijang, Busan, Korea. Historically, the most fission 99 Mo producers have been used highly enriched uranium (HEU) targets so far. However, to reduce the use of HEU in private sector for non-proliferation, 99 Mo producers are forced to convert their HEU-based process to use low enriched uranium (LEU) targets. Economic impact of a target conversion from HEU to LEU is significant. Overall cost for the production of the fission 99 Mo increases significantly with the conversion of fission 99 Mo targets from HEU to LEU. It is not only because the yield of LEU is only 50% of HEU, but also because radioactive waste production increases 200%. On the basis, worldwide efforts on the development of 99 Mo production process that is optimized for the LEU target become an important issue. In this study, fission 99 Mo process with non-irradiated LEU targets was presented except separation and purification steps. Pre- and post-irradiation tests of the fission 99 Mo target will be done in 4th quarter of 2016

  16. The Holistic Targeting (HOT) methodology as the means to improve Information Operations (IO) target development and prioritization

    OpenAIRE

    Ieva, Christopher S.

    2008-01-01

    Prioritization. In response to this challenge, this study proposes five recommendations to enhance IO integration into the Joint Targeting Cycle: the use of interim IO Joint Munitions Effectiveness Manual (JMEM) techniques to better forecast cognitive effects, the adoption of the Measure of Worth (MOW) model to assess IO effects, the HOT methodology to develop and prioritize IO targets, the use of compendium software facilitate targeting problem understanding and the network analysis to...

  17. Target reactor development problems

    International Nuclear Information System (INIS)

    Lathrop, K.D.; Vigil, J.C.

    1977-01-01

    Target-blanket design studies are discussed for an accelerator-breeder concept employing a linear accelerator in conjunction with a modified conventional power reactor to produce both fissile fuel and power. The following problems in target and blanket system design are discussed: radiation damage, heat removal, neutronic design, and economics

  18. Targets downstream of Cdk8 in Dictyostelium development

    Directory of Open Access Journals (Sweden)

    Skelton Jason

    2011-01-01

    Full Text Available Abstract Background Cdk8 is a component of the mediator complex which facilitates transcription by RNA polymerase II and has been shown to play an important role in development of Dictyostelium discoideum. This eukaryote feeds as single cells but starvation triggers the formation of a multicellular organism in response to extracellular pulses of cAMP and the eventual generation of spores. Strains in which the gene encoding Cdk8 have been disrupted fail to form multicellular aggregates unless supplied with exogenous pulses of cAMP and later in development, cdk8- cells show a defect in spore production. Results Microarray analysis revealed that the cdk8- strain previously described (cdk8-HL contained genome duplications. Regeneration of the strain in a background lacking detectable gene duplication generated strains (cdk8-2 with identical defects in growth and early development, but a milder defect in spore generation, suggesting that the severity of this defect depends on the genetic background. The failure of cdk8- cells to aggregate unless rescued by exogenous pulses of cAMP is consistent with a failure to express the catalytic subunit of protein kinase A. However, overexpression of the gene encoding this protein was not sufficient to rescue the defect, suggesting that this is not the only important target for Cdk8 at this stage of development. Proteomic analysis revealed two potential targets for Cdk8 regulation, one regulated post-transcriptionally (4-hydroxyphenylpyruvate dioxygenase (HPD and one transcriptionally (short chain dehydrogenase/reductase (SDR1. Conclusions This analysis has confirmed the importance of Cdk8 at multiple stages of Dictyostelium development, although the severity of the defect in spore production depends on the genetic background. Potential targets of Cdk8-mediated gene regulation have been identified in Dictyostelium which will allow the mechanism of Cdk8 action and its role in development to be determined.

  19. Inertial Confinement Fusion Target Component Fabrication and Technology Development report

    International Nuclear Information System (INIS)

    Steinman, D.

    1994-03-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities which took place under this contract during the period of October 1, 1992 through September 30, 1993. During this period, GA was assigned 18 tasks in support of the Inertial Confinement Fusion program and its laboratories. These tasks included ''Capabilities Activation'' and ''Capabilities Demonstration'' to enable us to begin production of glass and composite polymer capsules. Capsule delivery tasks included ''Small Glass Shell Deliveries'' and ''Composite Polymer Capsules'' for Lawrence Livermore National Laboratory (LLNL) and Los Alamos National Laboratory (LANL). We also were asked to provide direct ''Onsite Support'' at LLNL and LANL. We continued planning for the transfer of ''Micromachining Equipment from Rocky Flats'' and established ''Target Component Micromachining and Electroplating Facilities'' at GA. We fabricated over 1100 films and filters of 11 types for Sandia National Laboratory and provided full-time onsite engineering support for target fabrication and characterization. We initiated development of methods to make targets for the Naval Research Laboratory. We investigated spherical interferometry, built an automated capsule sorter, and developed an apparatus for calorimetric measurement of fuel fill for LLNL. We assisted LANL in the ''Characterization of Opaque b-Layered Targets.'' We developed deuterated and UV-opaque polymers for use by the University of Rochester's Laboratory for Laser Energetics (UR/LLE) and devised a triple-orifice droplet generator to demonstrate the controlled-mass nature of the microencapsulation process

  20. Development of 99Mo isotope production targets employing uranium metal foils

    International Nuclear Information System (INIS)

    Hofman, G.L.; Wiencek, T.C.; Wood, E.L.; Snelgrove, J.L.

    1997-01-01

    The Reduced Enrichment Research and Test Reactor Program has continued its effort in the past 3 yr to develop use of low-enriched uranium (LEU) to produce the fission product 99 Mo. This work comprises both target and chemical processing development and demonstration. Two major target systems are now being used to produce 99 Mo with highly enriched uranium-one employing research reactor fuel technology (either uranium-aluminum alloy or uranium aluminide-aluminum dispersion) and the other using a thin deposit of UO 2 on the inside of a stainless steel (SST) tube. This paper summarizes progress in irradiation testing of targets based on LEU uranium metal foils. Several targets of this type have been irradiated in the Indonesian RSG-GAS reactor operating at 22.5 MW

  1. Developed Countries 2020 Pledges Fall Short of IPCC Target What can we do

    Energy Technology Data Exchange (ETDEWEB)

    Guerin, E.; Colombier, M

    2009-07-01

    With the recent announcement by President Obama of the US emission reduction target, the map of developed countries pledges is now full. The US will come to Copenhagen with a -17% target in 2020 compared to 2005 levels that translates into a -4% compared to 1990 levels (together with a -42% target in 2030 that translates into a -33% compared to 1990. Some countries have put forward multiple pledges. They will only commit to the highest pledge if the Copenhagen agreement is deemed satisfactory. For example, the European Union (EU) stated it would move from -20% (the lower pledge) to -30% (the higher pledge) in 2020 compared to 1990 levels if developed countries undertake comparable emission cuts and if major developing countries undertake adequate mitigation actions. Countries also choose different base years in quantifying their pledges. These mitigation pledges by developed countries result in aggregate emissions of -14 to -19% in 2020 compared to 1990 levels, which fall well below the range established by the IPCC (Intergovernmental Panel of Climate Change). According to the IPCC, developed countries need to reduce their emissions by -25 to -40% in 2020 compared to 1990 levels to have approximately a 50% chance to limit the temperature increase to 2 deg. C above pre-industrial levels. It should be noted that some targets presented here (such as EU and US pledges) account for international offsets. To be consistent with IPCC figures, this fraction of expected reductions should not be accounted for. Only the domestic component should be considered. But as specified now, certain pledges are expected to fall further below target. For example, the EU's -20% target translates into -15%, with offsets excluded. This is quite problematic. First, from a climate point of view: developed countries are not making the emission reduction commitments necessary for stabilizing global temperatures at a level that averts dangerous climate change. Second, from a negotiation

  2. Developed Countries 2020 Pledges Fall Short of IPCC Target What can we do

    International Nuclear Information System (INIS)

    Guerin, E.; Colombier, M.

    2009-01-01

    With the recent announcement by President Obama of the US emission reduction target, the map of developed countries pledges is now full. The US will come to Copenhagen with a -17% target in 2020 compared to 2005 levels that translates into a -4% compared to 1990 levels (together with a -42% target in 2030 that translates into a -33% compared to 1990. Some countries have put forward multiple pledges. They will only commit to the highest pledge if the Copenhagen agreement is deemed satisfactory. For example, the European Union (EU) stated it would move from -20% (the lower pledge) to -30% (the higher pledge) in 2020 compared to 1990 levels if developed countries undertake comparable emission cuts and if major developing countries undertake adequate mitigation actions. Countries also choose different base years in quantifying their pledges. These mitigation pledges by developed countries result in aggregate emissions of -14 to -19% in 2020 compared to 1990 levels, which fall well below the range established by the IPCC (Intergovernmental Panel of Climate Change). According to the IPCC, developed countries need to reduce their emissions by -25 to -40% in 2020 compared to 1990 levels to have approximately a 50% chance to limit the temperature increase to 2 deg. C above pre-industrial levels. It should be noted that some targets presented here (such as EU and US pledges) account for international offsets. To be consistent with IPCC figures, this fraction of expected reductions should not be accounted for. Only the domestic component should be considered. But as specified now, certain pledges are expected to fall further below target. For example, the EU's -20% target translates into -15%, with offsets excluded. This is quite problematic. First, from a climate point of view: developed countries are not making the emission reduction commitments necessary for stabilizing global temperatures at a level that averts dangerous climate change. Second, from a negotiation point of

  3. Functional foam coatings inside tubing and custom developed diamond ignition targets

    International Nuclear Information System (INIS)

    Dawedeit, Christoph

    2014-01-01

    The development of inertial confinement fusion targets requires new efficient ablator materials and characteristic temperature measurements during confinement. Here, an aerogel coating process is developed to coat inside spheres and cylinders. The characteristic emission spectrum of doped aerogel inside diamond targets is used as temperature gauge during confinement. Coatings inside metal cylinders confirmed the generality of the coating procedure. In addition artificial diamond is characterized which represents an interesting ablator material.

  4. Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

    Science.gov (United States)

    Pang, Yuan-Ping; Brimijoin, Stephen; Ragsdale, David W; Zhu, Kun Yan; Suranyi, Robert

    2012-04-01

    Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market.

  5. Targeted therapies in development for non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Thanyanan Reungwetwattana

    2013-01-01

    Full Text Available The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC, the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2], RAS (rat sarcoma gene, BRAF (v-raf murine sarcoma viral oncogene homolog B1, MAPK (mitogen-activated protein kinase c-MET (c-mesenchymal-epithelial transition, FGFR (fibroblast growth factor receptor, DDR2 (discoidin domain receptor 2, PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha, PTEN (phosphatase and tensin homolog, AKT (protein kinase B, ALK (anaplastic lym phoma kinase, RET (rearranged during transfection, ROS1 (reactive oxygen species 1 and EPH (erythropoietin-producing hepatoma are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  6. Nonstructural Proteins of Alphavirus—Potential Targets for Drug Development

    Directory of Open Access Journals (Sweden)

    Farhana Abu Bakar

    2018-02-01

    Full Text Available Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors.

  7. Development of antibody-based c-Met inhibitors for targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Lee D

    2015-02-01

    Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

  8. Present status of spallation target development. JAERI/KEK Joint Project

    International Nuclear Information System (INIS)

    Hino, R.; Kaminaga, M.; Haga, K.

    2001-01-01

    The Japan Atomic Energy Research Institute (JAERI) and the High Energy Accelerator Research Organization (KEK) are promoting a plan to construct a neutron scattering facility under the JAERI/KEK Joint Project. Design and R and D works are being carried out vigorously for realizing the mercury target system consisting of the mercury target, moderators and reflectors working as a spallation neutron source, as well as a remote handling system for exchanging such components which will be highly irradiated. This report introduces an outline of the present status of design and development activities on the spallation target system. (author)

  9. Monitoring Water Targets in the Post-2015 Development Goals

    Science.gov (United States)

    Lawford, R. G.

    2015-12-01

    The Water Sustainable Development Goal (SDG) provides a comprehensive approach to developing water services in a way that ensures social equity, health, well-being and sustainability for all. In particular, the water goal includes targets related to sanitation, wastewater, water quality, water efficiency, integrated water management and ecosystems (details to be finalized in September 2015). As part of its implementation, methods to monitor target indicators must be developed. National governments will be responsible for reporting on progress toward these targets using national data sets and possibly information from global data sets that applies to their countries. Oversight of this process through the use of global data sets is desirable for encouraging the use of standardized information for comparison purposes. Disparities in monitoring due to very sparse data networks in some countries can be addressed by using geospatially consistent data products from space-based remote sensing. However, to fully exploit these data, capabilities will be needed to downscale information, to interpolate and assimilate data both in time and space, and to integrate these data with socio-economic data sets, model outputs and survey data in a geographical information system framework. Citizen data and other non-standard data types may also supplement national data systems. A comprehensive and integrated analysis and dissemination system is needed to enable the important contributions that satellites could make to achieving Water SDG targets. This presentation will outline the progress made in assessing the needs for information to track progress on the Water SDG, options for meeting these needs using existing data infrastructure, and pathways for expanding the role of Earth observations in SDG monitoring. It will also discuss the potential roles of Future Earth's Sustainable Water Futures Programme (SWFP) and the Group on Earth Observations (GEO) in coordinating these efforts.

  10. Target fabrication and development in the Centre d'Etudes de Limeil

    International Nuclear Information System (INIS)

    Clement, X.; Coudeville, A.; Eyharts, P.; Perrine, J.P.; Rouillard, R.

    1983-10-01

    The present state of research in Limeil laboratory for the production of inertial confinement fusion targets is described in this communication. A summary of typical areas, previously investigated, including new developments, is as follows: - production of hollow glass microspheres, having wide outside diameter range and aspect-ratio, using dried-alcogels, - preparation and fabrication of low density foams having plane or hemispherical shape, - deposition of a wide range of conductive materials as well as silicon and organic polymers, - development of laser and spark erosion machining which are useful tools for producing minute parts of complex targets, - characterization and analysis of plastic or coal metal coated targets, are done by using interferometry techniques and X-ray image analysis as well as X-ray absorption measurements

  11. Development of ion beam sputtering techniques for actinide target preparation

    International Nuclear Information System (INIS)

    Aaron, W.S.; Zevenbergen, L.A.; Adair, H.L.

    1985-01-01

    Ion beam sputtering is a routine method for the preparation of thin films used as targets because it allows the use of minimum quantity of starting material, and losses are much lower than most other vacuum deposition techniques. Work is underway in the Isotope Research Materials Laboratory (IRML) at ORNL to develop the techniques that will make the preparation of actinide targets up to 100 μg/cm 2 by ion beam sputtering a routinely available service from IRML. The preparation of the actinide material in a form suitable for sputtering is a key to this technique, as is designing a sputtering system that allows the flexibility required for custom-ordered target production. At present, development work is being conducted on low-activity in a bench-top system. The system will then be installed in a hood or glove box approved for radioactive materials handling where processing of radium, actinium, and plutonium isotopes among others will be performed. (orig.)

  12. Development of ion beam sputtering techniques for actinide target preparation

    Science.gov (United States)

    Aaron, W. S.; Zevenbergen, L. A.; Adair, H. L.

    1985-06-01

    Ion beam sputtering is a routine method for the preparation of thin films used as targets because it allows the use of a minimum quantity of starting material, and losses are much lower than most other vacuum deposition techniques. Work is underway in the Isotope Research Materials Laboratory (IRML) at ORNL to develop the techniques that will make the preparation of actinide targets up to 100 μg/cm 2 by ion beam sputtering a routinely available service from IRML. The preparation of the actinide material in a form suitable for sputtering is a key to this technique, as is designing a sputtering system that allows the flexibility required for custom-ordered target production. At present, development work is being conducted on low-activity actinides in a bench-top system. The system will then be installed in a hood or glove box approved for radioactive materials handling where processing of radium, actinium, and plutonium isotopes among others will be performed.

  13. Development of position measurement unit for flying inertial fusion energy target

    International Nuclear Information System (INIS)

    Tsuji, R; Endo, T; Yoshida, H; Norimatsu, T

    2016-01-01

    We have reported the present status in the development of a position measurement unit (PMU) for a flying inertial fusion energy (IFE) target. The PMU, which uses Arago spot phenomena, is designed to have a measurement accuracy smaller than 1 μm. By employing divergent, pulsed orthogonal laser beam illumination, we can measure the time and the target position at the pulsed illumination. The two-dimensional Arago spot image is compressed into one-dimensional image by a cylindrical lens for real-time processing. The PMU are set along the injection path of the flying target. The local positions of the target in each PMU are transferred to the controller and analysed to calculate the target trajectory. Two methods are presented to calculate the arrival time and the arrival position of the target at the reactor centre. (paper)

  14. Development of position measurement unit for flying inertial fusion energy target

    Science.gov (United States)

    Tsuji, R.; Endo, T.; Yoshida, H.; Norimatsu, T.

    2016-03-01

    We have reported the present status in the development of a position measurement unit (PMU) for a flying inertial fusion energy (IFE) target. The PMU, which uses Arago spot phenomena, is designed to have a measurement accuracy smaller than 1 μm. By employing divergent, pulsed orthogonal laser beam illumination, we can measure the time and the target position at the pulsed illumination. The two-dimensional Arago spot image is compressed into one-dimensional image by a cylindrical lens for real-time processing. The PMU are set along the injection path of the flying target. The local positions of the target in each PMU are transferred to the controller and analysed to calculate the target trajectory. Two methods are presented to calculate the arrival time and the arrival position of the target at the reactor centre.

  15. The development of molecularly targeted anticancer therapies: an Eli Lilly and Company perspective.

    Science.gov (United States)

    Perry, William L; Weitzman, Aaron

    2005-03-01

    The ability to identify activated pathways that drive the growth and progression of cancer and to develop specific and potent inhibitors of key proteins in these pathways promises to dramatically change the treatment of cancer: A patient's cancer could be characterized at the molecular level and the information used to select the best treatment options. The development of successful therapies not only requires extensive target validation, but also new approaches to evaluating drug efficacy in animal models and in the clinic compared to the development of traditional cytotoxic agents. This article highlights Eli Lilly and Company's approach to developing targeted therapies, from target identification and validation through evaluation in the clinic. A selection of drugs in the Lilly Oncology pipeline is also discussed.

  16. Development strategy and targets of CGNPG

    International Nuclear Information System (INIS)

    Zan Yunlong

    2002-01-01

    The development of nuclear power industry in Guangdong results from the steady implementation of a catch-up strategy aimed at the advanced world level in the nuclear power industry. China Guangdong Nuclear Power (Holding) Co., Ltd. (CGNPC) started from Daya Bay Nuclear Power Station (GNPS). In the form of joint venture, GNPS has obtained sophisticated technology, management expertise and human resources both at home and abroad, and has successfully completed the learning curve from importing, digesting, absorbing to innovating and self-improving. Under the principle of maintaining continuous nuclear power development by reinvesting the returns on the operating nuclear power stations, the second nuclear power project, Ling Ao Nuclear Power Station (LNPS) is progressing well and preparation for the third nuclear power project is now in full swing. With a rolling-on development mechanism being established, Daya Bay has become the cradle for nuclear power development in Guangdong. In the 21 st century, CGNPC is facing new challenges and opportunity. CGNPC will uphold the principle of maintaining continuous nuclear power development by reinvesting the returns on the operating nuclear power stations, brace itself for the market competition and explore sustained development of nuclear power in China by pursuing constant innovation in technology, management, system and concept. The strategy framework for future development of CGNPC is defined as follows: - to establish three-dimension strategic targets; - to pursue two-step development with the year 2015 as the dividing point; - to promote concerted development of nuclear power, associated industries and supporting services

  17. The development of fast tantalum foil targets for short-lived isotopes

    CERN Document Server

    Bennett, J R J; Drumm, P V; Ravn, H L

    2003-01-01

    The development of fast tantalum foil targets for short-lived isotopes was discussed. It was found that the effusion was faster but the diffusion out of the foils was a limiting factor. The performance of the targets at ISOLDE with beams of **1**1Li, **1**2Be and **1**4Be was also analyzed. (Edited abstract) 13 Refs.

  18. New developments in cryo-targets for the external COSY experiments

    CERN Document Server

    Abdel-Samad, S; Kilian, K

    2002-01-01

    For cooling the liquid hydrogen/deuterium target from room temperature to the operating temperature (15 K/19 K) until recently a long solid copper heat conductor and a short heat pipe was used between cooling machine and the target cell. Recently, a new target version with metallic heat conductor of minimal length and a long gravity-assisted heat pipe section was constructed. The target material is used as a heat transport medium and high heat transfer is achieved by liquid-gas circulation. This design drastically reduces the weight of the system to less than 10 g in the 32 cm long standard geometry as compared with the previous copper heat conductors of 600 g. Uncontrollable secondary interactions are thus avoided. The cycle time of cooling down or heating up is reduced. The characteristics at steady-state operating conditions of the new 32 cm heat pipe-target system have been measured for hydrogen, deuterium, nitrogen and methane as the working fluids. Also successful was the development of a 2 m long heat ...

  19. The Nicotinic Acetylcholine Receptor as a Target for Antidepressant Drug Development

    Directory of Open Access Journals (Sweden)

    Noah S. Philip

    2012-01-01

    Full Text Available An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR. This receptor, which is distributed widely in regions of the brain associated with depression, is also implicated in other important processes that are relevant to depression, such as stress and inflammation. The two classes of drugs that target nAChRs can be broadly divided into mecamylamine- and cytisine-based compounds. These drugs probably exert their effects via antagonism at α4β2 nAChRs, and strong preclinical data support the antidepressant efficacy of both classes when used in conjunction with other primary antidepressants (e.g., monoamine reuptake inhibitors. Although clinical data remain limited, preliminary results in this area constitute a compelling argument for further evaluation of the nAChR as a target for future antidepressant drug development.

  20. The LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2002-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada has been extracted from reactor targets employing highly enriched uranium (HEU). A reliable supply of HEU metal from the United States used in the manufacture of targets for the NRU research reactor has been a key factor to enable MDS Nordion to develop a secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets provides predictable, consistent yields for our high-volume molybdenum production process. Each link of the isotope supply chain, from isotope production to ultimate use by the physician, has been established using this proven and established method of HEU target irradiation and processing to extract molybdenum-99. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the construction of two MAPLE reactors and a New Processing Facility. The design of the MAPLE facilities was based on an established process developed by Atomic Energy of Canada Ltd. (AECL) - extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a three phase LEU Target Development and Conversion Program for the MAPLE facilities. Phase 1, the Initial Feasibility Study, which identified the technical issues to convert the MAPLE reactor targets from HEU to LEU for large scale commercial production was reported on at the RERTR- 2000 conference. The second phase of the LEU Target Development and Conversion Program was developed with extensive consultation and involvement of experts knowledgeable in target development, process system design, enriched uranium conversion chemistry and commercial scale reactor operations and molybdenum production. This paper will provide an overview of the Phase 2 Conversion Development Program, report on progress to date, and further

  1. Development and Verification of Body Armor Target Geometry Created Using Computed Tomography Scans

    Science.gov (United States)

    2017-07-13

    Computed Tomography Scans by Autumn R Kulaga, Kathryn L Loftis, and Eric Murray Approved for public release; distribution is...Army Research Laboratory Development and Verification of Body Armor Target Geometry Created Using Computed Tomography Scans by Autumn R Kulaga...Development and Verification of Body Armor Target Geometry Created Using Computed Tomography Scans 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c

  2. Development of a plutonium ceramic target for the MASHA separator

    Energy Technology Data Exchange (ETDEWEB)

    Shaughnessy, D.A.; Moody, K.J.; Kenneally, J.M.; Wild, J.F.; Stoyer, M.A.; Lougheed, R.W.; Yeremin, A.V.; Oganessian, Yu.Ts

    2004-04-05

    We are participating in the development of the target for the MASHA (Mass Analyzer of Super Heavy Atoms) on-line mass separator in Dubna. Along with recent upgrades of the U400 cyclotron, MASHA will provide for at least a ten-fold increase in the production- and-detection rate for element 114 atoms, and will allow us to measure their atomic masses precisely. The MASHA separator will employ a thick Pu ceramic target capable of tolerating temperatures in the vicinity of 2000 C without vaporizing the actinide compound. Reaction products will diffuse out of the target and will drift to an ECR ion source after which they will be transported through the separator and will impinge on a position-sensitive focal-plane detector array. Furthermore, operation of the MASHA hot target/ion source combination will provide chemical volatility information that will support our assignment of an atomic number of 114 to these nuclei. Taken together, these experiments on MASHA will allow us to make measurements that will cement our identification of element 114 and provide for future experiments in which the chemical properties of the heaviest elements are studied.

  3. Development of a Plutonium Ceramic Target for the MASHA Separator

    Science.gov (United States)

    Shaughnessy, D. A.; Moody, K. J.; Kenneally, J. M.; Wild, J. F.; Stoyer, M. A.; Lougheed, R. W.; Yeremin, A. V.; Oganessian, Yu. Ts.

    2004-04-01

    We are participating in the development of the target for the MASHA (Mass Analyzer of Super Heavy Atoms) on-line mass separator in Dubna. Along with recent upgrades of the U400 cyclotron, MASHA will provide for at least a ten-fold increase in the production- and-detection rate for element 114 atoms, and will allow us to measure their atomic masses precisely. The MASHA separator will employ a thick Pu ceramic target capa- ble of tolerating temperatures in the vicinity of 2000 C without vaporizing the actinide compound. Reaction products will diffuse out of the target and will drift to an ECR ion source after which they will be transported through the separator and will impinge on a position-sensitive focal-plane detector array. Furthermore, operation of the MASHA hot target/ion source combination will provide chemical volatility information that will support our assignment of an atomic number of 114 to these nuclei. Taken together, these experiments on MASHA will allow us to make measurements that will cement our identification of element 114 and provide for future experiments in which the chemical properties of the heaviest elements are studied.

  4. Development of a plutonium ceramic target for the MASHA separator

    International Nuclear Information System (INIS)

    Shaughnessy, D.A.; Moody, K.J.; Kenneally, J.M.; Wild, J.F.; Stoyer, M.A.; Lougheed, R.W.; Yeremin, A.V.; Oganessian, Yu.Ts.

    2004-01-01

    We are participating in the development of the target for the MASHA (Mass Analyzer of Super Heavy Atoms) on-line mass separator in Dubna. Along with recent upgrades of the U400 cyclotron, MASHA will provide for at least a ten-fold increase in the production- and-detection rate for element 114 atoms, and will allow us to measure their atomic masses precisely. The MASHA separator will employ a thick Pu ceramic target capable of tolerating temperatures in the vicinity of 2000 C without vaporizing the actinide compound. Reaction products will diffuse out of the target and will drift to an ECR ion source after which they will be transported through the separator and will impinge on a position-sensitive focal-plane detector array. Furthermore, operation of the MASHA hot target/ion source combination will provide chemical volatility information that will support our assignment of an atomic number of 114 to these nuclei. Taken together, these experiments on MASHA will allow us to make measurements that will cement our identification of element 114 and provide for future experiments in which the chemical properties of the heaviest elements are studied

  5. Sortase A: an ideal target for anti-virulence drug development.

    Science.gov (United States)

    Cascioferro, Stella; Totsika, Makrina; Schillaci, Domenico

    2014-12-01

    Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Target normal sheath acceleration analytical modeling, comparative study and developments

    International Nuclear Information System (INIS)

    Perego, C.; Batani, D.; Zani, A.; Passoni, M.

    2012-01-01

    Ultra-intense laser interaction with solid targets appears to be an extremely promising technique to accelerate ions up to several MeV, producing beams that exhibit interesting properties for many foreseen applications. Nowadays, most of all the published experimental results can be theoretically explained in the framework of the target normal sheath acceleration (TNSA) mechanism proposed by Wilks et al. [Phys. Plasmas 8(2), 542 (2001)]. As an alternative to numerical simulation various analytical or semi-analytical TNSA models have been published in the latest years, each of them trying to provide predictions for some of the ion beam features, given the initial laser and target parameters. However, the problem of developing a reliable model for the TNSA process is still open, which is why the purpose of this work is to enlighten the present situation of TNSA modeling and experimental results, by means of a quantitative comparison between measurements and theoretical predictions of the maximum ion energy. Moreover, in the light of such an analysis, some indications for the future development of the model proposed by Passoni and Lontano [Phys. Plasmas 13(4), 042102 (2006)] are then presented.

  7. Progress on LEU very high density fuel and target development in Argentina

    International Nuclear Information System (INIS)

    Balart, S.; Cabot, P.; Calzetta, O.; Duran, A.; Garces, J.; Hermida, J.D.; Manzini, A.; Pasqualini, E.; Taboada, H.

    2006-01-01

    Since last RRFM meeting, CNEA has continued on new LEU fuel and target development activities. Main goals are the plan to convert our RA-6 reactor from HEU to a new LEU core, to get a comprehensive understanding of U-Mo/Al compounds phase formation in dispersed and monolithic fuels, to develop possible solutions to VHD dispersed and monolithic fuels technical problems, to optimize techniques to recover U from silicide scrap samples as cold test for radiowaste separation for final conditioning of silicide spent fuels. and to improve the diffusion of LEU target and radiochemical technology for radioisotope production. Future plans include: - Completion of the RA-6 reactor conversion to LEU; - Improvement on fuel development and production facilities to implement new technologies, including NDT techniques to assess bonding quality; - Irradiation of miniplates and full scale fuel assembly at RA-3 and plans to perform irradiation on higher power and temperature regime reactors; - Optimization of LEU target and radiochemical techniques for radioisotope production. (author)

  8. Development of Targeted, Enzyme-Activated Nano-Conjugates for Hepatic Cancer Therapy

    Science.gov (United States)

    Kuruvilla, Sibu Philip

    Hepatocellular carcinoma (HCC) is the 5th most commonly-occurring cancer worldwide and the 2nd highest cause for cancer-related deaths globally. The current treatment strategy is the direct injection of a chemotherapeutic agent (e.g. doxorubicin; DOX) into the hepatic artery, through a process called hepatic arterial infusion (HAI). Unfortunately, HAI is severely hindered by limited therapeutic efficacy against the tumor and high systemic toxicity to surrounding organs (e.g. cardiotoxicity). This thesis focuses on the development of a targeted, nanoparticle-based drug delivery system aimed to improve the clinical treatment of HCC. In particular, we employ generation 5 (G5) poly(amido amine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands attached to the surface through a poly(ethylene glycol) (PEG) brush. DOX is attached to the G5 surface through two different enzyme-sensitive linkages, L3 or L4, to achieve controllable release of the drug inside hepatic cancer cells. The combination of NAcGal-PEG targeting branches with either L3- or L4-DOX linkages led to the development of P1 and P2 particles, respectively. In Part 1, we discuss the development of these particles and measure their ability to target and kill hepatic cancer cells in vitro. In Part 2, we investigate the antitumor activity of P1 and P2 particles in tumor-bearing mice in comparison to the free drug, and we measure the cardiac function of mice undergoing treatment to assess differences in DOX-induced cardiotoxicity. Finally, in Part 3, we explore multi-valent targeting of G5 dendrimers in pursuit of further improving their specificity to hepatic cancer cells. Ultimately, this thesis provides insight into the utility of nanoparticle-based drug delivery systems that can potentially be translated to the clinic to improve cancer therapy.

  9. Development of target ion source systems for radioactive beams at GANIL

    Energy Technology Data Exchange (ETDEWEB)

    Bajeat, O., E-mail: bajeat@ganil.fr [GANIL, BP 55027, 14076 CAEN Cedex 05 (France); Delahaye, P. [GANIL, BP 55027, 14076 CAEN Cedex 05 (France); Couratin, C. [GANIL, BP 55027, 14076 CAEN Cedex 05 (France); LPC Caen, 6 bd Maréchal Juin, 14050 CAEN Cedex (France); Dubois, M.; Franberg-Delahaye, H.; Henares, J.L.; Huguet, Y.; Jardin, P.; Lecesne, N.; Lecomte, P.; Leroy, R.; Maunoury, L.; Osmond, B.; Sjodin, M. [GANIL, BP 55027, 14076 CAEN Cedex 05 (France)

    2013-12-15

    Highlights: • For Spiral 1, a febiad ion source has been connected to a graphite target. • For Spiral 2, an oven made with a carbon resistor is under development. • We made some measurement of effusion in the Spiral 2 target. • A laser ion source is under construction. -- Abstract: The GANIL facility (Caen, France) is dedicated to the acceleration of heavy ion beams including radioactive beams produced by the Isotope Separation On-Line (ISOL) method at the SPIRAL1 facility. To extend the range of radioactive ion beams available at GANIL, using the ISOL method two projects are underway: SPIRAL1 upgrade and the construction of SPIRAL2. For SPIRAL1, a new target ion source system (TISS) using the VADIS FEBIAD ion source coupled to the SPIRAL1 carbon target will be tested on-line by the end of 2013 and installed in the cave of SPIRAL1 for operation in 2015. The SPIRAL2 project is under construction and is being design for using different production methods as fission, fusion or spallation reactions to cover a large area of the chart of nuclei. It will produce among others neutron rich beams obtained by the fission of uranium induced by fast neutrons. The production target made from uranium carbide and heated at 2000 °C will be associated with several types of ion sources. Developments currently in progress at GANIL for each of these projects are presented.

  10. Development of plasma targets for interaction experiments at Tokyo Institute of Technology

    International Nuclear Information System (INIS)

    Hosokai, T.; Miyamoto, S.; Ogawa, M.

    1996-01-01

    A plasma target of z-pinch discharge is developed to obtain a hydrogen plasma of density approaching 10 18 cm -3 . The target plasma has a duration of about 1 μs for an initial gas pressure of 80 Pa. Prior to the gas flow type of target, the z-pinch process of a gas-filled discharge tube was studied by comparison with a computer simulation. The behavior of the z pinch is understood in terms of the dynamics of a shock wave and a current boundary sheet. A laser-induced plasma is also examined as an alternative plasma target free from the plasma lens effect. (orig.)

  11. Peptide deformylase as an antibacterial drug target: target validation and resistance development.

    Science.gov (United States)

    Apfel, C M; Locher, H; Evers, S; Takács, B; Hubschwerlen, C; Pirson, W; Page, M G; Keck, W

    2001-04-01

    New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition of Escherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry their N-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10(-7)). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

  12. Polarized few-nucleon targets: new developments

    International Nuclear Information System (INIS)

    Haeusser, O.

    1992-09-01

    We discuss recent improvements in producing polarized few-nucleon targets for nuclear and particle physics experiments. The emphasis is on progress with polarized gas targets intended for experiments at electron and proton storage rings. (author) 54 refs., 1 tab

  13. Polarized few-nucleon targets: new developments

    Energy Technology Data Exchange (ETDEWEB)

    Haeusser, O

    1992-09-01

    We discuss recent improvements in producing polarized few-nucleon targets for nuclear and particle physics experiments. The emphasis is on progress with polarized gas targets intended for experiments at electron and proton storage rings. (author) 54 refs., 1 tab.

  14. Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy.

    Science.gov (United States)

    Naganawa, Mika; Gallezot, Jean-Dominique; Rossano, Samantha; Carson, Richard E

    2017-12-11

    Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

  15. Recent advances in developing small molecules targeting RNA.

    Science.gov (United States)

    Guan, Lirui; Disney, Matthew D

    2012-01-20

    RNAs are underexploited targets for small molecule drugs or chemical probes of function. This may be due, in part, to a fundamental lack of understanding of the types of small molecules that bind RNA specifically and the types of RNA motifs that specifically bind small molecules. In this review, we describe recent advances in the development and design of small molecules that bind to RNA and modulate function that aim to fill this void.

  16. Fast reactor development strategy targets study in China

    International Nuclear Information System (INIS)

    Xu Mi

    2008-01-01

    China is a big developing Country who needs a huge energy resources and a rapid growing rate. Considering energy resources limited and environment issues it is sure that the nuclear energy will be becoming one of the main energy resources. The Government has decided to develop the nuclear power capacity to 40 GW in 2020. It is envisaged that it will reach to 240 GW in 2050. It is stimulate us to consider conscientiously the development of the fast breeder reactor's and related closed nuclear fuel cycle by the limitation of Uranium resources and uncertainties of international Uranium market. Followings are the proposed strategic targets of fast reactor development in China. (1) To realize the operation of commercial fast breeder reactors with an unit size of 800-900 MWe and one site-multi reactors in 2030. (2) To develop the nuclear power capacity to 240 GW in 2050. (3) To replace step by step the fossil fuel utilization in large scale by nuclear energy beyond 2050. (authors)

  17. An update on anticancer drug development and delivery targeting carbonic anhydrase IX

    Directory of Open Access Journals (Sweden)

    Justina Kazokaitė

    2017-11-01

    Full Text Available The expression of carbonic anhydrase (CA IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors.

  18. Study of solid target preparation for developing I-124, Pd-103, Cu-64 radioisotopes based cyclotron

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Hong; Park, Hyun; Lee, Ji Sub; Lee, Dong Hoon; Chun, Kwon Soo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Choi, Hee Dong [Seoul National Univ., Seoul (Korea, Republic of)

    2005-07-01

    The decay characteristics of I-124, Pd-103 and Cu-64 radioisotopes produced by cyclotron have considered useful agents for diagnostic imaging or therapy. Numbers of radioisotopes used in medical applications or promised for development are produced with solid targets. The aims of developing solid targets are to obtain large quantities of radionuclides from accelerators. The scope of the study is to develop optimized target system and chemical procedures of these radioisotopes. In order to increase the availability of the radionuclides, the investigation for the design of the solid target and different procedures yielding efficient production of high specific activity will be carrying. In this work, we will present the issue of the primary target design concept.

  19. Biofuels development in China: Technology options and policies needed to meet the 2020 target

    International Nuclear Information System (INIS)

    Chang, Shiyan; Zhao, Lili; Timilsina, Govinda R.; Zhang, Xiliang

    2012-01-01

    China promulgated the Medium and Long-Term Development Plan for Renewable Energy in 2007, which included sub-targets of 2010 and 2020 for various renewable energy technologies. Almost all the 2010 sub-targets have been met and even surpassed except non-grain fuel ethanol. There is debate surrounding the questions of whether and how the country will be able to meet the 2020 biofuels target. This paper provides the assessment of potential technology pathways to achieve the 2020 target regarding their respective resource potential and supply cost. Barriers and policy options are identified based on broad literatures review. And an overview of biofuels projections is presented to provide insight into the comparison of various policy scenarios. The study shows that China can potentially satisfy non-grain fuel ethanol target by 2020 from technology perspective. But she will probably fall far short of this target if current situations continue. Additional policy efforts are needed. Meanwhile, the target of biodiesel production has high probability to be achieved. However, if given support policies, it will develop better. - Highlights: ► I. Non-grain feedstocks such as cassava, sweet sorghum and sweet potato grown in low productive arable lands or unutilized lands have enough potential to meet ethanol targets in 2020. ► II. If current situations continue, China will fall far short of the 2020 target. ► III. The target of biodiesel production has high probability to be achieved, while, if given support policies, it will develop better. ► IV. Supply cost is one of the major barriers faced by all biofuels pathways. ► V. Various policy measures would be necessary to overcome the costs barriers to biofuels in China.

  20. Development of a Novel Targeted RNAi Delivery Technology inTherapies for Metabolic Diseases

    Science.gov (United States)

    2017-10-01

    report Impact on other disciplines: Nothing to report Impact on technology transfer: Nothing to report Impact on society : Nothing to report 5. CHANGES...AWARD NUMBER: W81XWH-15-1-0569 TITLE: Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases PRINCIPAL...COVERED 30Sep2016 - 29Sep2017 4. TITLE AND SUBTITLE Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases 5a

  1. Conceptual design of a 10-MJ driver for a high gain target development facility

    International Nuclear Information System (INIS)

    Olson, R.E.

    1987-01-01

    Commercial application of inertial confinement fusion (ICF) will require inexpensive, high gain (>80) fusion targets. It is thought that the development of such targets will require a 5 to 10 year search effort utilizing a dedicated nuclear research facility with a driver capable of providing a 10 MJ, 300 to 1000 TW pulse of on-target energy. The Terget Development Facility (TDF) is a light ion driven concept for such a facility. A TDF driver based upon extrapolations from present-day pulsed power technology is described in the present paper

  2. Development of dissolution process for metal foil target containing low enriched uranium

    International Nuclear Information System (INIS)

    Srinivasan, B.; Hutter, J.C.; Johnson, G.K.; Vandegrift, G.F.

    1994-01-01

    About six times more low enriched uranium (LEU) metal is needed to produce the same quantity of 99 Mo as from a high enriched uranium (HEU) oxide target, under similar conditions of neutron irradiation. In view of this, the post-irradiation processing procedures of the LEU target are likely to be different from the Cintichem process procedures now in use for the HEU target. The authors have begun a systematic study to develop modified procedures for LEU target dissolution and 99 Mo separation. The dissolution studies include determination of the dissolution rate, chemical state of uranium in the solution, and the heat evolved in the dissolution reaction. From these results the authors conclude that a mixture of nitric and sulfuric acid is a suitable dissolver solution, albeit at higher concentration of nitric acid than in use for the HEU targets. Also, the dissolver vessel now in use for HEU targets is inadequate for the LEU target, since higher temperature and higher pressure will be encountered in the dissolution of LEU targets. The desire is to keep the modifications to the Cintichem process to a minimum, so that the switch from HEU to LEU can be achieved easily

  3. Feasible climate targets. The roles of economic growth, coalition development and expectations

    International Nuclear Information System (INIS)

    Blanford, Geoffrey J.; Richels, Richard G.; Rutherford, Thomas F.

    2009-01-01

    The analysis presented here follows the design specified by the Energy Modeling Forum (EMF) Transition Scenarios study on achieving climate stabilization goals with delayed participation by developing countries. We use the MERGE model to evaluate the core EMF scenarios for both the international and the US-specific studies. Our results indicate that a radiative forcing target equivalent to 450 ppmv CO 2 -e cannot be met even allowing for full participation and overshoot during the entire 21st century. With delayed participation of developing countries, a target of 550 ppmv CO 2 -e is only attainable with pessimistic assumptions about economic growth, and even then only at very high cost. A target of 650 ppmv CO 2 -e can be met with delayed participation for a more affordable cost. We highlight sensitivities to the core scenarios in two key dimensions: (1) the effect of the unfolding global financial crisis on the rate of economic growth and (2) the willingness of initially non-participating countries to agree at the beginning of the next commitment period (i.e. 2012) to join the coalition at a pre-specified date in the future. We find that while the recession does not fundamentally change the crucial role of developing country involvement, advance agreement on their part to future targets could substantially reduce costs for all countries. (author)

  4. Future technological developments to fulfill AG2020 targets

    DEFF Research Database (Denmark)

    Markussen, Mads Ville; Østergård, Hanne; Borch, Kristian

    2010-01-01

    This report constitute an analysis of selected technologies that are anticipated to underpin the images described in Giaoutzi et al (2008) and it proposes policy measures to promote these technologies. It builds on Borch et al (2008) where a more detailed description of technologies can be found....... as the threats for development of the technology in the respective images. Finally policies for promoting and spreading technologies are proposed.......This report constitute an analysis of selected technologies that are anticipated to underpin the images described in Giaoutzi et al (2008) and it proposes policy measures to promote these technologies. It builds on Borch et al (2008) where a more detailed description of technologies can be found....... Based on the technological narratives and imperatives, we select a set of present available technologies that are able to support the society in reaching the targets set up by AG2020. For each of these technologies, we evaluate the strengths and weaknesses of the technology to reach the target as well...

  5. Conceptual design of a 6-10 MJ driver for a high gain target development facility

    International Nuclear Information System (INIS)

    Olson, R.E.

    1986-01-01

    Commercial application of inertial confinement fusion would require low yield (≅200-500 MJ), high gain (≥80) fusion targets. It is thought that the development off such targets would reqiure a 5-10 year research program utilizing one or more dedicated nuclear facilities with drivers capable of delivering on-target pulses of 6-10 MJ at the rate of several shots per day. The ''Target Development Facility'' (TDF) is the light ion driven version of such a facility. A TDF driver concept based upon reasonable extrapolation from present-day technology is described in this paper

  6. New Improved Nuclear Data for Nuclear Criticality and Safety

    International Nuclear Information System (INIS)

    Guber, Klaus H.; Leal, Luiz C.; Lampoudis, C.; Kopecky, S.; Schillebeeckx, P.; Emiliani, F.; Wynants, R.; Siegler, P.

    2011-01-01

    The Geel Electron Linear Accelerator (GELINA) was used to measure neutron total and capture cross sections of 182,183,184,186 W and 63,65 Cu in the energy range from 100 eV to ∼200 keV using the time-of-flight method. GELINA is the only high-power white neutron source with excellent timing resolution and ideally suited for these experiments. Concerns about the use of existing cross-section data in nuclear criticality calculations using Monte Carlo codes and benchmarks were a prime motivator for the new cross-section measurements. To support the Nuclear Criticality Safety Program, neutron cross-section measurements were initiated using GELINA at the EC-JRC-IRMM. Concerns about data deficiencies in some existing cross-section evaluations from libraries such as ENDF/B, JEFF, or JENDL for nuclear criticality calculations were the prime motivator for new cross-section measurements. Over the past years many troubles with existing nuclear data have emerged, such as problems related to proper normalization, neutron sensitivity backgrounds, poorly characterized samples, and use of improper pulse-height weighting functions. These deficiencies may occur in the resolved- and unresolved-resonance region and may lead to erroneous nuclear criticality calculations. An example is the use of the evaluated neutron cross-section data for tungsten in nuclear criticality safety calculations, which exhibit discrepancies in benchmark calculations and show the need for reliable covariance data. We measured the neutron total and capture cross sections of 182,183,184,186 W and 63,65 Cu in the neutron energy range from 100 eV to several hundred keV. This will help to improve the representation of the cross sections since most of the available evaluated data rely only on old measurements. Usually these measurements were done with poor experimental resolution or only over a very limited energy range, which is insufficient for the current application.

  7. Guidelines for target costing adoption in the development of products for the residential real estate market

    Directory of Open Access Journals (Sweden)

    Reymard Savio Sampaio de Melo

    Full Text Available Abstract This study focuses on the problems associated with the traditional practice of reducing costs in construction and the need to increase business competitiveness in the residential real estate sector. In this context, target costing is a promising approach to improve the competitiveness of companies by ensuring that the products launched on the market do not jeopardize the company's results and value delivery to customers. However, far too little attention is paid to target costing implementation by companies that develop residential real state products for sale and face strong market competition. Thus, this paper seeks to investigate whether the standard framework of target costing in the literature applies - with or without adjustments - to real estate developers. Case study was the research strategy adopted. Guidelines are proposed for the introduction of target costing in the development process of residential real estate products. The proposed guidelines are related to the three main sections of the target costing process: market-driven costing, product-level target costing and component-level target costing.

  8. Development of a nickel plated aluminum krypton-81m target system.

    Science.gov (United States)

    Alrumayan, F; Okarvi, S M; Nagatsu, K; Yanbawi, S; Aljammaz, I

    2017-03-01

    A fully automated system was developed to produce rubidium-81 ( 81 Rb), based on the nat Kr (p, n) 81 Rb reaction. The energy incident on the target was 26MeV. Only 6MeV was stopped inside the gas and the remainder was stopped by a specially designed flange. The target body was characterized by its conical shape and its inner walls were chemically plated with 100±10µm of nickel (Ni). Ni is advantageous as a fairly good conductor of heat whose surface can resist solutions. Additionally, the Ni plated target allowed potassium chloride to dissolve 81 Rb, with no further effect on the target body. The system produced 81 Rb with a production yield of approximately 4.5mCi/µAh, which is close to the calculated expected yield of 5.3mCi/µAh. The system is able to deliver reliable and reproducible radioactivity for patients and can be operated up to 1500µAh before preventive maintenance is due. Key steps in designing the 81 Rb target for selected energy ranges are reported here. Copyright © 2016. Published by Elsevier Ltd.

  9. Recent developments in the target facilities at Argonne National Laboratory

    International Nuclear Information System (INIS)

    Greene, J.P.; Thomas, G.E.

    1989-01-01

    A description is given of recent developments in the target facility at Argonne National Laboratory (ANL). Highlights include equipment upgrades which enable us to provide enhanced capabilities for support of the Argonne Heavy-Ion ATLAS Accelerator Project. Also, future plans and additional equipment acquisitions will be discussed. (orig.)

  10. Development of a cluster-jet target for PANDA

    International Nuclear Information System (INIS)

    Gruber, A.; Marton, J.; Widmann, E.; Zmeskal, J.; PANDA Cluster Jet Target Group

    2006-01-01

    Full text: The Stefan Meyer Institute (SMI) is part of the international PANDA collaboration. The universal detector will be constructed for the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). PANDA will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. The physics program of PANDA will comprehend charmonium spectroscopy below and above open charm threshold, search for exotics (glueballs, hybrids), lambda and double-lambda hypernuclei studies and the investigation of in-medium modifications of charmed mesons - an experimentally unexplored field. SMI contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the antiproton - cluster jet interaction zone: in order to reach the desired target density, an optimization of the nozzle and the skimmer arrangement is essential. A density-profile monitor for the cluster-jet was designed and built at SMI. Several nozzle types have been studied using different gases, temperatures and inlet pressures. To ensure low background the residual gas load in the interaction zone has to be minimized. The installation of NEG (non-evaporative-getter) coated beam pipes is planned. A prototype of the interaction zone has been set up at SMI. The pumping capacity of NEG and the reactivation cycles were tested. The status of the development of the cluster-jet target and studies of the interaction region will be presented (author)

  11. Oligodendrocyte Development in the Absence of Their Target Axons In Vivo.

    Directory of Open Access Journals (Sweden)

    Rafael Almeida

    Full Text Available Oligodendrocytes form myelin around axons of the central nervous system, enabling saltatory conduction. Recent work has established that axons can regulate certain aspects of oligodendrocyte development and myelination, yet remarkably oligodendrocytes in culture retain the ability to differentiate in the absence of axons and elaborate myelin sheaths around synthetic axon-like substrates. It remains unclear the extent to which the life-course of oligodendrocytes requires the presence of, or signals derived from axons in vivo. In particular, it is unclear whether the specific axons fated for myelination regulate the oligodendrocyte population in a living organism, and if so, which precise steps of oligodendrocyte-cell lineage progression are regulated by target axons. Here, we use live-imaging of zebrafish larvae carrying transgenic reporters that label oligodendrocyte-lineage cells to investigate which aspects of oligodendrocyte development, from specification to differentiation, are affected when we manipulate the target axonal environment. To drastically reduce the number of axons targeted for myelination, we use a previously identified kinesin-binding protein (kbp mutant, in which the first myelinated axons in the spinal cord, reticulospinal axons, do not fully grow in length, creating a region in the posterior spinal cord where most initial targets for myelination are absent. We find that a 73% reduction of reticulospinal axon surface in the posterior spinal cord of kbp mutants results in a 27% reduction in the number of oligodendrocytes. By time-lapse analysis of transgenic OPC reporters, we find that the reduction in oligodendrocyte number is explained by a reduction in OPC proliferation and survival. Interestingly, OPC specification and migration are unaltered in the near absence of normal axonal targets. Finally, we find that timely differentiation of OPCs into oligodendrocytes does not depend at all on the presence of target axons

  12. Recent developments in the target facilities at Argonne National Laboratory

    International Nuclear Information System (INIS)

    Greene, J.P.; Thomas, G.E.

    1988-01-01

    A description is given of recent developments in the target facility at Argonne National Laboratory. Highlights include equipment upgrades which enables us to provide enhanced capabilities for support of the Argonne Heavy-Ion ATLAS Accelerator Project. Also future plans and additional equipment acquisitions will be discussed. 3 refs., 3 tabs

  13. Developing Internet interventions to target the individual impact of stigma in health conditions

    Directory of Open Access Journals (Sweden)

    Neil Thomas

    2015-09-01

    Full Text Available A number of health problems are associated with significant stigma, a social phenomenon in which individuals become the object of negative stereotypes. In addition to experiencing negative reactions from others, stigmatised individuals and groups can experience harmful consequences when they internalise these negative prevailing attitudes. The objective of this paper was to consider the potential to develop Internet-based health-related interventions explicitly targeting the effects of stigma on the individual. A review of the literature was conducted to synthesise current conceptualisations of stigma and self-stigma across a number of groups, and to identify current intervention developments. Self-stigma reduction strategies developed for in-person services include cognitive reframing, myth busting, contact with other members of the stigmatised group, and disclosure promotion. The development and provision of interventions targeting self-stigma within an online environment is in its infancy. Our review considers there to be particular potential of online interventions for this target, associated with the capacity of the Internet to promote having contact with peers within one’s stigmatised group, and for user interaction and empowerment. We conclude that self-stigma is a domain in which there is significant potential for innovation with health-related interventions, and provide a number of recommendations for online intervention development.

  14. Developing, Implementing, and Evaluating a Condom Promotion Program Targeting Sexually Active Adolescents.

    Science.gov (United States)

    Alstead, Mark; Campsmith, Michael; Halley, Carolyn Swope; Hartfield, Karen; Goldblum, Gary; Wood, Robert W.

    1999-01-01

    Describes the development, implementation, and evaluation of an HIV prevention program promoting condom use among sexually active adolescents. It mobilized target communities to guide program development and implementation; created a mass media campaign to promote correct condom use; and recruited public agencies and organizations to distribute…

  15. A target development program for beamhole spallation neutron sources in the megawatt range

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, G.S.; Atchison, F. [Rutherford Appleton Laboratory, Oxon (United Kingdom)] [and others

    1995-10-01

    Spallation sources as an alternative to fission neutron sources have been operating successfully up to 160 kW of beam power. With the next generation of these facilities aiming at the medium power range between 0.5 and 5 MW, loads on the targets will be high enough to make present experience of little relevance. With the 0.6 MW continuous facility SINQ under construction, and a 5 MW pulsed facility (ESS) under study in Europe, a research and development program is about to be started which aimes at assessing the limits of stationary and moving solid targets and the feasibility and potential benefits of flowing liquid metal targets. Apart from theoretical work and examination of existing irradiated material, including used targets from ISIS, it is intended to take advantage of the SINQ solid rod target design to improve the relevant data base by building the target in such a way that individual rods can be equipped as irradiation capsules.

  16. Developing plan and pre-conceptual design of target system for JAERI`s high intensity neutron source

    Energy Technology Data Exchange (ETDEWEB)

    Hino, Ryutaro; Kaminaga, Masanori; Haga, Katsuhiro; Ishikura, Syuichi [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Nakamura, Fumito; Uchida, Shoji

    1997-11-01

    This paper presents an outline of developing plan of a target system and topics obtained by a pre-conceptual design, which aims to establish a technology base of the target system and to make clear a system concept. In the plan, two types of target - solid and mercury targets - are to be developed for a neutron scattering facility. Information obtained through the development shall be applied to designs of an irradiation and a transmutation facilities. Through the pre-conceptual design, system arrangement, scale etc. were made clear: total weight will be 12000 ton, and 26 beam lines with beam shutters will be equipped for 4 moderators. Engineering problems were also made clear through the design; high flux heat removal, dynamic stress caused by thermal shock and pressure wave, loop technology for the mercury target and a slurry moderator consisting of methane pellets and liquefied hydrogen. We are now constructing new test apparatuses and arranging computer codes for solving these problems. (author)

  17. Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents

    Directory of Open Access Journals (Sweden)

    Roxanne P. Smith

    2016-07-01

    Full Text Available Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways are potential targets for the development of antimicrobial agents because they play a central role in bacterial pathogenesis. In particular, the DsbA/DsbB system catalyses disulfide bond formation in a wide array of virulence factors, which are essential for many pathogens to establish infections and cause disease. These redox enzymes are well placed as antimicrobial targets because they are taxonomically widespread, share low sequence identity with human proteins, and many years of basic research have provided a deep molecular understanding of these systems in bacteria. In this review, we discuss disulfide bond catalytic pathways in bacteria and their significance in pathogenesis. We also review the use of different approaches to develop inhibitors against Dsb proteins as potential anti-virulence agents, including fragment-based drug discovery, high-throughput screening and other structure-based drug discovery methods.

  18. Target development for the SINQ high-power neutron spallation source

    International Nuclear Information System (INIS)

    Wagner, Werner

    2002-01-01

    SINQ is a 1 MW class research spallation neutron source, driven by the PSI proton accelerator system. In terms of beam power, it is, by a large margin, the most powerful spallation neutron source currently in operation worldwide. As a consequence, target load levels prevail in SINQ which are beyond the realm of existing experience. Therefore, an extensive materials irradiation program (STIP) is currently underway which will help to select the proper structural material and make dependable life time estimates accounting for the real operating conditions that prevail in the facility. In parallel, both theoretical and experimental work is going on within the MEGAPIE (MEGAwatt Pilot Experiment) project, to develop a liquid lead-bismuth spallation target for a beam power level of 1MW

  19. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development Concept Stage Report

    Energy Technology Data Exchange (ETDEWEB)

    McKay, H.N. (Illuminating Engineering Society of North America, New York, NY (USA)); Deringer, J.J. (American Inst. of Architects, Washington, DC (USA)); Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Hall, J.D. (Deringer Group, Riva, MD (USA))

    1990-09-01

    This report documents eight tasks performed as part of the Whole-Building Energy Design Targets project, in which detailed conceptual approaches were produced for each element of the proposed Targets model. The eight task reports together describe the important modules proposed for inclusion in the Targets model: input module, energy module, characteristic development moduel, building cost module, analysis control module, energy cost module, search routines module, and economic analysis module. 16 refs., 16 figs., 5 tabs.

  20. The Pim kinases: new targets for drug development.

    Science.gov (United States)

    Swords, Ronan; Kelly, Kevin; Carew, Jennifer; Nawrocki, Stefan; Mahalingam, Devalingam; Sarantopoulos, John; Bearss, David; Giles, Francis

    2011-12-01

    The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

  1. Development of tumor-targeted near infrared probes for fluorescence guided surgery.

    Science.gov (United States)

    Kelderhouse, Lindsay E; Chelvam, Venkatesh; Wayua, Charity; Mahalingam, Sakkarapalayam; Poh, Scott; Kularatne, Sumith A; Low, Philip S

    2013-06-19

    Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions. While nontargeted fluorescent dyes have been shown to passively accumulate in some tumors, the resulting tumor-to-background ratios are often poor, and the boundaries between malignant and healthy tissues can be difficult to define. To circumvent these problems, our laboratory has developed high affinity tumor targeting ligands that bind to receptors that are overexpressed on cancer cells and deliver attached molecules selectively into these cells. In this study, we explore the use of two tumor-specific targeting ligands (i.e., folic acid that targets the folate receptor (FR) and DUPA that targets prostate specific membrane antigen (PSMA)) to deliver near-infrared (NIR) fluorescent dyes specifically to FR and PSMA expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here that all FR- and PSMA-targeted NIR probes examined bind cultured cancer cells in the low nanomolar range. Moreover, upon intravenous injection into tumor-bearing mice with metastatic disease, these same ligand-NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues.

  2. Modeling to Support the Development of Habitat Targets for Piping Plovers on the Missouri River

    Energy Technology Data Exchange (ETDEWEB)

    Buenau, Kate E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-05-05

    Report on modeling and analyses done in support of developing quantative sandbar habitat targets for piping plovers, including assessment of reference, historical, dams present but not operated, and habitat construction calibrated to meet population viability targets.

  3. SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery.

    Science.gov (United States)

    Zha, Haihong; Cai, Yuping; Yin, Yandong; Wang, Zhuozhong; Li, Kang; Zhu, Zheng-Jiang

    2018-03-20

    The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS 2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).

  4. An update on the LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.; Eng, B.Sc; Eng, P.

    2002-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada, has been extracted from reactor targets employing highly enriched uranium (HEU). A reliable supply of HEU metal from the United States used in the manufacture of targets for the NRU research reactor has been a key factor to enable MDS Nordion to develop a secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets provides predictable, consistent yields for our high-volume molybdenum production process. Each link of the isotope supply chain, from isotope production to ultimate use by the physician, has been established using this proven and established method of HEU target irradiation and processing to extract molybdenum-99. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the construction of two MAPLE reactors and a New Processing Facility. The design of the MAPLE facilities was based on an established process developed by Atomic Energy of Canada Ltd. (AECL)-extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a three phase LEU Target Development and Conversion Program for the MAPLE facilities. Phase 1, the Initial Feasibility Study, which identified the technical issues to convert the MAPLE reactor targets from HEU to LEU for large scale commercial production was reported on at the RERTR-2000 conference. The second phase of the LEU Target Development and Conversion Program was developed with extensive consultation and involvement of experts knowledgeable in target development, process system design, enriched uranium conversion chemistry and commercial scale reactor operations and molybdenum production. This paper will provide an overview of the Phase 2 Conversion Development Program, report on progress to date, and further

  5. Development of Cursor-on-Target Control for Semi-Autonomous Unmanned Aircraft Systems

    National Research Council Canada - National Science Library

    Crouse, Joshua D

    2007-01-01

    .... The goal of this research is to develop a preliminary Cursor-on-Target control system to enable the operator to guide the unmanned aircraft with minimal workload during high task phases of flight...

  6. The Argonne laser-driven D target: Recent developments and progress

    International Nuclear Information System (INIS)

    Fedchak, J.A.; Bailey, K.; Cummings, W.J.

    1997-01-01

    The first direct measurements of nuclear tensor polarization p zz in a laser-driven polarized D target have been performed at Argonne. We present p zz and electron polarization P e data taken at a magnetic field of 600 G in the optical pumping cell. These results are highly indicative that spin-temperature equilibrium is achieved in the system. To prevent spin relaxation of D and K atoms as well as the molecular recombination of D atoms, the walls of the laser-driven D target are coated with organosilane compounds. We discuss a new coating technique, the open-quotes afterwashclose quotes, developed at Argonne which has yielded stable atomic fraction results when the coating is exposed to K. We also present new coating techniques for glass and Cu substrates

  7. Chinas carbon-intensity target: climate actors and policy developments

    Energy Technology Data Exchange (ETDEWEB)

    Stensdal, Iselin

    2012-11-01

    China has become the largest GHG emitting country, and announced in 2009 its first policy objective measured in carbon emissions. The carbon-intensity target is to reduce the carbon intensity by 40-45 % by 2020 compared to 200 levels. Since then there has been further policy developments in order to attain the reduction carbon intensity and steer China towards a low-carbon development. The 12th 5-year plan (2011-2015) is strong on incentives for reducing China's carbon intensity such as energy conservation measures and the establishment of new market-based mechanisms. While the central government forms the policies, the implementation is dependent on a range of actors. In addition to the climate change bureaucracy, the positive forces and actors on GHG mitigation is presented. All in all, there are promising developments in China for the years to come.(auth)

  8. Recent developments of target and ion sources to produce ISOL beams

    CERN Document Server

    Stora, Thierry

    2013-01-01

    In this review on target and ion sources for ISOL (Isotope Separation OnLine) beams, important develop- ments from the past five years are highlighted. While at precedent EMIS conferences, a particular focus was given to a single topics, for instance specifically on ion sources or on chemical purification tech- niques, here each of the important elements present in an ISOL production unit is discussed. Fast diffus- ing nanomaterials, uranium-based targets, high power targets for next generation facilities, purification by selective adsorption, new ion sources are all part of this review. For each of these selected topics, the reported results lead to significant gains in intensity, purity, or quality of the delivered beam, or in the production of new isotope beams. Often the outcome resulted from the combination of original ideas with state-of-the-art investigations; this was carried out using very different scientific disciplines, lead- ing to understanding of the underlying chemical or physical mechanisms a...

  9. Recent Developments in Fabrication of Direct Drive Cylinder Targets for Hydrodynamics Experiments at the OMEGA Laser

    International Nuclear Information System (INIS)

    Nobile, A.; Balkey, M.M.; Bartos, J.J.; Batha, S.H.; Day, R.D.; Elliott, J.E.; Elliott, N.E.; Gomez, V.M.; Hatch, D.J.; Lanier, N.E.; Fincke, J.R.; Manzanares, R.; Pierce, T.H.; Sandoval, D.L.; Schmidt, D.W.; Steckle, W.P.

    2004-01-01

    Experimental campaigns are being conducted at the 60 beam OMEGA laser at the University of Rochester's Laboratory for Laser Energetics to acquire data to validate hydrodynamic models in the high energy-density regime. This paper describes targets that have been developed and constructed for these experimental campaigns. Targets are 860 μm inner diameter by 2.2 mm length cylinders with 70 μm thick polymer ablator. On the ablator inner surface and located halfway along the axis of the cylinder is a 500 μm wide Al marker band. Band thicknesses in the range 8-16 microns are used. CH foam with densities in the range 30-90 mg/cc fills the inside of the cylinder. While these targets have been fabricated for years, several new improvements and features have recently been developed. Improvements include the use of epoxy instead of polystyrene for the ablator, and the use of electrodeposited Al for the marker band. A critical feature of the target is the surface feature that is placed on the marker band. Experiments are aimed at understanding the hydrodynamic behavior of imploding cylinders as a function of this surface feature. Recent development work has focused on production of engineered surface features on the target marker band. Using a fast tool servo on a diamond turning lathe, a wide range of specified surface features have been produced. This paper will address improvements to the cylinder targets as well as current development efforts

  10. Development of target-tracking algorithms using neural network

    Energy Technology Data Exchange (ETDEWEB)

    Park, Dong Sun; Lee, Joon Whaoan; Yoon, Sook; Baek, Seong Hyun; Lee, Myung Jae [Chonbuk National University, Chonjoo (Korea)

    1998-04-01

    The utilization of remote-control robot system in atomic power plants or nuclear-related facilities grows rapidly, to protect workers form high radiation environments. Such applications require complete stability of the robot system, so that precisely tracking the robot is essential for the whole system. This research is to accomplish the goal by developing appropriate algorithms for remote-control robot systems. A neural network tracking system is designed and experimented to trace a robot Endpoint. This model is aimed to utilized the excellent capabilities of neural networks; nonlinear mapping between inputs and outputs, learning capability, and generalization capability. The neural tracker consists of two networks for position detection and prediction. Tracking algorithms are developed and experimented for the two models. Results of the experiments show that both models are promising as real-time target-tracking systems for remote-control robot systems. (author). 10 refs., 47 figs.

  11. Development of surface perturbation target and thin silicon foil target used to research Rayleigh-Taylor instability in inertial confinement fusion experiment

    International Nuclear Information System (INIS)

    Zhou Bin; Sun Qi; Huang Yaodong; Shen Jun; Wu Guangming; Wang Jue

    2004-01-01

    The developments of the surface perturbation target and the thin silicon foil target used to research Rayleigh-Taylor instability in the resolved experiments of Inertial Confinement Fusion (ICF) are carried out. Based on the laser interference process combined with the figure-transfer process, the surface perturbation target with sine modulated perturbation is gotten, the wavelength is in the range of 20-100 μm and the amplitude is several micrometers. The thin silicon foil within the thickness about 3-4 μm is prepared by semiconductor process together with heavy-doped self-stop etching. Combined with ion beam etching, the check or the stripe patterns are transferred to the surface of thin silicon foils, and then the silicon grating foil is obtained

  12. Developing Culturally Targeted Diabetes Educational Materials for Older Russian-Speaking Immigrants.

    Science.gov (United States)

    Van Son, Catherine R

    2014-07-01

    Older adults who immigrate late in life face many challenges adapting to a new country. Immigrants bring their cultural beliefs and behaviors with them, which can influence their ability to make dietary changes required when they have type 2 diabetes. Culturally targeted patient education materials are needed to improve immigrants' health literacy and abilities to self-manage diabetes. Currently, there is a scarcity of diabetes patient education materials to meet the educational needs of the Russian-speaking immigrant group. The purpose of this article is to describe a project in which culturally targeted diabetes education materials for older Russian-speaking immigrants were designed and developed. Culturally targeted patient education materials are essential if they are to be accepted and used by clients from different ethnic minority populations. The creation of culturally relevant materials requires a team effort and community stakeholder input. The availability of materials on the internet facilitates access and use by health care providers. Culturally targeted education materials are an important component in addressing health literacy in ethnic minority populations. Next steps require that these materials be evaluated to test their impact on diabetes self-management behaviors and clinical outcomes such as adherence, amount of physical activity, and blood glucose levels. © 2014 The Author(s).

  13. Development of high-performance alkali-hybrid polarized 3He targets for electron scattering

    Science.gov (United States)

    Singh, Jaideep T.; Dolph, P. A. M.; Tobias, W. A.; Averett, T. D.; Kelleher, A.; Mooney, K. E.; Nelyubin, V. V.; Wang, Yunxiao; Zheng, Yuan; Cates, G. D.

    2015-05-01

    Background: Polarized 3He targets have been used as effective polarized neutron targets for electron scattering experiments for over twenty years. Over the last ten years, the effective luminosity of polarized 3He targets based on spin-exchange optical pumping has increased by over an order of magnitude. This has come about because of improvements in commercially-available lasers and an improved understanding of the physics behind the polarization process. Purpose: We present the development of high-performance polarized 3He targets for use in electron scattering experiments. Improvements in the performance of polarized 3He targets, target properties, and operating parameters are documented. Methods: We utilize the technique of alkali-hybrid spin-exchange optical pumping to polarize the 3He targets. Spectrally narrowed diode lasers used for the optical pumping greatly improved the performance. A simulation of the alkali-hybrid spin-exchange optical pumping process was developed to provide guidance in the design of the targets. Data was collected during the characterization of 24 separate glass target cells, each of which was constructed while preparing for one of four experiments at Jefferson Laboratory in Newport News, Virginia. Results: From the data obtained we made determinations of the so-called X -factors that quantify a temperature-dependent and as-yet poorly understood spin-relaxation mechanism that limits the maximum achievable 3He polarization to well under 100%. The presence of the X -factor spin-relaxation mechanism was clearly evident in our data. Good agreement between the simulation and the actual target performance was obtained by including details such as off-resonant optical pumping. Included in our results is a measurement of the K -3He spin-exchange rate coefficient kseK=(7.46 ±0.62 ) ×10-20cm3/s over the temperature range 503 K to 563 K. Conclusions: In order to achieve high performance under the operating conditions described in this paper

  14. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  15. Development of annular targets for 99MO production-1999

    International Nuclear Information System (INIS)

    Conner, C.; Lewandowski, E. F.; Snelgrove, J. L.; Liberatore, M. W.; Walker, D. E.; Wiencek, T. C.; McGann, D. J.; Hofman, G. L.; Vandegrift, G. F.

    1999-01-01

    The new annular target performed well during irradiation. The target is inexpensive and provides good heat transfer during irradiation. Based on these and previous tests, we conclude that targets with zirconium tubes and either nickel-plated or zinc-plated foils work well. We proved that we could use aluminum target tubes, which are much cheaper and easier to work with than the zirconium tubes. In aluminum target tubes nickel-plated fission-recoil barriers work well and prevent bonding of the foil to the new target tubes during irradiation. Also, zinc-plated and aluminum-foil barriers appear promising in anodized aluminum tubes. Additional tests are anticipated to address such issues as fission-recoil barrier thickness and uranium foil composition. Overall, however, the target was successful and will provide an inexpensive, efficient way to irradiate LEU metal foil for the production of 99 Mo

  16. Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics

    Directory of Open Access Journals (Sweden)

    Moizza Mansoor

    2008-01-01

    Full Text Available Antisense oligonucleotides (As-ODNs are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt, 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases.

  17. Development of whole-building energy design targets for commercial buildings: Phase 1, Planning: Volume 2, Technical report

    Energy Technology Data Exchange (ETDEWEB)

    Crawley, D.B.; Briggs, R.S.; Jones, J.W.; Seaton, W.W.; Kaufman, J.E.; Deringer, J.J.; Kennett, E.W.

    1987-08-01

    This is the second volume of the Phase 1 report and discusses the 10 tasks performed in Phase 1. The objective of this research is to develop a methodology for setting energy design targets to provide voluntary guidelines for the buildings industry. The whole-building energy targets project is being conducted at the Pacific Northwest Laboratory (PNL) for the US Department of Energy (DOE) to encourage the construction of energy-efficient buildings by informing designers and owners about cost-effective goals for energy use in new commercial buildings. The outcome of this research will be a flexible methodology for setting such targets. The tasks are listed and discussed in this report as follows: Task 1 - Develop Detailed Project Goals and Objectives; Task 2 - Establish Buildings-Industry Liaison; Task 3 - Develop Approaches to the Energy Targets Model, Building Operations, and Climate; Task 4 - Develop an Approach for Treating Economic Considerations; Task 5 - Develop an Approach for Treating Energy Sources; Task 6 - Collect Energy-Use Data; Task 7 - Survey Energy Expert Opinion; Task 8 - Evaluation Procedure Specification and Integration; Task 9 - Phase 1 Report Development; and Task 10 - Phase 1 Review Planning.

  18. Status of SINQ, the only MW spallation neutron source-highlighting target development and industrial applications

    International Nuclear Information System (INIS)

    Wagner, Werner; Dai, Yong; Glasbrenner, Heike; Grosse, Mirco; Lehmann, Eberhard

    2006-01-01

    SINQ is a continuous spallation neutron source, driven by PSI's 590 MeV proton accelerator. Receiving a stable proton current of 1.3 mA, SINQ is the presently most powerful accelerator-driven facility worldwide. Besides the primary designation of SINQ to serve as user facility for neutron scattering and neutron imaging, PSI seeks to play a leading role in the development of the facility, focusing on spallation targets and materials research for high-dose radiation environments. Accompanying these activities, SINQ has established several projects serving a more general, profound development towards high-power spallation targets: the most prominent ones being SINQ Target Irradiation Program (STIP) and megawatt pilot experiment for a liquid metal target (MEGAPIE), complemented by LiSoR and VIMOS. Within the user program, SINQ is aspiring to attract an appropriate contingent of industrial applications. The paper highlights the potential for industrial applications by means of selected examples from strain mapping and neutron imaging

  19. Development of targeted messages to promote smoking cessation among construction trade workers

    Science.gov (United States)

    Strickland, J. R.; Smock, N.; Casey, C.; Poor, T.; Kreuter, M. W.; Evanoff, B. A.

    2015-01-01

    Blue-collar workers, particularly those in the construction trades, are more likely to smoke and have less success in quitting when compared with white-collar workers. Little is known about health communication strategies that might influence this priority population. This article describes our formative work to develop targeted messages to increase participation in an existing smoking cessation program among construction workers. Using an iterative and sequential mixed-methods approach, we explored the culture, health attitudes and smoking behaviors of unionized construction workers. We used focus group and survey data to inform message development, and applied audience segmentation methods to identify potential subgroups. Among 144 current smokers, 65% reported wanting to quit smoking in the next 6 months and only 15% had heard of a union-sponsored smoking cessation program, despite widespread advertising. We tested 12 message concepts and 26 images with the target audience to evaluate perceived relevance and effectiveness. Participants responded most favorably to messages and images that emphasized family and work, although responses varied by audience segments based on age and parental status. This study is an important step towards integrating the culture of a high-risk group into targeted messages to increase participation in smoking cessation activities. PMID:25231165

  20. Targeted p120-catenin ablation disrupts dental enamel development

    DEFF Research Database (Denmark)

    Bartlett, John D; Dobeck, Justine M; Tye, Coralee E

    2010-01-01

    Dental enamel development occurs in stages. The ameloblast cell layer is adjacent to, and is responsible for, enamel formation. When rodent pre-ameloblasts become tall columnar secretory-stage ameloblasts, they secrete enamel matrix proteins, and the ameloblasts start moving in rows that slide...... by one another. This movement is necessary to form the characteristic decussating enamel prism pattern. Thus, a dynamic system of intercellular interactions is required for proper enamel development. Cadherins are components of the adherens junction (AJ), and they span the cell membrane to mediate...... attachment to adjacent cells. p120 stabilizes cadherins by preventing their internalization and degradation. So, we asked if p120-mediated cadherin stability is important for dental enamel formation. Targeted p120 ablation in the mouse enamel organ had a striking effect. Secretory stage ameloblasts detached...

  1. Identification of miRNAs and their target genes in developing soybean seeds by deep sequencing

    Directory of Open Access Journals (Sweden)

    Chen Shou-Yi

    2011-01-01

    Full Text Available Abstract Background MicroRNAs (miRNAs regulate gene expression by mediating gene silencing at transcriptional and post-transcriptional levels in higher plants. miRNAs and related target genes have been widely studied in model plants such as Arabidopsis and rice; however, the number of identified miRNAs in soybean (Glycine max is limited, and global identification of the related miRNA targets has not been reported in previous research. Results In our study, a small RNA library and a degradome library were constructed from developing soybean seeds for deep sequencing. We identified 26 new miRNAs in soybean by bioinformatic analysis and further confirmed their expression by stem-loop RT-PCR. The miRNA star sequences of 38 known miRNAs and 8 new miRNAs were also discovered, providing additional evidence for the existence of miRNAs. Through degradome sequencing, 145 and 25 genes were identified as targets of annotated miRNAs and new miRNAs, respectively. GO analysis indicated that many of the identified miRNA targets may function in soybean seed development. Additionally, a soybean homolog of Arabidopsis SUPPRESSOR OF GENE SLIENCING 3 (AtSGS3 was detected as a target of the newly identified miRNA Soy_25, suggesting the presence of feedback control of miRNA biogenesis. Conclusions We have identified large numbers of miRNAs and their related target genes through deep sequencing of a small RNA library and a degradome library. Our study provides more information about the regulatory network of miRNAs in soybean and advances our understanding of miRNA functions during seed development.

  2. EBF factors drive expression of multiple classes of target genes governing neuronal development.

    Science.gov (United States)

    Green, Yangsook S; Vetter, Monica L

    2011-04-30

    Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  3. Revisiting the case for intensity targets: Better incentives and less uncertainty for developing countries

    International Nuclear Information System (INIS)

    Marschinski, Robert; Edenhofer, Ottmar

    2010-01-01

    In the debate on post-Kyoto global climate policy, intensity targets, which set a maximum amount of emissions per GDP, figure as prominent alternative to Kyoto-style absolute emission targets, especially for developing countries. This paper re-examines the case for intensity targets by critically assessing several of its properties, namely (i) reduction of cost-uncertainty, (ii) reduction of 'hot air', (iii) compatibility with international emissions trading, (iv) incentive to decouple carbon emissions and economic output (decarbonization), and, (v) use as a substitute for banking/borrowing. Relying on simple analytical models, it is shown that the effect on cost-uncertainty is ambiguous and depends on parameter values, and that the same holds for the risk of 'hot air'; that the intensity target distorts international emissions trading; that despite potential asymmetries in the choice of abatement technology between absolute and intensity target, the incentive for a lasting transformation of the energy system is not necessarily stronger under the latter; and, finally, that only a well-working intensity target could substitute banking/borrowing to some extent-but also vice versa. Overall, the results suggest that due to the increased complexity and the potentially only modest benefits of an intensity target, absolute targets remain a robust choice for a cautious policy maker.

  4. A drug development perspective on targeting tumor-associated myeloid cells.

    Science.gov (United States)

    Majety, Meher; Runza, Valeria; Lehmann, Christian; Hoves, Sabine; Ries, Carola H

    2018-02-01

    Despite decades of research, cancer remains a devastating disease and new treatment options are needed. Today cancer is acknowledged as a multifactorial disease not only comprising of aberrant tumor cells but also the associated stroma including tumor vasculature, fibrotic plaques, and immune cells that interact in a complex heterotypic interplay. Myeloid cells represent one of the most abundant immune cell population within the tumor stroma and are equipped with a broad functional repertoire that promotes tumor growth by suppressing cytotoxic T cell activity, stimulating neoangiogenesis and tissue remodeling. Therefore, myeloid cells have become an attractive target for pharmacological intervention. In this review, we summarize the pharmacological approaches to therapeutically target tumor-associated myeloid cells with a focus on advanced programs that are clinically evaluated. In addition, for each therapeutic strategy, the preclinical rationale as well as advantages and challenges from a drug development perspective are discussed. © 2017 Federation of European Biochemical Societies.

  5. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    Science.gov (United States)

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  6. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    Science.gov (United States)

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de. © The Author(s) 2016. Published by Oxford University Press.

  7. Cdc7 kinase - a new target for drug development.

    Science.gov (United States)

    Swords, Ronan; Mahalingam, Devalingam; O'Dwyer, Michael; Santocanale, Corrado; Kelly, Kevin; Carew, Jennifer; Giles, Francis

    2010-01-01

    The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development.

  8. Brand market positions estimation and defining the strategic targets of its development

    OpenAIRE

    S.M. Makhnusha

    2010-01-01

    In this article the author generalizes the concept of brand characteristics which influenceits profitability and market positions. An approach to brand market positions estimation anddefining the strategic targets of its development is proposed.Keywords: brand, brand expansion, brand extension, brand value, brand power, brandrelevance, brand awareness.

  9. The LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2003-01-01

    The availability of isotope grade, Highly Enriched Uranium (HEU), from the United States for use in the manufacture of targets for molybdenum-99 production in AECL's NRU research reactor has been a key factor to enable MDS Nordion to develop a reliable, secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets is a proven and established method that has reliably produced medical isotopes for several decades. The HEU process provides predictable, consistent yields for our high-volume, molybdenum-99 production. Other medical isotopes such as I-131 and Xe-133, which play an important role in nuclear medicine applications, are also produced from irradiated HEU targets as a by-product of the molybdenum-99 process. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the commissioning of two MAPLE reactors and an associated isotope processing facility (the New Processing Facility). The new MAPLE facilities, which will be dedicated exclusively to medical isotope production, will provide an essential contribution to a secure, robust global healthcare system. Design and construction of these facilities has been based on a life cycle management philosophy for the isotope production process. This includes target irradiation, isotope extraction and waste management. The MAPLE reactors will operate with Low Enriched Uranium (LEU) fuel, a significant contribution to the objectives of the RERTR program. The design of the isotope production process in the MAPLE facilities is based on an established process - extraction of isotopes from HEU target material. This is a proven technology that has been demonstrated over more than three decades of operation. However, in support of the RERTR program and in compliance with U.S. legislation, MDS Nordion has undertaken a LEU Target Development and Conversion Program for the MAPLE facilities. This paper will provide an

  10. Characterization and development of an active scintillating target for nuclear reaction studies on actinides

    Energy Technology Data Exchange (ETDEWEB)

    Belier, Gilbert, E-mail: gilbert.belier@cea.fr [CEA, DAM, DIF, DPTA, Centre du Grand Rue, 91297 Arpajon (France); Aupiais, Jean; Varignon, Cyril; Vayre, Sylvain [CEA, DAM, DIF, DPTA, Centre du Grand Rue, 91297 Arpajon (France)

    2012-02-01

    This article presents the development of a new kind of active actinide target, based on organic liquid scintillators containing the dissolved isotope. Amongst many advantages one can mention the very high detection efficiency, the Pulse Shape Discrimination capability, the fast response allowing high count rates and good time resolution and the ease of fabrication. The response of this target to fission fragments has been studied. The discrimination of alpha, fission and proton recoil events is demonstrated. The alpha decay and fission detection efficiencies are simulated and compared to measurements. Finally the use of such a target in the context of fast neutron induced reactions is discussed.

  11. Characterization and development of an active scintillating target for nuclear reaction studies on actinides

    International Nuclear Information System (INIS)

    Belier, Gilbert; Aupiais, Jean; Varignon, Cyril; Vayre, Sylvain

    2012-01-01

    This article presents the development of a new kind of active actinide target, based on organic liquid scintillators containing the dissolved isotope. Amongst many advantages one can mention the very high detection efficiency, the Pulse Shape Discrimination capability, the fast response allowing high count rates and good time resolution and the ease of fabrication. The response of this target to fission fragments has been studied. The discrimination of alpha, fission and proton recoil events is demonstrated. The alpha decay and fission detection efficiencies are simulated and compared to measurements. Finally the use of such a target in the context of fast neutron induced reactions is discussed.

  12. International Nuclear Target Development Society workshop 1983: proceedings

    International Nuclear Information System (INIS)

    Thomas, G.

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included

  13. Developing a de novo targeted knock-in method based on in utero electroporation into the mammalian brain.

    Science.gov (United States)

    Tsunekawa, Yuji; Terhune, Raymond Kunikane; Fujita, Ikumi; Shitamukai, Atsunori; Suetsugu, Taeko; Matsuzaki, Fumio

    2016-09-01

    Genome-editing technology has revolutionized the field of biology. Here, we report a novel de novo gene-targeting method mediated by in utero electroporation into the developing mammalian brain. Electroporation of donor DNA with the CRISPR/Cas9 system vectors successfully leads to knock-in of the donor sequence, such as EGFP, to the target site via the homology-directed repair mechanism. We developed a targeting vector system optimized to prevent anomalous leaky expression of the donor gene from the plasmid, which otherwise often occurs depending on the donor sequence. The knock-in efficiency of the electroporated progenitors reached up to 40% in the early stage and 20% in the late stage of the developing mouse brain. Furthermore, we inserted different fluorescent markers into the target gene in each homologous chromosome, successfully distinguishing homozygous knock-in cells by color. We also applied this de novo gene targeting to the ferret model for the study of complex mammalian brains. Our results demonstrate that this technique is widely applicable for monitoring gene expression, visualizing protein localization, lineage analysis and gene knockout, all at the single-cell level, in developmental tissues. © 2016. Published by The Company of Biologists Ltd.

  14. EBF factors drive expression of multiple classes of target genes governing neuronal development

    Directory of Open Access Journals (Sweden)

    Vetter Monica L

    2011-04-01

    Full Text Available Abstract Background Early B cell factor (EBF family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. Results We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. Conclusions The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  15. Developments in numerical simulation of IFE target and chamber physics

    International Nuclear Information System (INIS)

    Velarde, G.; Minguez, E.; Alonso, E.; Gil, J.M.; Malerba, L.; Marian, J.; Martel, P.; Martinez-Val, J.M.; Munoz, R.; Ogando, F.; Perlado, J.M.; Piera, M.; Reyes, S.; Rubiano, J.G.; Sanz, J.; Sauvan, P.; Velarde, M.; Velarde, P.

    2000-01-01

    The work presented outlines the global frame given at the Institute of Nuclear Fusion (DENIM) for having an integral perspective of the different research areas with the development of Inertial Fusion for energy generation. The coupling of a new radiation transport (RT) solver with an existing multi-material fluid dynamics code using Adaptive Mesh Refinement (ARM) is presented in Section 2, including improvements and additional information about the solver precision. In Section 3, new developments in the atomic physics codes under target conditions, to determine populations, opacity data and emissivities have been performed. Exotic and innovative ideas about Inertial Fusion Energy (IFE), as catalytic fuels and Z-pinches have been explored, and they are explained in Section 4. Numerical simulations demonstrate important reductions in the tritium inventory. Section 5 is devoted to safety and environment of the IFE. Uncertainties analysis in activation calculations have been included in the ACAB activation code, and also calculations on pulse activation in IFE reactors and on the activation of target debris in NIF are presented. A comparison of the accidental releases of tritium from some IFE reactors computed using MACCS2 code is explained. Finally, Section 6 contains the research on the basic mechanisms of neutron damage in SiC (low-activation material) and FeCu alloy using the DENIM/LLNL molecular dynamics code MDCASK. (authors)

  16. Intra?Target Microdosing ? A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

    OpenAIRE

    Burt, T; MacLeod, D; Lee, K; Santoro, A; DeMasi, DK; Hawk, T; Feinglos, M; Rowland, M; Noveck, RJ

    2017-01-01

    Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers receive...

  17. Putting together the psoriasis puzzle: an update on developing targeted therapies

    Directory of Open Access Journals (Sweden)

    Leanne M. Johnson-Huang

    2012-07-01

    Full Text Available Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23–Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.

  18. Development of epidermal growth factor receptor targeted therapy in pancreatic cancer.

    Science.gov (United States)

    Qing, Liu; Qing, Wang

    2018-02-01

    The epidermal growth factor receptor (EGFR) family are a series of important cancer therapeutic targets involved in cancer biology. These genes play an important role in tumor biological characteristics including angiogenesis, cell survival, invasion and glucose metabolism. In recent years, progresses have been achieved upon the cellular and molecular biological characteristics of EGFR and its role in cancer development based on the study of tumor specimens and experimental animal model. EGFR(HER1/ErbB) is overexpressed in over sixty percent of triple-negative breast cancers and occurs in pancreatic, bladder, lung and head-and-neck cancers. Up to now, EGFR inhibitors have been applied in various of cancer, such as lung, breast, bladder and head and neck cancers etc., in which the combination of EGFR inhibitors plus chemotherapeutic agents is now seen as the standard of care for advanced/metastatic pancreatic cancer. For these reasons, EGFR inhibitors and their therapeutic effect for pancreatic cancer is becoming the focus in Laboratory and clinical research. In this paper, research progress of the development of epidermal growth factor receptor targeted therapy in pancreatic cancer is introduced.

  19. International Nuclear Target Development Society workshop 1983: proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G. (ed.)

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included. (WHK)

  20. Correction of the calculation of beam loading based in the RF power diffusion equation

    International Nuclear Information System (INIS)

    Silva, R. da.

    1980-01-01

    It is described an empirical correction based upon experimental datas of others authors in ORELA, GELINA and SLAC accelerators, to the calculation of the energy loss due to the beam loading effect as stated by the RF power diffusion equation theory an accelerating structure. It is obtained a dependence of this correction with the electron pulse full width half maximum, but independent of the electron energy. (author) [pt

  1. DISC1 pathway in brain development: exploring therapeutic targets for major psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Atsushi eKamiya

    2012-03-01

    Full Text Available Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward in our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of Disrupted in schizophrenia 1 (DISC1, a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.

  2. Development of residual thermal stress-relieving structure of CFC monoblock target for JT-60SA divertor

    Energy Technology Data Exchange (ETDEWEB)

    Tsuru, Daigo, E-mail: tsuru.daigo@jaea.go.jp; Sakurai, Shinji; Nakamura, Shigetoshi; Ozaki, Hidetsugu; Seki, Yohji; Yokoyama, Kenji; Suzuki, Satoshi

    2015-10-15

    Highlights: • We carried out numerical simulations on residual thermal stress of targets for the JT-60SA divertor. • We developed three measures to reduce residual thermal stress. • We proposed two structures of CFC monoblock target for the JT-60SA divertor. • We confirmed the effectiveness of the structure by infrared thermography inspection and high heat flux test. - Abstract: Carbon fibre-reinforced carbon composite (CFC) monoblock target for JT-60SA divertor is under development towards the mass-production. CFC monoblocks, WCu interlayers and a CuCrZr cooling tube at the centre of the monoblocks were bonded by vacuum brazing in a high temperature, to a target. If residual thermal stress due to difference of thermal expansions between CFC and CuCrZr exceeds the maximum allowable stress of the CFC after the bonding, cracks are generated in the CFC monoblock and heat removal capacity of the target degrades. In this paper, new structures of the targets were proposed, to reduce residual thermal stress and to mitigate the degradation of heat removal capacity of the targets. Some measures, including slitting of the CFC monoblock aside of the cooling tube, replacement of the interlayer material and shifting the position of the cooling tube, were implemented. The effectiveness of the measures was evaluated by numerical simulations. Target mock-ups with the proposed structures were manufactured. Infrared thermography inspection and high heat flux test were carried out on the mock-ups in order to evaluate the heat removal capacity.

  3. Nuclear measurements and reference materials annual progress report, january - december 1988

    International Nuclear Information System (INIS)

    1989-01-01

    The 1988 progress report of the Central Bureau for Nuclear Measurements (CBNM) is presented. The major changes in the role and orientation of the Joint Research Center, of which CBNM is an institute, are included. The main tasks of CBNM, which involve the program on Nuclear Measurements and Reference Materials, are given. Technical activities concerning the GELINA electron beam and Van de Graaff accelerators are reported. The study of transition radiation at linear electron accelerators, and the development of isotope dilution mass spectrometry, for trace analysis and isotope abundance measurements in iron and gallium, are summarized. The scientific and technical support to the commission, work for third parties, and contribution to conferences are presented

  4. The use of application-specific performance targets and engineering considerations to guide hydrogen storage materials development

    Energy Technology Data Exchange (ETDEWEB)

    Stetson, Ned T., E-mail: ned.stetson@ee.doe.gov [U.S. Department of Energy, 1000 Independence Ave., SW, EE-2H, Washington, DC 20585 (United States); Ordaz, Grace; Adams, Jesse; Randolph, Katie [U.S. Department of Energy, 1000 Independence Ave., SW, EE-2H, Washington, DC 20585 (United States); McWhorter, Scott [Savannah River National Laboratory, Aiken, SC 29808 (United States)

    2013-12-15

    Highlights: •Portable power and material handling equipment as early market technology pathways. •Engineering based system-level storage-materials requirements. •Application based targets. -- Abstract: The Hydrogen and Fuel Cells Technologies Office, carried out through the DOE Office of Energy Efficiency and Renewable Energy, maintains a broad portfolio of activities to enable the commercialization of fuel cells across a range of near, mid and long-term applications. Improved, advanced hydrogen storage technologies are seen as a critical need for successful implementation of hydrogen fuel cells in many of these applications. To guide and focus materials development efforts, the DOE develops system performance targets for the specific applications of interest, and carries out system engineering analyses to determine the system-level performance delivered when the materials are incorporated into a complete system. To meet the needs of applications, it is important to consider the system-level performance, not just the material-level properties. An overview of the DOE’s hydrogen storage efforts in developing application-specific performance targets and systems engineering to guide hydrogen storage materials identification and development is herein provided.

  5. The use of application-specific performance targets and engineering considerations to guide hydrogen storage materials development

    International Nuclear Information System (INIS)

    Stetson, Ned T.; Ordaz, Grace; Adams, Jesse; Randolph, Katie; McWhorter, Scott

    2013-01-01

    Highlights: •Portable power and material handling equipment as early market technology pathways. •Engineering based system-level storage-materials requirements. •Application based targets. -- Abstract: The Hydrogen and Fuel Cells Technologies Office, carried out through the DOE Office of Energy Efficiency and Renewable Energy, maintains a broad portfolio of activities to enable the commercialization of fuel cells across a range of near, mid and long-term applications. Improved, advanced hydrogen storage technologies are seen as a critical need for successful implementation of hydrogen fuel cells in many of these applications. To guide and focus materials development efforts, the DOE develops system performance targets for the specific applications of interest, and carries out system engineering analyses to determine the system-level performance delivered when the materials are incorporated into a complete system. To meet the needs of applications, it is important to consider the system-level performance, not just the material-level properties. An overview of the DOE’s hydrogen storage efforts in developing application-specific performance targets and systems engineering to guide hydrogen storage materials identification and development is herein provided

  6. Recent Developments in the VISRAD 3-D Target Design and Radiation Simulation Code

    Science.gov (United States)

    Macfarlane, Joseph; Golovkin, Igor; Sebald, James

    2017-10-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, Z, and LMJ. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. VISRAD includes a variety of user-friendly graphics for setting up targets and displaying results, can readily display views from any point in space, and can be used to generate image sequences for animations. We will discuss recent improvements to conveniently assess beam capture on target and beam clearance of diagnostic components, as well as plans for future developments.

  7. Modern condition and possibilities of development of a moral component in a target orientation of the teenager

    Directory of Open Access Journals (Sweden)

    Shylova Nina Ihorivna

    2016-10-01

    Full Text Available The article considers the basic criteria of a moral component in a target orientation of the teenager, whose level of development being defined through the testing of pupils in Mykolaiv city. The article present the results given by the usage of two techniques, defines the ways and prospects of the further development of a moral component in a target orientation of teenagers.

  8. Cytomegalovirus protease targeted prodrug development.

    Science.gov (United States)

    Sabit, Hairat; Dahan, Arik; Sun, Jing; Provoda, Chester J; Lee, Kyung-Dall; Hilfinger, John H; Amidon, Gordon L

    2013-04-01

    Human cytomegalovirus (HCMV) is a prevalent virus that infects up to 90% of the population. The goal of this research is to determine if small molecular prodrug substrates can be developed for a specific HCMV encoded protease and thus achieve site-specific activation. HCMV encodes a 256 amino acid serine protease that is responsible for capsid assembly, an essential process for herpes virus production. The esterase activity of the more stable HCMV A143T/A144T protease mutant was evaluated with model p-nitrophenol (ONp) esters, Boc-Xaa-ONp (Ala, Leu, Ile, Val, Gln, Phe at the Xaa position). We demonstrate that the A143T/A144T mutant has esterase activity toward specific small ester compounds, e.g., Boc-L-Ala-ONp. Mono amino acid and dipeptide prodrugs of ganciclovir (GCV) were also synthesized and evaluated for hydrolysis by the A143T/A144T protease mutant in solution. Hydrolysis of these prodrugs was also evaluated in Caco-2 cell homogenates, human liver microsomes (HLMs), and rat and human plasma. For the selectivity potential of the prodrugs, the hydrolysis ratio was evaluated as a percentage of prodrug hydrolyzed by the HCMV protease over the percentages of prodrug hydrolyses by Caco-2 cell homogenates, HLMs, and human/rat plasma. A dipeptide prodrug of ganciclovir, Ac-l-Gln-l-Ala-GCV, emerged as a potential selective prodrug candidate. The results of this research demonstrate that targeting prodrugs for activation by a specific protease encoded by the infectious HCMV pathogen may be achievable.

  9. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development

    OpenAIRE

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-01-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and express...

  10. Integrating Biodiversity and Ecosystem Services in the Post-2015 Development Agenda: Goal Structure, Target Areas and Means of Implementation

    Directory of Open Access Journals (Sweden)

    Paul L. Lucas

    2013-12-01

    Full Text Available The United Nations’ discussions on defining a new set of post-2015 development goals focus on poverty eradication and sustainable development. Biodiversity and ecosystem services are essential for poverty eradication, which is also one of the foundations of the Strategic Plan for Biodiversity of the Convention on Biological Diversity (CBD. Based on an assessment of current proposals of goals and targets, and a quantitative pathway analysis to meet long term biodiversity and food security goals, this paper discusses how biodiversity and ecosystem services can be integrated into a broad set of goals and targets, and concludes with relevant target areas and means of implementation for which specific targets need to be defined. Furthermore, it responds to the call of the CBD to consider the Strategic Plan for Biodiversity and the related Aichi biodiversity targets in the post-2015 development agenda. The paper’s analysis identifies three overlapping but also supplemental ways to integrate biodiversity and ecosystem services in the post-2015 agenda: integrated goals, goals addressing earth system functioning and goals addressing environmental limits. It further concludes seven target areas to be included under the goals to address biodiversity and ecosystem services in the context of food and agriculture: access to food, demand for agricultural products, sustainable intensification, ecosystem fragmentation, protected areas, essential ecosystem services and genetic diversity. The Strategic Plan for Biodiversity provides a good basis for integrating biodiversity and ecosystem services in the post-2015 development agenda. Many Aichi targets address the proposed target areas and the means of implementation discussed, while they need to be complemented with targets that specifically address human well-being, as well as institutions and governance.

  11. Development and evaluation of camptothecin loaded polymer stabilized nanoemulsion: Targeting potential in 4T1-breast tumour xenograft model.

    Science.gov (United States)

    Sugumaran, Abimanyu; Ponnusamy, Chandrasekar; Kandasamy, Palanivel; Krishnaswami, Venkateshwaran; Palanichamy, Rajaguru; Kandasamy, Ruckmani; Lakshmanan, Manikandan; Natesan, Subramanian

    2018-04-30

    Targeted delivery of anticancer agents is poised to improve cancer therapy, for which polymers can serve as targeting ligands or nanocarriers for chemotherapeutic agents. In this study, we have developed and evaluated the efficacy of a camptothecin (CPT)-loaded polymer stabilized nanoemulsion (PSNE) for the passive targeted delivery to breast cancer. Based on the pseudo-ternary phase diagrams, PSNEs were developed using capmul MCM:poloxamer 407 (4:1), solutol HS 15:simulsol P23 (1:2) and water. CPT polymer mixture was developed by solvent evaporation technique. The PSNEs were characterized for droplet size distribution, plasma protein adsorption, drug release, in-vivo targeting potential, hemolytic potential, cytotoxicity, genotoxicity, in-vivo biodistribution and CPT lactone ring stability. The developed PSNEs showed uniform droplet distribution, extended drug release (76.59±6.12% at 24h), acceptable hemolytic potential, significant cytotoxicity (IC 50 =176±4.3ng/mL) and genotoxicity against MCF-7 cancer cells but low DNA damage potential in human peripheral blood lymphocytes. The efficiency of PSNEs for the targeted delivery of CPT into the tumour regions was documented in 4T1-breast tumour xenografted BALB/c mice. In-vivo biodistribution study shows that 7105.84±568.46ng/g of CPT was passively targeted from PSNE to breast cancer tissue. About 80% of the lactone form was stable for 24h. Taken together, our study provides a promising strategy for developing PSNE-targeted drug delivery system for the breast cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development.

    Science.gov (United States)

    Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie; Barozzi, Iros; Osterwalder, Marco; Akiyama, Jennifer A; Lincoln, Joy; Lopez-Rios, Javier; Visel, Axel; Zuniga, Aimée; Zeller, Rolf

    2017-05-23

    The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. Target post-evaluation of China's “12th Five-Year” oil and gas exploration and development planning and its “13th Five-Year” target prediction

    Directory of Open Access Journals (Sweden)

    Jiping Pan

    2016-03-01

    Full Text Available In the turn of 12th and 13th “Five-Year Plan” of China, the global oil and gas market changes greatly. In this regard, the target post-evaluation of the “12th Five-Year” oil and gas exploration and development planning was conducted, which is of significant importance to scientifically and reasonably making the specific “13th Five-Year” oil and gas exploration and development target planning. The post-evaluation results indicate that, in the period of “12th Five-Year Plan”, the oil and gas exploration and development targets of China were satisfactorily completed, but some deficiencies still existed. For example, the target of oil production (2 × 108 t was overfulfilled, while the target of oil reserves (65 × 108 t remained 6.4% outstanding. The target of gas reserves (3.5 × 1012 m3 was overfulfilled, while the target of gas production (1385 × 108 m3 remained 6.2% outstanding. Moreover, the targets of unconventional gases were not satisfactorily completed-shale gas being better than coalbed methane (CBM. Failures to fulfill some targets in “12th Five-Year Plan” were primarily attributed to the slowdown of oil and gas consumption growth, sharp drop of oil price, downgrading of resources, and changes of statistic basis under the new normal. The forecast results suggest that, in the period of “13th Five-Year Plan”, given USD50–70/bbl of world oil price, China's annual average incremental conventional oil and gas in place will be 10.0 × 108–12.0 × 108 t and 6000 × 108–8000 × 108 m3 respectively, annual average incremental shale gas and CBM in place will be 1000 × 108–2000 × 108 m3 and 500 × 108–1000 × 108 m3 respectively, and annual oil production will be about 2.0 × 108 t. By 2020, China's annual gas production will approach 1800 × 108–2000 × 108 m3 (shale gas: 200 × 108 m3, and CBM: 150 × 108 m3.

  14. A conversion development program to LEU targets for medical isotope production in the MAPLE Facilities

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2000-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada has been extracted from reactor targets employing highly enriched uranium (HEU). The molybdenum extraction process from the HEU targets provided predictable, consistent yields for our high-volume molybdenum production process. A reliable supply of HEU for the NRU research reactor targets has enabled MDS Nordion to develop a secure chain of medical isotope supply for the international nuclear medicine community. Each link of the isotope supply chain, from isotope production to patient application, has been established on a proven method of HEU target irradiation and processing. To ensure a continued reliable and timely supply of medical isotopes, the design of the MAPLE facilities was based on our established process - extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a program to convert the MAPLE facilities to LEU targets. An initial feasibility study was initiated to identify the technical issues to convert the MAPLE targets from HEU to LEU. This paper will present the results of the feasibility study. It will also describe future challenges and opportunities in converting the MAPLE facilities to LEU targets for large scale, commercial medical isotope production. (author)

  15. Development of a cluster-jet target for PANDA

    International Nuclear Information System (INIS)

    Gruber, A.; Marton, J.; Widmann, E.; Zmeskal, J.; Orth, H.; Luehning, J.

    2008-01-01

    Full text: The Stefan Meyer Institut (SMI) is part of the international PANDA collaboration. The universal detector will be constructed at the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). PANDA will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. The physics program of PANDA will encompass charmonium spectroscopy below and above open charm threshold, search for exotics (glueballs, hybrids), lambda and double-lambda hypernuclei studies and the investigation of in-medium modifications of charmed mesons - an experimentally unexplored field. SMI contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the vacuum system of the antiproton - target interaction zone. In order to reach the desired target density, an optimization of the cold head, the nozzle and the skimmer arrangement is essential. A density-profile monitor for the cluster-jet was designed and built at SMI. Several nozzle types will be studied using different gases, temperatures and inlet pressures. Additionally we, together with the cluster-jet target group at GSI, are carrying out R and D for improving the jet-density. The Genova/Fermilab cluster-jet target used for these measurements has been in use at Fermilab for the experiments E760 and E835 and has been transferred to GSI for this purpose. The setup of the density-profile monitor at SMI and several measurements at GSI will be presented. (author)

  16. Research and development on materials for the SPES target

    Directory of Open Access Journals (Sweden)

    Corradetti Stefano

    2014-03-01

    Full Text Available 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.

  17. Development of windowless liquid lithium targets for fragmentation and fission of 400-kW uranium beams

    CERN Document Server

    Nolen, J A; Hassanein, A; Novick, V J; Plotkin, P; Specht, J R

    2003-01-01

    The driver linac of the proposed rare isotope accelerator facility is designed to deliver 2x10 sup 1 sup 3 uranium ions per second at 400 MeV/u on target for radionuclide production via the fission and fragmentation mechanisms. The ion optics of the large acceptance, high-resolution fragment separators that follow the production target require primary beam spot widths of 1 mm. To cope with the resulting high power densities, windowless liquid lithium targets are being developed. The present designs build on existing experience with liquid lithium and liquid sodium systems that have been used for fusion and fission applications. However, no completely windowless systems have been developed or tested to date. For the beam power indicated above (400 kW), the flow requirements are up to about 20 m/s and 10 l/s linear and volume flow rates, respectively. The required target thickness is 1-1.5 g/cm sup 2 (2-3 cm lithium thickness). At this time a prototype windowless system with a lithium thickness of 1-2 cm is und...

  18. Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system

    International Nuclear Information System (INIS)

    Cao Quanliang; Han Xiaotao; Li Liang

    2011-01-01

    Deep magnetic capture and clinical application are the current trends for magnetic targeted drug delivery system. More promising and possible strategies are needed to overcome the current limitations and further improve the magnetic targeting technique. Recent advances in the development of targeting magnet system show promise in progressing this technology from the laboratory to the clinic. Starting from well-known basic concepts, current limitations of magnetic targeted drug delivery system are analyzed. Meanwhile, the design concepts and evaluations of some effective improvements in magnet system are discussed and reviewed with reference to (i) reasonable design of magnet system; (ii) control modes of magnet system used to generate dynamical magnetic fields; and (iii) magnetic field driving types. - Research Highlights: → The current limitations of MTDDS for deep capture and clinical application are analyzed. → The development of magnet system shows promise in progressing MTDDS to clinical application. → The design concepts and evaluations of improvements in magnet system are reviewed and discussed. → The key to improve magnet system lies in controllable magnets and different excitations.

  19. Disruption of Aedes aegypti olfactory system development through chitosan/siRNA nanoparticle targeting of semaphorin-1a.

    Directory of Open Access Journals (Sweden)

    Keshava Mysore

    Full Text Available Despite the devastating impact of mosquito-borne illnesses on human health, surprisingly little is known about mosquito developmental biology, including development of the olfactory system, a tissue of vector importance. Analysis of mosquito olfactory developmental genetics has been hindered by a lack of means to target specific genes during the development of this sensory system. In this investigation, chitosan/siRNA nanoparticles were used to target semaphorin-1a (sema1a during olfactory system development in the dengue and yellow fever vector mosquito Aedes aegypti. Immunohistochemical analyses and anterograde tracing of antennal sensory neurons, which were used to track the progression of olfactory development in this species, revealed antennal lobe defects in sema1a knockdown fourth instar larvae. These findings, which correlated with a larval odorant tracking behavioral phenotype, identified previously unreported roles for Sema1a in the developing insect larval olfactory system. Analysis of sema1a knockdown pupae also revealed a number of olfactory phenotypes, including olfactory receptor neuron targeting and projection neuron defects coincident with a collapse in the structure and shape of the antennal lobe and individual glomeruli. This study, which is to our knowledge the first functional genetic analysis of insect olfactory development outside of D. melanogaster, identified critical roles for Sema1a during Ae. aegypti larval and pupal olfactory development and advocates the use of chitosan/siRNA nanoparticles as an effective means of targeting genes during post-embryonic Ae. aegypti development. Use of siRNA nanoparticle methodology to understand sensory developmental genetics in mosquitoes will provide insight into the evolutionary conservation and divergence of key developmental genes which could be exploited in the development of both common and species-specific means for intervention.

  20. Retrotransposon-centered analysis of piRNA targeting shows a shift from active to passive retrotransposon transcription in developing mouse testes

    Directory of Open Access Journals (Sweden)

    Mourier Tobias

    2011-09-01

    Full Text Available Abstract Background Piwi-associated RNAs (piRNAs bind transcripts from retrotransposable elements (RTE in mouse germline cells and seemingly act as guides for genomic methylation, thereby repressing the activity of RTEs. It is currently unknown if and how Piwi proteins distinguish RTE transcripts from other cellular RNAs. During germline development, the main target of piRNAs switch between different types of RTEs. Using the piRNA targeting of RTEs as an indicator of RTE activity, and considering the entire population of genomic RTE loci along with their age and location, this study aims at further elucidating the dynamics of RTE activity during mouse germline development. Results Due to the inherent sequence redundancy between RTE loci, assigning piRNA targeting to specific loci is problematic. This limits the analysis, although certain features of piRNA targeting of RTE loci are apparent. As expected, young RTEs display a much higher level of piRNA targeting than old RTEs. Further, irrespective of age, RTE loci near protein-coding coding genes are targeted to a greater extent than RTE loci far from genes. During development, a shift in piRNA targeting is observed, with a clear increase in the relative piRNA targeting of RTEs residing within boundaries of protein-coding gene transcripts. Conclusions Reanalyzing published piRNA sequences and taking into account the features of individual RTE loci provide novel insight into the activity of RTEs during development. The obtained results are consistent with some degree of proportionality between what transcripts become substrates for Piwi protein complexes and the level by which the transcripts are present in the cell. A transition from active transcription of RTEs to passive co-transcription of RTE sequences residing within protein-coding transcripts appears to take place in postnatal development. Hence, the previously reported increase in piRNA targeting of SINEs in postnatal testis development

  1. Development of Industrial-Scale Fission 99Mo Production Process Using Low Enriched Uranium Target

    Directory of Open Access Journals (Sweden)

    Seung-Kon Lee

    2016-06-01

    Full Text Available Molybdenum-99 (99Mo is the most important isotope because its daughter isotope, technetium-99m (99mTc, has been the most widely used medical radioisotope for more than 50 years, accounting for > 80% of total nuclear diagnostics worldwide. In this review, radiochemical routes for the production of 99Mo, and the aspects for selecting a suitable process strategy are discussed from the historical viewpoint of 99Mo technology developments. Most of the industrial-scale 99Mo processes have been based on the fission of 235U. Recently, important issues have been raised for the conversion of fission 99Mo targets from highly enriched uranium to low enriched uranium (LEU. The development of new LEU targets with higher density was requested to compensate for the loss of 99Mo yield, caused by a significant reduction of 235U enrichment, from the conversion. As the dramatic increment of intermediate level liquid waste is also expected from the conversion, an effective strategy to reduce the waste generation from the fission 99Mo production is required. The mitigation of radioxenon emission from medical radioisotope production facilities is discussed in relation with the monitoring of nuclear explosions and comprehensive nuclear test ban. Lastly, the 99Mo production process paired with the Korea Atomic Energy Research Institute's own LEU target is proposed as one of the most suitable processes for the LEU target.

  2. Target support for inertial confinement fusion

    International Nuclear Information System (INIS)

    Schultz, K.R.

    1995-08-01

    General Atomics (GA) plays an important industrial support role for the US Inertial Confinement Fusion (ICF) program in the area of target technology. This includes three major activities: target fabrication support, target handling systems development, and target chamber design. The work includes target fabrication for existing ICF experiments, target and target system development for future experiments, and target research and target chamber design for experiments on future machines, such as the National Ignition Facility (NIF)

  3. Identification and profiling of microRNAs and their target genes from developing caprine skeletal Muscle.

    Directory of Open Access Journals (Sweden)

    Yanhong Wang

    Full Text Available Goat is an important agricultural animal for meat production. Functional studies have demonstrated that microRNAs (miRNAs regulate gene expression at the post-transcriptional level and play an important role in various biological processes. Although studies on miRNAs expression profiles have been performed in various animals, relatively limited information about goat muscle miRNAs has been reported. To investigate the miRNAs involved in regulating different periods of skeletal muscle development, we herein performed a comprehensive research for expression profiles of caprine miRNAs during two developmental stages of skeletal muscles: fetal stage and six month-old stage. As a result, 15,627,457 and 15,593,721 clean reads were obtained from the fetal goat library (FC and the six month old goat library (SMC, respectively. 464 known miRNAs and 83 novel miRNA candidates were identified. Furthermore, by comparing the miRNA profile, 336 differentially expressed miRNAs were identified and then the potential targets of the differentially expressed miRNAs were predicted. To understand the regulatory network of miRNAs during muscle development, the mRNA expression profiles for the two development stages were characterized and 7322 differentially expressed genes (DEGs were identified. Then the potential targets of miRNAs were compared to the DEGs, the intersection of the two gene sets were screened out and called differentially expressed targets (DE-targets, which were involved in 231 pathways. Ten of the 231 pathways that have smallest P-value were shown as network figures. Based on the analysis of pathways and networks, we found that miR-424-5p and miR-29a might have important regulatory effect on muscle development, which needed to be further studied. This study provided the first global view of the miRNAs in caprine muscle tissues. Our results help elucidation of complex regulatory networks between miRNAs and mRNAs and for the study of muscle

  4. Development of lithium target for accelerator based neutron capture therapy

    International Nuclear Information System (INIS)

    Taskaev, Sergey; Bayanov, Boris; Belov, Victor; Zhoorov, Eugene

    2006-01-01

    Pilot innovative accelerator based neutron source for neutron capture therapy of cancer is now of the threshold of its operation at the BINP, Russia. One of the main elements of the facility is lithium target producing neutrons via threshold 7 Li(p,n) 7 Be reaction at 25 kW proton beam with energies 1.915 MeV or 2.5 MeV. The main problems of lithium target were determined to be: 7 Be radioactive isotope activation keeping lithium layer solid, presence of photons due to proton inelastic scattering on lithium nuclei, and radiation blistering. The results of thermal test of target prototype were presented as previous NCT Congress. It becomes clear that water is preferable for cooling the target, and that lithium target 10 cm in diameter is able to run before melting. In the present report, the conception of optimal target is proposed: thin metal disk 10 cm in diameter easy for detaching, with evaporated thin layer of pure lithium from the side of proton beam exposure, its back being intensively cooled with turbulent water flow to maintain lithium layer solid. Design of the target for the neutron source constructed at BINP is shown. The results of investigation of radiation blistering and lithium layer are presented. Target unit of facility is under construction now, and obtaining neutrons is expected in nearest future. (author)

  5. Development of a PVD-based manufacturing process of monolithic LEU irradiation targets for {sup 99}Mo production

    Energy Technology Data Exchange (ETDEWEB)

    Hollmer, Tobias

    2015-08-03

    {sup 99}Mo is the most important radioisotope in nuclear medicine. It is produced by fission of uranium in irradiation targets. The usage of cylindrical monolithic targets can ensure a safe supply of {sup 99}Mo and at the same reduce the amount of highly radioactive waste generated during production. To manufacture these targets, a novel PVD-based technique was developed. Both the feasibility and the high efficiency of this process were demonstrated in a prototype apparatus.

  6. THE PROGRAM-TARGET PLANNING AND MANAGEMENT OF DEVELOPMENT OF MEASURING EQUIPMENT PARK

    Directory of Open Access Journals (Sweden)

    Marichev Pavel Aleksandrovich

    2018-02-01

    Full Text Available Subject: study of the Park of Measuring Equipment (PME that includes hundreds of thousands of standard samples, measuring instruments, control and measuring devices and other measuring mechanisms with different areas of application, levels of reliability, service life, levels of technical perfection and levels of technical condition. Research objectives: 1. Development of a complex of mathematical models to simulate the processes of development of PME, control indicators of PME performance as a whole, purposefully control the stages of life cycle of measuring equipment samples. 2. Development of the method which, with a sufficient degree of validity and objectivity, would solve the tasks of management of procurement and repairs both in preparation of proposals for preliminary long-term plan documents (LTPD and to ensure control over the implementation of adopted plans. Thus, the method being developed should be fairly simple to use, easily adjustable for solving problems of different dimensions, suitable for solving the optimal control problem for PME as a whole, for a part of PME, and also suitable for solving a generalized problem for certain “aggregated objects” such as the Metrology Centers. Materials and methods: the methods of mathematical simulation, methods of comparative analysis, simplex method for solving linear programming problem, methods of program-target planning were used. Results: an approach to the solution of problems of program-target planning based on solving a series of linear programming problems has been developed. The results have been presented of using the approach both for formulation of proposals into the preliminary LTPD and also for introducing revisions (amendments to annual plans, which are implemented in the framework of the state defense order. Conclusions: the described method and algorithms constitute an effective tool for solving practical problems of target-oriented management of PME performance

  7. Development of highly heat-resistant target elements for fusion reactors; Entwicklung hochwaermebestaendiger Targetelemente fuer Fusionsreaktoren

    Energy Technology Data Exchange (ETDEWEB)

    Boscary, Jean; Stadler, R.; Greuner, H.; Smirnow, M.; Drescher, N.; Boeswirth, B.; Tretter, J.; Mendelevitch, B.

    2016-06-15

    The following topics are dealt with: Scientific and technical results for divertor components (''target elements'') of the Wendelstein 7-X facility, development of nondestructive test procedures at the cooling structures, development of an automatized procedure for the visual inspection, the ''scraper''-element. (HSI)

  8. Development of a liquid tin microjet target for an efficient laser-produced plasma extreme ultraviolet source

    Science.gov (United States)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-03-01

    A regenerative tin liquid microjet target was developed for a high average power extreme ultraviolet (EUV) source. The diameter of the target was smaller than 160 μm and good vacuum lower than 0.5 Pa was maintained during the operation. A maximum EUV conversion efficiency of 1.8% at the Nd:yttrium-aluminum-garnet laser intensity of around 2×1011 W/cm2 with a spot diameter of 175 μm (full width at half maximum) was observed. The angular distribution of the EUV emission remained almost isotropic, whereas suprathermal ions mainly emerged toward the target normal.

  9. Development of a liquid tin microjet target for an efficient laser-produced plasma extreme ultraviolet source

    International Nuclear Information System (INIS)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-01-01

    A regenerative tin liquid microjet target was developed for a high average power extreme ultraviolet (EUV) source. The diameter of the target was smaller than 160 μm and good vacuum lower than 0.5 Pa was maintained during the operation. A maximum EUV conversion efficiency of 1.8% at the Nd:yttrium-aluminum-garnet laser intensity of around 2x10 11 W/cm 2 with a spot diameter of 175 μm (full width at half maximum) was observed. The angular distribution of the EUV emission remained almost isotropic, whereas suprathermal ions mainly emerged toward the target normal

  10. Development of a liquid tin microjet target for an efficient laser-produced plasma extreme ultraviolet source.

    Science.gov (United States)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-03-01

    A regenerative tin liquid microjet target was developed for a high average power extreme ultraviolet (EUV) source. The diameter of the target was smaller than 160 microm and good vacuum lower than 0.5 Pa was maintained during the operation. A maximum EUV conversion efficiency of 1.8% at the Nd:yttrium-aluminum-garnet laser intensity of around 2 x 10(11) Wcm(2) with a spot diameter of 175 microm (full width at half maximum) was observed. The angular distribution of the EUV emission remained almost isotropic, whereas suprathermal ions mainly emerged toward the target normal.

  11. Development and Targeting Efficiency of Irinotecan Engineered ...

    African Journals Online (AJOL)

    Erah

    Conclusion: Proniosomes offer a suitable alternative colloidal carrier approach to achieving drug ... for the treatment of localized disease in the body ... analogue of the natural alkaloid, campto- ..... vasculature targeted tumor necrosis factor-α.

  12. More than Just Openness: Developing and Validating a Measure of Targeted Parent-Child Communication about Alcohol

    OpenAIRE

    Miller-Day, Michelle; Kam, Jennifer A.

    2010-01-01

    Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication—targeted parent-child communication about alcohol—and comparing the efficacy of targeted parent-child communication...

  13. Development of an thin, internal superconducting polarisation magnet for the polarised target

    Energy Technology Data Exchange (ETDEWEB)

    Altfelde, Timo; Bornstein, Marcel; Dutz, Hartmut; Goertz, Stefan; Miebach, Roland; Reeve, Scott; Runkel, Stefan; Sommer, Marco; Streit, Benjamin [Physikalisches Institut, Bonn (Germany)

    2015-07-01

    In order to improve the figure of merit of double-polarisation experiments at CB-ELSA in Bonn, the Polarised Target is working on a new dilution refrigerator. For maximum polarisation of nucleons low temperatures and a high homogeneous magnetic field within the target area is needed. A thin, superconducting magnet is in development, which will create a continuous longitudinal magnetic field of 2.5 T and which will be used within the new refrigerator. The solenoidal geometry of this magnet uses two additional correction coils, placed at a well defined calculated position, for reaching the homogeneity criteria of 10{sup -4} needed for the dynamic nuclear polarisation process. Practically, the superconducting wires as well as the correction coils have to be placed with maximum precision: Small fluctuations of the distance between the current loops can diminish the requested homogeneity.

  14. Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis.

    Science.gov (United States)

    Reiche, Michael A; Warner, Digby F; Mizrahi, Valerie

    2017-01-01

    Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR) as well as extensively drug-resistant (XDR) strains of M. tuberculosis , and the complications posed by co-infection with the human immunodeficiency virus (HIV) and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis . Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the development of drug

  15. Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

    Directory of Open Access Journals (Sweden)

    Michael A. Reiche

    2017-11-01

    Full Text Available Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB, an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR as well as extensively drug-resistant (XDR strains of M. tuberculosis, and the complications posed by co-infection with the human immunodeficiency virus (HIV and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis. Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the

  16. SU-E-J-57: First Development of Adapting to Intrafraction Relative Motion Between Prostate and Pelvic Lymph Nodes Targets

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Y; Colvill, E; O’Brien, R; Keall, P [Radiation Physics Laboratory, University of Sydney, NSW (Australia); Booth, J [Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW (Australia)

    2015-06-15

    Purpose Large intrafraction relative motion of multiple targets is common in advanced head and neck, lung, abdominal, gynaecological and urological cancer, jeopardizing the treatment outcomes. The objective of this study is to develop a real-time adaptation strategy, for the first time, to accurately correct for the relative motion of multiple targets by reshaping the treatment field using the multi-leaf collimator (MLC). Methods The principle of tracking the simultaneously treated but differentially moving tumor targets is to determine the new aperture shape that conforms to the shifted targets. Three dimensional volumes representing the individual targets are projected to the beam’s eye view. The leaf openings falling inside each 2D projection will be shifted according to the measured motion of each target to form the new aperture shape. Based on the updated beam shape, new leaf positions will be determined with optimized trade-off between the target underdose and healthy tissue overdose, and considerations of the physical constraints of the MLC. Taking a prostate cancer patient with pelvic lymph node involvement as an example, a preliminary dosimetric study was conducted to demonstrate the potential treatment improvement compared to the state-of- art adaptation technique which shifts the whole beam to track only one target. Results The world-first intrafraction adaptation system capable of reshaping the beam to correct for the relative motion of multiple targets has been developed. The dose in the static nodes and small bowel are closer to the planned distribution and the V45 of small bowel is decreased from 110cc to 75cc, corresponding to a 30% reduction by this technique compared to the state-of-art adaptation technique. Conclusion The developed adaptation system to correct for intrafraction relative motion of multiple targets will guarantee the tumour coverage and thus enable PTV margin reduction to minimize the high target dose to the adjacent organs

  17. MiR-200a is involved in rat epididymal development by targeting β-catenin mRNA

    Institute of Scientific and Technical Information of China (English)

    Xiaojiang Wu; Botao Zhao; Wei Li; Yue Chen; Ruqiang Liang; Lin Li; Youxin Jin; Kangcheng Ruan

    2012-01-01

    The expression of 350 microRNAs (miRNAs) in epididymis of rat from postnatal development to adult (from postnatal days 7-70) was profiled with home-made miRNA microarray.Among them,48 miRNAs changed significantly, in which the expression of miR-200a increased obviously with time,in a good agreement with that obtained from northern blot analysis.The real-time quantitative-polymerase chain reaction result indicated that temporal expression of rat β-catenin was exactly inversed to that of miR-200a during rat epididymal development,implying that miR-200a might also target β-catenin mRNA in rat epididymis as reported by Saydam et al.in humans.The bioinformatic analysis indicated that 3' untranslated region of rat β-catenin mRNA did contain a putative binding site for miR-200a.Meanwhile,it was found that the sequence of this binding site was different from that of human β-catenin mRNA with a deletion of two adjacent nucleotides (U and C).But the results of luciferase targeting assay in HEK 293T cells and the overexpression of miR-200a in rat NRK cells demonstrated that miR-200a did target rat β-catenin mRNA and cause the suppression of its expression.All these results show that miR-200a should be involved in rat epididymal development by targeting β-catenin mRNA of rat and suppressing its expression.

  18. NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.

    Directory of Open Access Journals (Sweden)

    Miriam Aza-Carmona

    Full Text Available SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD and Langer mesomelic dysplasia (LMD, while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1 the natriuretic peptide precursor B gene (NPPB involved in the endochondral ossification signalling and directly activated by SHOX; and 2 Aggrecan (ACAN, a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9 via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.

  19. NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.

    Science.gov (United States)

    Aza-Carmona, Miriam; Barca-Tierno, Veronica; Hisado-Oliva, Alfonso; Belinchón, Alberta; Gorbenko-del Blanco, Darya; Rodriguez, Jose Ignacio; Benito-Sanz, Sara; Campos-Barros, Angel; Heath, Karen E

    2014-01-01

    SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1) the natriuretic peptide precursor B gene (NPPB) involved in the endochondral ossification signalling and directly activated by SHOX; and 2) Aggrecan (ACAN), a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9) via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.

  20. Target tissue influences on cholinergic development of parasympathetic motor neurons

    International Nuclear Information System (INIS)

    Tuttle, J.B.; Pilar, G.

    1986-01-01

    The normal function of neurons in the nervous system depends upon the orderly formation and maintenance of appropriate connections with other neurons and with non-neural target tissues. Having formed an appropriate synapse, the authors attempt to find how the interaction influences the subsequent program of neuronal differentiation and survival. The studies were made on neurons from the avian ciliary ganglion and their terminals in the iris. Concomitantly in time with the shift from an embryonic, fatiguable junction to the mature, more secure transmission, there is a large change in the capacity for ACh synthesis measured using radiolableled substrate. Only at this point in development does one detect and increase in the amount of tritium-ACh synthesized from tritium-choline in response to a pre-conditioning depolarization. The studies of development in vivo have provided a description of the steps taking place during maturation of a neuromuscular junction

  1. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

    Science.gov (United States)

    Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

    2016-01-01

    The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

  2. Targeting Parents for Childhood Weight Management: Development of a Theory-Driven and User-Centered Healthy Eating App

    Science.gov (United States)

    Lahiri, Sudakshina; Brown, Katherine Elizabeth

    2015-01-01

    Background The proliferation of health promotion apps along with mobile phones' array of features supporting health behavior change offers a new and innovative approach to childhood weight management. However, despite the critical role parents play in children’s weight related behaviors, few industry-led apps aimed at childhood weight management target parents. Furthermore, industry-led apps have been shown to lack a basis in behavior change theory and evidence. Equally important remains the issue of how to maximize users’ engagement with mobile health (mHealth) interventions where there is growing consensus that inputs from the commercial app industry and the target population should be an integral part of the development process. Objective The aim of this study is to systematically design and develop a theory and evidence-driven, user-centered healthy eating app targeting parents for childhood weight management, and clearly document this for the research and app development community. Methods The Behavior Change Wheel (BCW) framework, a theoretically-based approach for intervention development, along with a user-centered design (UCD) philosophy and collaboration with the commercial app industry, guided the development process. Current evidence, along with a series of 9 focus groups (total of 46 participants) comprised of family weight management case workers, parents with overweight and healthy weight children aged 5-11 years, and consultation with experts, provided data to inform the app development. Thematic analysis of focus groups helped to extract information related to relevant theoretical, user-centered, and technological components to underpin the design and development of the app. Results Inputs from parents and experts working in the area of childhood weight management helped to identify the main target behavior: to help parents provide appropriate food portion sizes for their children. To achieve this target behavior, the behavioral diagnosis

  3. Targeting Parents for Childhood Weight Management: Development of a Theory-Driven and User-Centered Healthy Eating App.

    Science.gov (United States)

    Curtis, Kristina Elizabeth; Lahiri, Sudakshina; Brown, Katherine Elizabeth

    2015-06-18

    The proliferation of health promotion apps along with mobile phones' array of features supporting health behavior change offers a new and innovative approach to childhood weight management. However, despite the critical role parents play in children's weight related behaviors, few industry-led apps aimed at childhood weight management target parents. Furthermore, industry-led apps have been shown to lack a basis in behavior change theory and evidence. Equally important remains the issue of how to maximize users' engagement with mobile health (mHealth) interventions where there is growing consensus that inputs from the commercial app industry and the target population should be an integral part of the development process. The aim of this study is to systematically design and develop a theory and evidence-driven, user-centered healthy eating app targeting parents for childhood weight management, and clearly document this for the research and app development community. The Behavior Change Wheel (BCW) framework, a theoretically-based approach for intervention development, along with a user-centered design (UCD) philosophy and collaboration with the commercial app industry, guided the development process. Current evidence, along with a series of 9 focus groups (total of 46 participants) comprised of family weight management case workers, parents with overweight and healthy weight children aged 5-11 years, and consultation with experts, provided data to inform the app development. Thematic analysis of focus groups helped to extract information related to relevant theoretical, user-centered, and technological components to underpin the design and development of the app. Inputs from parents and experts working in the area of childhood weight management helped to identify the main target behavior: to help parents provide appropriate food portion sizes for their children. To achieve this target behavior, the behavioral diagnosis revealed the need for eliciting change in

  4. Development of the HERA-Β-target-control system and study of target operation at the HERA storage ring

    International Nuclear Information System (INIS)

    Issever, S.

    2001-03-01

    The HERA-B experiment investigates the physics of heavy quarks, which are produced in pN reactions of the 920 GeV protons of HERA with the HERA-B internal fixed target. It consists out of eight wires, which surround the proton beam from four sides and is a high luminosity particle source. As being the closest mechanical device to the proton beam, it has to be operated very carefully and thus needs a secure and automatic control system, which additionally must be efficient and reliable to guarantee an efficient HERA-B data taking. The implementation of the target control system and its performance as well as dedicated studies of target-beam physics are presented. These include the measurement of the aperture limitation, usual target operational position, target efficiency, target independent proton loss in HERA and the scrape velocity of the target. The source of rate fluctuations is investigated in detail; among many dependencies environmental noise has a major impact on the rate fluctuations. Further studies include the analysis of beam position fluctuations and its correlation to the rate fluctuations; the rate changes about a factor of 2, if the beam is changing its position by 10 μm. This rate sensitivity is also verified directly by means of step function measurements. Furthermore the step function measurements can be used to study target-beam dynamics on time scales as short as a second. Experiments to reduce the rate sensitivity - the so called beam tail shaping measurements - are presented as well. During target operation a current, which is proportional to the interaction rate, is measured and used to determine the rate of each single wire. It is shown, that the source of this current is delta electron production. Finally the multiwire performance of the target control system is presented. (orig.)

  5. The role of sensory perception in the development and targeting of tobacco products.

    Science.gov (United States)

    Carpenter, Carrie M; Wayne, Geoffrey Ferris; Connolly, Gregory N

    2007-01-01

    To examine tobacco industry research on smoking-related sensory effects, including differences in sensory perception across smoker groups, and to determine whether this research informed targeted product development and impacted the development of commercial tobacco products. We searched previously secret internal tobacco industry documents available online through document databases housed at Tobacco Documents Online, the British American Tobacco Document Archive and the Legacy Tobacco Documents Library. We identified relevant documents using a snowball sampling method to first search the databases using an initial set of key words and to then establish further search terms. Sensory research is a priority within the tobacco industry directly impacting commercial markets both in the United States and internationally. Sensory factors contribute to smoker satisfaction and product acceptance, and play an important role in controlling puffing behavior. Cigarette manufacturers have capitalized on distinct sensory preferences across gender, age and ethnic groups by tailoring products for specific populations. Regulation of tobacco products is needed to address product changes that are used to reinforce or contribute to tobacco dependence; for instance, the incorporation of additives that target attributes such as smoothness, harshness and aftertaste. Greater understanding of the role of sensory effects on smoking behavior may also help to inform the development of tobacco treatment options that support long-term tobacco abstinence.

  6. Mechanical design and development of a high power target system for the SLC Positron Source

    International Nuclear Information System (INIS)

    Reuter, E.; Mansour, D.; Porter, T.; Sax, W.; Szumillo, A.

    1991-12-01

    In order to bring the SLC Positron Source luminosity up to design specifications, the previous (stationary) positron target had to be replaced with a version which could reliably dissipate the higher power levels and cyclic pulsed thermal stresses of the high intensity 33GeV electron beam. In addition to this basic requirement, the new target system had to meet SLAC's specifications for Ultra High Vacuum, be remotely controllable, ''radiation hard,'' and designed in such a way that it could be removed and replaced quickly and easily with minimum personnel exposure to radiation. It was also desirable to integrate the target and collection components into a compact, easily manufacturable, and easily maintainable module. This paper briefly summarize the mechanical design and development of the new modular target system, its associated controls and software, alignment, and the quick removal system. Operational experience gained with the new system over the first running cycle is also summarized

  7. Let-7a is a direct EWS-FLI-1 target implicated in Ewing's sarcoma development.

    Directory of Open Access Journals (Sweden)

    Claudio De Vito

    Full Text Available Ewing's sarcoma family tumors (ESFT are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17-92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.

  8. Development of Antibody-Based Vaccines Targeting the Tumor Vasculature.

    Science.gov (United States)

    Zhuang, Xiaodong; Bicknell, Roy

    2016-01-01

    A functional vasculature is essential for tumor progression and malignant cell metastasis. Endothelial cells lining blood vessels in the tumor are exposed to a unique microenvironment, which in turn induces expression of specific proteins designated as tumor endothelial markers (TEMs). TEMs either localized at the plasma membrane or secreted into the extracellular matrix are accessible for antibody targeting, which can be either infused or generated de novo via vaccination. Recent studies have demonstrated vaccines against several TEMs can induce a strong antibody response accompanied by a potent antitumor effect in animal models. These findings present an exciting field for novel anticancer therapy development. As most of the TEMs are self-antigens, breaking tolerance is necessary for a successful vaccine. This chapter describes approaches to efficiently induce a robust antibody response against the tumor vasculature.

  9. Identification of estrogen target genes during zebrafish embryonic development through transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Ruixin Hao

    Full Text Available Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 µM 17β-estradiol (E2 or vehicle from 3 hours to 4 days post fertilization (dpf, harvested at 1, 2, 3 and 4 dpf, and subjected to RNA extraction for transcriptome analysis using microarrays. Differentially expressed genes by E2-treatment were analyzed with hierarchical clustering followed by biological process and tissue enrichment analysis. Markedly distinct sets of genes were up and down-regulated by E2 at the four different time points. Among these genes, only the well-known estrogenic marker vtg1 was co-regulated at all time points. Despite this, the biological functional categories targeted by E2 were relatively similar throughout zebrafish development. According to knowledge-based tissue enrichment, estrogen responsive genes were clustered mainly in the liver, pancreas and brain. This was in line with the developmental dynamics of estrogen-target tissues that were visualized using transgenic zebrafish containing estrogen responsive elements driving the expression of GFP (Tg(5xERE:GFP. Finally, the identified embryonic estrogen-responsive genes were compared to already published estrogen-responsive genes identified in male adult zebrafish (Gene Expression Omnibus database. The expressions of a few genes were co-regulated by E2 in both embryonic and adult zebrafish. These could potentially be used as estrogenic biomarkers for exposure to estrogens or estrogenic endocrine disruptors in zebrafish. In conclusion, our data suggests that estrogen effects on early embryonic zebrafish development are stage- and tissue- specific.

  10. 100-B/C Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    R.W. Ovink

    2010-03-18

    This report documents the process used to identify source area target analytes in support of the 100-B/C remedial investigation/feasibility study addendum to DOE/RL-2008-46. This report also establishes the analyte exclusion criteria applicable for 100-B/C use and the analytical methods needed to analyze the target analytes.

  11. Inertial confinement fusion target component fabrication and technology development support. Annual report 10/1/98 through 9/30/99

    International Nuclear Information System (INIS)

    Gibson, Jane

    1999-01-01

    General Atomics (GA) has served as the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor for the U.S. Department of Energy since December 30, 1990. This report documents the technical activities of the period October 1, 1998 through September 30, 1999. During this period, GA and our partner Schafer Corporation were assigned 17 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct ''Onsite Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory (SNL). We fabricated and delivered over 1790 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNL. We produced more than 1380 glass and plastic target capsules over a wide range of sizes and designs (plus over 300 near target-quality capsules) for LLNL, LANL, SNL, and University of Rochester/Laboratory for Laser Energetic (UR/LLE). We also delivered various target foils and films for Naval Research Lab (NRL) and UWLLE in FY99. We fabricated a device to polish NIF-sized beryllium shells and prepared a laboratory for the safe operation of beryllium polishing activities. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY99, the GA/Schafer portion of the GA/Schafer-UR/LLE-LANL team effort for design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA was completed. All components of the OCTS were procured, fabricated, assembled, tested, and shipped to UR/LLE. Only minor documentation tasks remain to be done in FY00. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D2 or deuterium

  12. Climate targets for all countries: the options

    International Nuclear Information System (INIS)

    Philibert, C.; Pershing, J.

    2001-01-01

    This paper assesses five options for targets that could be taken by all countries to meet the ultimate objective of the Climate Change Convention: fixed, binding targets, dynamic targets; non-binding targets; sectoral targets, policies and measures. Each is evaluated according to criteria of environmental effectiveness, cost-effectiveness, contribution to economic growth and sustainable development, and equity. While fixed, binding targets continue to be viable for industrialized countries, they do not seem suitable for many developing countries in the near future. Dynamic targets could alleviate developing countries' concerns about constraining their development as well as broader concerns about possible introduction of 'hot air' in a world trading regime; they could also be considered for some or all industrialized countries. Non-binding targets could be politically appealing to developing counties, alleviate fears about development and/or hot air, but might only allow conditional participation in emissions trading by developing countries. Sectoral targets could offer a pragmatic first step - although their cost-effectiveness might be questioned. Finally, targets based on commitments to implement specific policies and measures might drive mitigation action and be part of negotiated packages including financial and technological cooperation. All these options may coexist in the future. (authors)

  13. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development concept stage report

    Energy Technology Data Exchange (ETDEWEB)

    Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Deringer, J.J. (Deringer Group, Riva, MD (USA)); Hall, J.D. (American Inst. of Architects, Washington, DC (USA)) (comps.)

    1990-09-01

    The Whole-Building Energy Design Targets project is being conducted for the US Department of Energy (DOE) by the Pacific Northwest Laboratory (PNL). The objective of the project is to develop a flexible methodology for setting energy performance guidelines with which architects, engineers, planners, and owners can assess energy efficiency in commercial building design. This volume, the third in the four-volume report on the Targets project concept stage, contains the minutes of the workshops as well as summaries of the expert's written comments prepared at the close of each workshop. In Section 2, the building energy simulation workshop is summarized. Section 3 provides a summary of the building cost workshop.

  14. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1997--September 30, 1998

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, J. [ed.

    1998-12-01

    During this period, General Atomics (GA) and their partner Schafer Corporation were assigned 17 formal tasks in support of the Inertial Confinement Fusion (ICF) program and its five laboratories. A portion of the effort on these tasks included providing direct ``On-site Support`` at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). They fabricated and delivered over 1,200 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNLA. They produced more than 1,300 glass and plastic target capsules for LLNL, LANL, SNLA, and the University of Rochester/Laboratory for Laser Energetics (UR/LLE). They also delivered nearly 2,000 various target foils and films for Naval Research Lab (NRL) and UR/LLE in FY98. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY98, great progress was made by the GA/Schafer-UR/LLE-LANL team in the design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA. The design phase was concluded for all components of the OCTS and all major components were procured and nearly all were fabricated. Many of the components were assembled and tested, and some have been shipped to UR/LLE. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D{sub 2} or deuterium-tritium (DT) fuel. They are part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. They also contributed cryogenic support and developed concepts for NIF cryogenic targets. This report summarizes and documents the technical progress made on these tasks.

  15. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1997 - September 30, 1998

    International Nuclear Information System (INIS)

    Gibson, J.

    1998-12-01

    During this period, General Atomics (GA) and their partner Schafer Corporation were assigned 17 formal tasks in support of the Inertial Confinement Fusion (ICF) program and its five laboratories. A portion of the effort on these tasks included providing direct ''On-site Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). They fabricated and delivered over 1,200 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNLA. They produced more than 1,300 glass and plastic target capsules for LLNL, LANL, SNLA, and the University of Rochester/Laboratory for Laser Energetics (UR/LLE). They also delivered nearly 2,000 various target foils and films for Naval Research Lab (NRL) and UR/LLE in FY98. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY98, great progress was made by the GA/Schafer-UR/LLE-LANL team in the design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA. The design phase was concluded for all components of the OCTS and all major components were procured and nearly all were fabricated. Many of the components were assembled and tested, and some have been shipped to UR/LLE. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. They are part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. They also contributed cryogenic support and developed concepts for NIF cryogenic targets. This report summarizes and documents the technical progress made on these tasks

  16. TargetCompare: A web interface to compare simultaneous miRNAs targets.

    Science.gov (United States)

    Moreira, Fabiano Cordeiro; Dustan, Bruno; Hamoy, Igor G; Ribeiro-Dos-Santos, André M; Dos Santos, Andrea Ribeiro

    2014-01-01

    MicroRNAs (miRNAs) are small non-coding nucleotide sequences between 17 and 25 nucleotides in length that primarily function in the regulation of gene expression. A since miRNA has thousand of predict targets in a complex, regulatory cell signaling network. Therefore, it is of interest to study multiple target genes simultaneously. Hence, we describe a web tool (developed using Java programming language and MySQL database server) to analyse multiple targets of pre-selected miRNAs. We cross validated the tool in eight most highly expressed miRNAs in the antrum region of stomach. This helped to identify 43 potential genes that are target of at least six of the referred miRNAs. The developed tool aims to reduce the randomness and increase the chance of selecting strong candidate target genes and miRNAs responsible for playing important roles in the studied tissue. http://lghm.ufpa.br/targetcompare.

  17. Identification of Spt5 target genes in zebrafish development reveals its dual activity in vivo.

    Directory of Open Access Journals (Sweden)

    Keerthi Krishnan

    Full Text Available Spt5 is a conserved essential protein that represses or stimulates transcription elongation in vitro. Immunolocalization studies on Drosophila polytene chromosomes suggest that Spt5 is associated with many loci throughout the genome. However, little is known about the prevalence and identity of Spt5 target genes in vivo during development. Here, we identify direct target genes of Spt5 using fog(sk8 zebrafish mutant, which disrupts the foggy/spt5 gene. We identified that fog(sk8 and their wildtype siblings differentially express less than 5% of genes examined. These genes participate in diverse biological processes from stress response to cell fate specification. Up-regulated genes exhibit shorter overall gene length compared to all genes examined. Through chromatin immunoprecipitation in zebrafish embryos, we identified a subset of developmentally critical genes that are bound by both Spt5 and RNA polymerase II. The protein occupancy patterns on these genes are characteristic of both repressive and stimulatory elongation regulation. Together our findings establish Spt5 as a dual regulator of transcription elongation in vivo and identify a small but diverse set of target genes critically dependent on Spt5 during development.

  18. Development of industrial-scale fission {sup 99}Mo production process using low enriched uranium target

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Kon; Lee, Jun Sig [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Beyer, Gerd J. [Grunicke Strasse 15, Leipzig (Germany)

    2016-06-15

    Molybdenum-99 ({sup 99}Mo) is the most important isotope because its daughter isotope, technetium-99m ({sup 99}mTc), has been the most widely used medical radioisotope for more than 50 years, accounting for > 80% of total nuclear diagnostics worldwide. In this review, radiochemical routes for the production of {sup 99}Mo, and the aspects for selecting a suitable process strategy are discussed from the historical viewpoint of {sup 99}Mo technology developments. Most of the industrial-scale {sup 99}Mo processes have been based on the fission of {sup 235}U. Recently, important issues have been raised for the conversion of fission {sup 99}Mo targets from highly enriched uranium to low enriched uranium (LEU). The development of new LEU targets with higher density was requested to compensate for the loss of {sup 99}Mo yield, caused by a significant reduction of {sup 235}U enrichment, from the conversion. As the dramatic increment of intermediate level liquid waste is also expected from the conversion, an effective strategy to reduce the waste generation from the fission {sup 99}Mo production is required. The mitigation of radioxenon emission from medical radioisotope production facilities is discussed in relation with the monitoring of nuclear explosions and comprehensive nuclear test ban. Lastly, the {sup 99}Mo production process paired with the Korea Atomic Energy Research Institute's own LEU target is proposed as one of the most suitable processes for the LEU target.

  19. Targeted p120-catenin ablation disrupts dental enamel development.

    Science.gov (United States)

    Bartlett, John D; Dobeck, Justine M; Tye, Coralee E; Perez-Moreno, Mirna; Stokes, Nicole; Reynolds, Albert B; Fuchs, Elaine; Skobe, Ziedonis

    2010-09-16

    Dental enamel development occurs in stages. The ameloblast cell layer is adjacent to, and is responsible for, enamel formation. When rodent pre-ameloblasts become tall columnar secretory-stage ameloblasts, they secrete enamel matrix proteins, and the ameloblasts start moving in rows that slide by one another. This movement is necessary to form the characteristic decussating enamel prism pattern. Thus, a dynamic system of intercellular interactions is required for proper enamel development. Cadherins are components of the adherens junction (AJ), and they span the cell membrane to mediate attachment to adjacent cells. p120 stabilizes cadherins by preventing their internalization and degradation. So, we asked if p120-mediated cadherin stability is important for dental enamel formation. Targeted p120 ablation in the mouse enamel organ had a striking effect. Secretory stage ameloblasts detached from surrounding tissues, lost polarity, flattened, and ameloblast E- and N-cadherin expression became undetectable by immunostaining. The enamel itself was poorly mineralized and appeared to be composed of a thin layer of merged spheres that abraded from the tooth. Significantly, p120 mosaic mouse teeth were capable of forming normal enamel demonstrating that the enamel defects were not a secondary effect of p120 ablation. Surprisingly, blood-filled sinusoids developed in random locations around the developing teeth. This has not been observed in other p120-ablated tissues and may be due to altered p120-mediated cell signaling. These data reveal a critical role for p120 in tooth and dental enamel development and are consistent with p120 directing the attachment and detachment of the secretory stage ameloblasts as they move in rows.

  20. Culture medium, gas atmosphere and MAPK inhibition affect regulation of RNA-binding protein targets during mouse preimplantation development.

    Science.gov (United States)

    Calder, Michele D; Watson, Patricia H; Watson, Andrew J

    2011-11-01

    During oogenesis, mammalian oocytes accumulate maternal mRNAs that support the embryo until embryonic genome activation. RNA-binding proteins (RBP) may regulate the stability and turnover of maternal and embryonic mRNAs. We hypothesised that varying embryo culture conditions, such as culture medium, oxygen tension and MAPK inhibition, affects regulation of RBPs and their targets during preimplantation development. STAU1, ELAVL1, KHSRP and ZFP36 proteins and mRNAs were detected throughout mouse preimplantation development, whereas Elavl2 mRNA decreased after the two-cell stage. Potential target mRNAs of RBP regulation, Gclc, Slc2a1 and Slc7a1 were detected during mouse preimplantation development. Gclc mRNA was significantly elevated in embryos cultured in Whitten's medium compared with embryos cultured in KSOMaa, and Gclc mRNA was elevated under high-oxygen conditions. Inhibition of the p38 MAPK pathway reduced Slc7a1 mRNA expression while inhibition of ERK increased Slc2a1 mRNA expression. The half-lives of the potential RBP mRNA targets are not regulated in parallel; Slc2a1 mRNA displayed the longest half-life. Our results indicate that mRNAs and proteins encoding five RBPs are present during preimplantation development and more importantly, demonstrate that expression of RBP target mRNAs are regulated by culture medium, gas atmosphere and MAPK pathways.

  1. ANL progress in developing an LEU target and process for Mo-99 production: Cooperation with CNEA

    International Nuclear Information System (INIS)

    Gelis, A.V.; Vandegrift, G.F.; Aase, S.B.; Bakel, A.J.; Falkenberg, J.R.; Regalbuto, M.C.; Quigley, K.J.

    2003-01-01

    The primary mission of the Reduced Enrichment in Research and Test Reactors (RERTR) Program is to facilitate the conversion of research and test-reactor fuel and targets from high-enriched uranium (HEU) to low-enriched uranium (LEU). One of the current goals at Argonne National Laboratory (ANL) is to assist the Argentine Comision Nacional de Energia Atomica (CNEA) in developing an LEU foil target and a process for 99 Mo production. Specifically addressed in this paper is ANL R and D related to this conversion: (1) designing a prototype production vessel for digesting irradiated LEU foils in alkaline solutions and (2) developing a new digestion method to address all issues related to HEU to LEU conversion. (author)

  2. Development of a liquid {sup 3}He target for experimental studies of antikaon-nucleon interaction at J-PARC

    Energy Technology Data Exchange (ETDEWEB)

    Iio, M., E-mail: masami.iio@kek.jp [RIKEN Nishina Center, RIKEN, Saitama 351-0198 (Japan); High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan); Ishimoto, S. [High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan); Sato, M. [Department of Physics, The University of Tokyo, Tokyo 113-0033 (Japan); Enomoto, S. [Department of Physics, Osaka University, Osaka 560-0043 (Japan); Hashimoto, T. [Department of Physics, The University of Tokyo, Tokyo 113-0033 (Japan); Suzuki, S. [High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan); Iwasaki, M. [RIKEN Nishina Center, RIKEN, Saitama 351-0198 (Japan); Department of Physics, Tokyo Institute of Technology, Tokyo 152-8551 (Japan); Hayano, R.S. [Department of Physics, The University of Tokyo, Tokyo 113-0033 (Japan)

    2012-09-21

    A liquid {sup 3}He target system was developed for experimental studies of kaonic atoms and kaonic nuclei at J-PARC. {sup 3}He gas is liquefied in a heat exchanger cooled below 3.2 K by decompression of liquid {sup 4}He. To maintain a large acceptance of the cylindrical detector system for decay particles of kaonic nuclei, efficient heat transport between the separate target cell and the main unit is realized using circulation of liquid {sup 3}He. To minimize the amount of material, a vacuum vessel containing a carbon fiber reinforced plastic cylinder having an inside diameter of 150 mm and a thickness of 1 mm was produced. A target cell made of pure beryllium and beryllium-aluminum alloy was developed not only to minimize the amount of material but also to obtain high X-ray transmission. During a cooling test, the target cell was kept at 1.3 K at a pressure of 33 mbar. The total estimated heat load to the components including the target cell and heat exchanger cooled by liquid {sup 4}He decompression, was 0.21 W, and the liquid {sup 4}He consumption rate was 50 L/day.

  3. Assessing the universal health coverage target in the Sustainable Development Goals from a human rights perspective.

    Science.gov (United States)

    Chapman, Audrey R

    2016-12-15

    The UN's Sustainable Development Goals (SDGs), adopted in September 2015, include a comprehensive health goal, "to ensure healthy lives and promote well-being at all ages." The health goal (SDG 3) has nine substantive targets and four additional targets which are identified as a means of implementation. One of these commitments, to achieve universal health coverage (UHC), has been acknowledged as central to the achievement of all of the other health targets. As defined in the SDGs, UHC includes financial risk protection, access to quality essential health-care services, and access to safe, effective, quality and affordable essential medicines and vaccines for all. This article evaluates the extent to which the UHC target in the SDGs conforms with the requirements of the right to health enumerated in the International Covenant on Economic, Social and Cultural Rights, the Convention on the Rights of the Child, and other international human rights instruments and interpreted by international human rights bodies. It does so as a means to identify strengths and weaknesses in the framing of the UHC target that are likely to affect its implementation. While UHC as defined in the SDGs overlaps with human rights standards, there are important human rights omissions that will likely weaken the implementation and reduce the potential benefits of the UHC target. The most important of these is the failure to confer priority to providing access to health services to poor and disadvantaged communities in the process of expanding health coverage and in determining which health services to provide. Unless the furthest behind are given priority and strategies adopted to secure their participation in the development of national health plans, the SDGs, like the MDGs, are likely to leave the most disadvantaged and vulnerable communities behind.

  4. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1995--September 30, 1996

    International Nuclear Information System (INIS)

    Hoppe, M.

    1997-02-01

    On December 30, 1990, the U.S. Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. In September 1995 this contract ended and a second contract was issued for us to continue this ICF target support work. This report documents the technical activities of the period October 1, 1995 through September 30, 1996. During this period, GA and our partners WJ Schafer Associates (WJSA) and Soane Technologies, Inc. (STI) were assigned 14 formal tasks in support of the Inertial Confinement Fusion program and its five laboratories. A portion of the effort on these tasks included providing direct open-quotes Onsite Supportclose quotes at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). We fabricated and delivered over 800 gold-plated hohlraum mandrels to LLNL, LANL and SNLA. We produced nearly 1,200 glass and plastic target capsules for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). We also delivered over 100 flat foil targets for Naval Research Lab (NRL) and SNLA in FY96. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require capsules containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. We are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Substantial progress has been made on ways to both create and characterize viable layers. During FY96, significant progress was made in the design of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA

  5. Development of a thin, internal superconducting polarisation magnet for the polarised target

    Energy Technology Data Exchange (ETDEWEB)

    Bornstein, Marcel; Dutz, Hartmut; Goertz, Stefan; Reeve, Scott; Runkel, Stefan [Physikalisches Institut, Bonn Univ. (Germany)

    2016-07-01

    In order to improve the figure of merit of double-polarisation experiments at CB-ELSA in Bonn, the Polarised Target is working on a new dilution refrigerator. For maximum polarisation of nucleons low temperatures and a high homogeneous magnetic field within the target area is needed. A thin, superconducting magnet is in development, which will create a continuous longitudinal magnetic field of 2.5 T and which will be used within the new refrigerator. The solenoidal geometry of this magnet uses two additional correction coils, placed at a well defined calculated position, for reaching the homogeneity criteria of 10{sup -4} needed for the dynamic nuclear process. Practically, the superconducting wires as well as the correction coils have to be placed with maximum precision: Small fluctuations of the distance between the current loops can diminish the requested homogeneity. A second build prototype passes first tests and looks promising to fulfil the particular requirements.

  6. Development and optimization of targeted radionuclide tumor therapy using folate based radiopharmaceuticals

    CERN Document Server

    Reber, Josefine Astrid

    The folate receptor (FR) has been used for a quarter of a century as a tumor-associated target for selective delivery of drugs and imaging agents to cancer cells. While several folic acid radioconjugates have been successfully employed for imaging purposes in (pre)clinical studies, a therapeutic application of folic acid radioconjugates has not yet reached the critical stage which would allow a clinical translation. Due to a substantial expression of the FR in the proximal tubule cells, radiofolates accumulate in the kidneys which are at risk of damage by particle-radiation. To improve this situation, we aimed to develop and evaluate strategies for the performance of FR-targeted radionuclide therapy by decreasing the renal uptake of radiofolates and thereby reducing potential nephrotoxic effects. Two different strategies were investigated. First, the combination of radiofolates with chemotherapeutic agents such as pemetrexed (PMX) and 5-fluorouracil (5-FU) and secondly, an approach based on radioiodinated fol...

  7. Organelle targeting: third level of drug targeting

    Directory of Open Access Journals (Sweden)

    Sakhrani NM

    2013-07-01

    Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

  8. Recent developments in laser-fusion target coatings

    International Nuclear Information System (INIS)

    Fries, R.J.; Catlett, D.S.; Fossey, D.; Mayer, A.; McCreary, W.J.; Powell, B.W.; Simonsic, G.A.

    1976-01-01

    Techniques to fabricate hollow, spherical, multilayered laser-fusion targets are described. The first is a glow discharge polymerization process for plastic coating. A chemical vapor deposition process for depositing Mo/Re alloys is also discussed along with some new techniques for electrodeless plating and for electroplating a wide variety of metals

  9. Analytical models for development of high performance metal targets irradiated in IPEN-CNEN/SP Cyclone 30 and Cyclone 18 cyclotrons

    International Nuclear Information System (INIS)

    Oliveira, Henrique Barcellos de

    2009-01-01

    Analytical models were developed that describe the basic elements for metal targets irradiation in cyclotrons. Important parameters such as maximum beam current value and thermal power deposited on target were obtained and compared with practical situations. In an unprecedented way, were determined analytically the features found in intense thermal transient situations, when high protons concentrations in a small region of the beam cause intense temperature gradients in small regions of the target. Comparing with results found in the literature showed that the developed models are satisfactory, in view of all limitations of the proposed model. (author)

  10. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1993--September 30, 1994

    Energy Technology Data Exchange (ETDEWEB)

    Hoppe, M. [ed.

    1995-04-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. During the period, GA was assigned 17 tasks in support of the Inertial Confinement Fusion program and its laboratories. This year they achieved full production capabilities for the micromachining, dimensional characterization and gold plating of hohlraums. They fabricated and delivered 726 gold-plated mandrels of 27 different types to LLNL and 48 gold-plated mandrels of two different types to LANL. They achieved full production capabilities in composite capsule production ad delivered in excess of 240 composite capsules. They continuously work to improve performance and capabilities. They were also directed to dismantle, remove, and disposition all equipment at the previous contractor (KMSF) that had radioactive contamination levels low enough that they could be exposed to the general public without radiological constraints. GA was also directed to receive and store the tritium fill equipment. They assisted LANL in the development of techniques for characterization of opaque targets. They developed deuterated and UV-opaque polymers for use by the University of Rochester`s Laboratory for Laser Energetics (UR/LLE) and devised a triple-orifice droplet generator to demonstrate the controlled-mass nature of the microencapsulation process. The ICF program is anticipating experiments at NIF and the Omega Upgrade. Both facilities will require capsules containing layered D{sub 2} or D-T fuel. They continued engineering and assembly of equipment for a cryogenic target handling system for UR/LLE that will fill, transport, layer, and characterize targets filled with cryogenic deuterium or deuterium-tritium fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments.

  11. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1993--September 30, 1994

    International Nuclear Information System (INIS)

    Hoppe, M.

    1995-04-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. During the period, GA was assigned 17 tasks in support of the Inertial Confinement Fusion program and its laboratories. This year they achieved full production capabilities for the micromachining, dimensional characterization and gold plating of hohlraums. They fabricated and delivered 726 gold-plated mandrels of 27 different types to LLNL and 48 gold-plated mandrels of two different types to LANL. They achieved full production capabilities in composite capsule production ad delivered in excess of 240 composite capsules. They continuously work to improve performance and capabilities. They were also directed to dismantle, remove, and disposition all equipment at the previous contractor (KMSF) that had radioactive contamination levels low enough that they could be exposed to the general public without radiological constraints. GA was also directed to receive and store the tritium fill equipment. They assisted LANL in the development of techniques for characterization of opaque targets. They developed deuterated and UV-opaque polymers for use by the University of Rochester's Laboratory for Laser Energetics (UR/LLE) and devised a triple-orifice droplet generator to demonstrate the controlled-mass nature of the microencapsulation process. The ICF program is anticipating experiments at NIF and the Omega Upgrade. Both facilities will require capsules containing layered D 2 or D-T fuel. They continued engineering and assembly of equipment for a cryogenic target handling system for UR/LLE that will fill, transport, layer, and characterize targets filled with cryogenic deuterium or deuterium-tritium fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments

  12. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  13. Recent progress in the development of a polarized proton target for reactions with radioactive ion beams

    International Nuclear Information System (INIS)

    Urrego-Blanco, J.P.; Bingham, C.R.; Brandt, B. van den; Galindo-Uribarri, A.; Gomez del Campo, J.; Hautle, P.; Konter, J.A.; Padilla-Rodal, E.; Schmelzbach, P.A.

    2007-01-01

    Polarization observables in nuclear reactions with stable beams have provided important information concerning structural properties of nuclei and reaction mechanisms and hold great promise in the context of exotic nuclei. We report on the development of a polarized target based on plastic foils of 20-200 μm thickness to be used with radioactive ion beams. The operation of such a target requires a moderately high magnetic field and very low temperatures. The plastic foil is placed inside a chamber attached to the mixing chamber of a 3 He- 4 He dilution refrigerator. Cooling of the foil is achieved via a superfluid film of 4 He that can be supplied through two capillaries. The chamber has two thin, highly uniform silicon nitride windows. An NMR coil is attached to the target to monitor the polarization. Results of a first test to characterize the target system, using the elastic scattering of 38 MeV 12 C by protons in inverse kinematics are presented

  14. Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective.

    Science.gov (United States)

    Fornaro, Michele; Kardash, Lubna; Novello, Stefano; Fusco, Andrea; Anastasia, Annalisa; De Berardis, Domenico; Perna, Giampaolo; Carta, Mauro Giovanni

    2018-03-01

    Bipolar disorder (BD) is a considerable burden to the affected individual. The need for novel drug targets and improved drug design (DD) in BD is therefore clear. Areas covered: The following article provides a brief, narrative, clinician-oriented overview of the most promising novel pharmacological targets for BD along with a concise overview regarding the general DD process and the unmet needs relevant to BD. Expert opinion: A number of novel potential drug targets have been investigated. With the notable exception of the kynurenine pathway, available evidence is too scarce to highlight a definitive roadmap for forthcoming DD in BD. BD itself may present with different facets, as it is a polymorphic clinical spectrum. Therefore, promoting clinical-case stratification should be based on precision medicine, rather than on novel biological targets. Furthermore, the full release of raw study data to the scientific community and the development of uniform clinical trial standards (including more realistic outcomes) should be promoted to facilitate the DD process in BD.

  15. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    International Nuclear Information System (INIS)

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy; Bronson, Roderick T.; Hornick, Jason L.; Cohen, David E.; Ukomadu, Chinweike

    2015-01-01

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors

  16. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    Energy Technology Data Exchange (ETDEWEB)

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Bronson, Roderick T. [Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115 (United States); Hornick, Jason L. [Department of Pathology, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Cohen, David E. [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Ukomadu, Chinweike, E-mail: cukomadu@partners.org [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2015-09-18

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors.

  17. High-efficiency target-ion sources for RIB generation

    International Nuclear Information System (INIS)

    Alton, G.D.

    1993-01-01

    A brief review is given of high-efficiency ion sources which have been developed or are under development at ISOL facilities which show particular promise for use at existing, future, or radioactive ion beam (RIB) facilities now under construction. Emphasis will be placed on those sources which have demonstrated high ionization efficiency, species versatility, and operational reliability and which have been carefully designed for safe handling in the high level radioactivity radiation fields incumbent at such facilities. Brief discussions will also be made of the fundamental processes which affect the realizable beam intensities in target-ion sources. Among the sources which will be reviewed will be selected examples of state-of-the-art electron-beam plasma-type ion sources, thermal-ionization, surface-ionization, ECR, and selectively chosen ion source concepts which show promise for radioactive ion beam generation. A few advanced, chemically selective target-ion sources will be described, such as sources based on the use of laser-resonance ionization, which, in principle, offer a more satisfactory solution to isobaric contamination problems than conventional electromagnetic techniques. Particular attention will be given to the sources which have been selected for initial or future use at the Holifield Radioactive Ion Beam Facility now under construction at the Oak Ridge National Laboratory

  18. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    International Nuclear Information System (INIS)

    Zhang, Pengpeng; Shan, Tizhong; Liang, Xinrong; Deng, Changyan; Kuang, Shihuan

    2014-01-01

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor flox/flox mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor flox/flox mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function

  19. Design of the FMIT lithium target

    International Nuclear Information System (INIS)

    Hassberger, J.A.; Annese, C.E.; Greenwell, R.K.; Ingham, J.G.; Miles, R.R.; Miller, W.C.

    1981-01-01

    Development of the liquid lithium target for the Fusion Materials Irradiation Test (FMIT) Facility is described. The target concept, major design goals and design requirements are presented. Progress made in the research and development areas leading to detailed design of the target is discussed. This progress, including experimental and analytic results, demonstrates that the FMIT target design is capable of meeting its major design goals and requirements

  20. The Development of a Framework for Target Diagnostic Centralized Control System (TDCCS) in ICF Experiments

    International Nuclear Information System (INIS)

    Zhang Chi; Wang Jian; Yu Xiaoqi; Yang Dong

    2008-01-01

    A framework for target diagnostic centralized control system (TDCCS) in inertial confinement fusion (ICF) experiment has been developed. The developed framework is based on the common object request broker architecture (CORBA) standard and part of the concept from the ICFRoot (a framework based on ROOT for ICF experiments) framework design. This framework is of a component architecture, including a message bus, command executer, status processor, parser and proxy. To test the function of the framework, a simplified prototype of the TDCCS has been developed as well.

  1. Guidelines to PET measurements of the target occupancy in the brain for drug development

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

    2016-11-15

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

  2. Summary abstract: microspot target development with seeded and patterned plasma polymers

    International Nuclear Information System (INIS)

    Letts, S.A.; Miller, D.E.; Corley, R.A.; Tillotson, T.M.; Witt, L.A.

    1985-01-01

    In inertial confinement fusion (ICF) energy is transferred from the laser to the target through the interaction of extremely high intensity laser light with the target plasma. To better understand laser-plasma interactions, a new class of targets was designed to study long scale-length plasmas (many hundred times the laser wavelength) by measurement of the temperature and density of the plasma as a function of time. The specifications for the target called for a freestanding hydrocarbon polymer (CH) film with a sharply defined spot (microspot) in the center seeded with either silicon or sulfur. The target film was fabricated using a three-step procedure which consisted of deposition of the hydrocarbon film, definition of the microspot, and then deposition of a seeded spot through a mask. In the final assembly step, the film containing the microspot was mounted over a 1.5 mm diam hole in a support. The support was either a plastic ring or a copper foil electroplated with 3 μm of gold. The fabrication of this type of target is described

  3. Targeting DDX3 in cancer: personalized drug development and delivery

    NARCIS (Netherlands)

    Bol, G.M.

    2013-01-01

    Cancer begins when a cell in an organ of our body starts to grow uncontrollably. Only recently has it become clear that targeting the cancer cells’ dependency on specific proteins, rather than their origin, has greater therapeutic potential. The vast majority of potential targets for cancer therapy

  4. Development of a higher power cooling system for lithium targets.

    Science.gov (United States)

    Phoenix, B; Green, S; Scott, M C; Bennett, J R J; Edgecock, T R

    2015-12-01

    The accelerator based Boron Neutron Capture Therapy beam at the University of Birmingham is based around a solid thick lithium target cooled by heavy water. Significant upgrades to Birmingham's Dynamitron accelerator are planned prior to commencing a clinical trial. These upgrades will result in an increase in maximum achievable beam current to at least 3 mA. Various upgrades to the target cooling system to cope with this increased power have been investigated. Tests of a phase change coolant known as "binary ice" have been carried out using an induction heater to provide a comparable power input to the Dynamitron beam. The experimental data shows no improvement over chilled water in the submerged jet system, with both systems exhibiting the same heat input to target temperature relation for a given flow rate. The relationship between the cooling circuit pumping rate and the target temperature in the submerged jet system has also been tested. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Targeting DNA repair systems in antitubercular drug development.

    Science.gov (United States)

    Minias, Alina; Brzostek, Anna; Dziadek, Jaroslaw

    2018-01-28

    Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

    Science.gov (United States)

    Glasgow, Micah D. K.; Chougule, Mahavir B.

    2016-01-01

    Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

  7. A compact multi-plate fission chamber for the simultaneous measurement of 233U capture and fission cross-sections

    Directory of Open Access Journals (Sweden)

    Bacak M.

    2017-01-01

    Full Text Available 233U plays the essential role of fissile nucleus in the Th-U fuel cycle. A particularity of 233U is its small neutron capture cross-section which is about one order of magnitude lower than the fission cross-section on average. Therefore, the accuracy in the measurement of the 233U capture cross-section essentially relies on efficient capture-fission discrimination thus a combined setup of fission and γ-detectors is needed. At CERN n_TOF the Total Absorption Calorimeter (TAC coupled with compact fission detectors is used. Previously used MicroMegas (MGAS detectors showed significant γ-background issues above 100 eV coming from the copper mesh. A new measurement campaign of the 233U capture cross-section and alpha ratio is planned at the CERN n_TOF facility. For this measurement, a novel cylindrical multi ionization cell chamber was developed in order to provide a compact solution for 14 active targets read out by 8 anodes. Due to the high specific activity of 233U fast timing properties are required and achieved with the use of customized electronics and the very fast ionizing gas CF4 together with a high electric field strength. This paper describes the new fission chamber and the results of the first tests with neutrons at GELINA proving that it is suitable for the 233U measurement.

  8. Development of beryllium-based neutron target system with three-layer structure for accelerator-based neutron source for boron neutron capture therapy.

    Science.gov (United States)

    Kumada, Hiroaki; Kurihara, Toshikazu; Yoshioka, Masakazu; Kobayashi, Hitoshi; Matsumoto, Hiroshi; Sugano, Tomei; Sakurai, Hideyuki; Sakae, Takeji; Matsumura, Akira

    2015-12-01

    The iBNCT project team with University of Tsukuba is developing an accelerator-based neutron source. Regarding neutron target material, our project has applied beryllium. To deal with large heat load and blistering of the target system, we developed a three-layer structure for the target system that includes a blistering mitigation material between the beryllium used as the neutron generator and the copper heat sink. The three materials were bonded through diffusion bonding using a hot isostatic pressing method. Based on several verifications, our project chose palladium as the intermediate layer. A prototype of the neutron target system was produced. We will verify that sufficient neutrons for BNCT treatment are generated by the device in the near future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Darrell R.

    2012-10-25

    The purpose of this project is to develop a new radiolabeled peptide for imaging and treating metastatic melanoma. The immunoconjugate consists of a receptor-specific peptide that targets melanoma cells. The beta-emitter lead-212 (half-life = 10.4 hours) is linked by coordination chemistry to the peptide. After injection, the peptide targets melanoma receptors on the surfaces of melanoma cells. Lead-212 decays to the alpha-emitter bismuth-212 (half-life = 60 minutes). Alpha-particles that hit melanoma cell nuclei are likely to kill the melanoma cell. For cancer cell imaging, the lead-212 is replaced by lead-203 (half-life = 52 hours). Lead-203 emits 279 keV photons (80.1% abundance) that can be imaged and measured for biodistribution analysis, cancer imaging, and quantitative dosimetry.

  10. Development of monoclonal antibodies and quantitative ELISAs targeting insulin-degrading enzyme

    Directory of Open Access Journals (Sweden)

    Dickson Dennis W

    2009-10-01

    Full Text Available Abstract Background Insulin-degrading enzyme (IDE is a widely studied zinc-metalloprotease implicated in the pathogenesis of type 2 diabetes mellitus, Alzheimer disease (AD and varicella zoster virus infection. Despite more than six decades of research on IDE, progress has been hampered by the lack of well-characterized reagents targeting this biomedically important protease. To address this important need, we generated and characterized new mouse monoclonal antibodies (mAbs targeting natively folded human and rodent IDE. Results Eight monoclonal hybridoma cell lines were derived in house from mice immunized with full-length, natively folded, recombinant human IDE. The mAbs derived from these lines were shown to detect IDE selectively and sensitively by a wide range of methods. Two mAbs in particular—designated 6A1 and 6H9—proved especially selective for IDE in immunocytochemical and immunohistochemical applications. Using a variety of methods, we show that 6A1 selectively detects both human and rodent IDE, while 6H9 selectively detects human, but not rodent, IDE, with both mAbs showing essentially no cross reactivity with other proteins in these applications. Using these novel anti-IDE mAbs, we also developed sensitive and quantitative sandwich ELISAs capable of quantifying IDE levels present in human brain extracts. Conclusion We succeeded in developing novel mAbs that selectively detect rodent and/or human IDE, which we have shown to be suitable for a wide range of applications, including western blotting, immunoprecipitation, immunocytochemistry, immunohistochemistry, and quantitative sandwich ELISAs. These novel anti-IDE mAbs and the assays derived from them constitute important new tools for addressing many unresolved questions about the basic biology of IDE and its role in multiple highly prevalent human diseases.

  11. Research and Development of Target Recognition and Location Crawling Platform based on Binocular Vision

    Science.gov (United States)

    Xu, Weidong; Lei, Zhu; Yuan, Zhang; Gao, Zhenqing

    2018-03-01

    The application of visual recognition technology in industrial robot crawling and placing operation is one of the key tasks in the field of robot research. In order to improve the efficiency and intelligence of the material sorting in the production line, especially to realize the sorting of the scattered items, the robot target recognition and positioning crawling platform based on binocular vision is researched and developed. The images were collected by binocular camera, and the images were pretreated. Harris operator was used to identify the corners of the images. The Canny operator was used to identify the images. Hough-chain code recognition was used to identify the images. The target image in the image, obtain the coordinates of each vertex of the image, calculate the spatial position and posture of the target item, and determine the information needed to capture the movement and transmit it to the robot control crawling operation. Finally, In this paper, we use this method to experiment the wrapping problem in the express sorting process The experimental results show that the platform can effectively solve the problem of sorting of loose parts, so as to achieve the purpose of efficient and intelligent sorting.

  12. Development of a high-heat-flux target for multimegawatt, multisecond neutral beams at ORNL

    International Nuclear Information System (INIS)

    Combs, S.K.; Milora, S.L.; Bush, C.E.

    1984-01-01

    A high-heat-flux target has been developed for intercepting multimegawatt, multisecond neutral beam power at the Oak Ridge National Laboratory (ORNL). Water-cooled copper swirl tubes are used for the heat transfer medium; these tubes exhibit an enhancement in burnout heat flux over conventional axial-flow tubes. The target consists of 126 swirl tubes (each 0.95 cm in outside diameter with 0.16-cm-thick walls and approx. =1 m long) arranged in a V-shape. Two arrays of parallel tubes inclined at an angle α to the beam axis form the V-shape, and this geometry reduces the surface heat flux by a factor of 1/sin α (for the present design, α =13 0 and 21 0 ). In tests with the ORNL long-pulse ion source (13- by 43-cm grid), the target has handled up to 3-MW, 30-s beam pulses with no deleterious effects. The peak power density was estimated at approx. =15 kW/cm 2 normal to the beam axis (5.4 kW/cm 2 maximum on tube surfaces). The water flow rate through the target was 41.6 L/s (660 gpm) or 0.33 L/s (5.2 gpm) per tube (axial flow velocity = 11.6 m/s). The corresponding pressure drop across the target was 1.14 MPa (165 psi) with an inlet pressure of 1.45 MPa (210 psia). Data are also presented from backup experiments in which individual tubes were heated by a small ion source (10-cm-diam grid) to characterize tube performance. These results suggest that the target should handle peak power densities in the range 25 to 30 kW/cm 2 normal to the beam axis (approx. =10 kW/cm 2 maximum on tube surfaces) with the present flow parameters. This translates to beam power levels of 5 to 6 MW for equivalent beam optics

  13. [Current Status and Development of Traditional Chemotherapy in Non-small Cell Lung Cancer under the Background of Targeted Therapy].

    Science.gov (United States)

    Zhang, Guowei; Wang, Huijuan; Zhang, Mina; Li, Peng; Ma, Zhiyong

    2015-09-20

    In recent years, along with rapid development of targeted therapy in non-small cell lung cancer, traditional chemotherapy get less and less attention. Yet it still can not be ignored in the current that how to locate and use traditional chemotherapy so patients could derive maximum benefit. For this purpose, through the literature review and analysis, we point out there are still many traditional chemotherapy irreplaceable places whatever patients' driver gene status. And there are some new treatment modalities of traditional chemotherapy which have been developed to further improve patients' survival. At the same time, through exposition of predictive bio-markers development in chemotherapy, we pointed out that the future of traditional chemotherapy must be part of "targeted therapy".

  14. Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

    International Nuclear Information System (INIS)

    Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

    2014-01-01

    Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe 3 O 4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe 3 O 4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue. (papers)

  15. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    radiolabelled regulatory peptides and their metabolically stabilised analogues. Antigen epitopes: Antibodies, as unlabelled biological drugs, are becoming of increasing interest. They exert an antibody-dependent cellular cytotoxicity which leads to lysis of tumour cells. Radiolabelled versions of these (and other) antibodies are being developed worldwide. The disadvantage of the long circulating time of antibodies can be solved by engineering fragments such as diabodies, bivalent single chain variable fragments (scFv), minibodies or by pretargeting approaches. Transmembrane transporters: Other interesting targets are transporters for radiolabelled amino acids and nutrients. Cancer cells require an increased supply of many such nutrients and obtain these by increased expression of some types of amino-acid transporter. A more detailed analysis of the relationship between amino-acid uptake and transporter expression in normal and malignant cells would be very valuable in identifying the clinical therapeutic potential of this class of tracer. Tumour blood supply: Tumours require an efficient blood supply to grow and metastatise and active angiogenesis of new blood vessels is a feature of many tumours. Specific receptors expressed during this process represent a novel class of targets for TRT. Extra-cellular matrix: Recently, another relevant class of target antigens has raised interest. Lectins, or carbohydrate binding proteins, recognize specific oligosaccharide structures on glycoproteins and glycolipids. It is well known that protein and lipid glycosylation are consistently altered in cancer cells for the aberrant activity of specific glycosyltransferase and glycosydases. Experimental evidence demonstrated that tumor growth and progression may depend, at least in part, on the presence of altered glycoproteins on the cell surface, which can mediate aberrant receptor-ligand interactions. (author)

  16. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Pengpeng [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Shan, Tizhong; Liang, Xinrong [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Deng, Changyan [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Kuang, Shihuan, E-mail: skuang@purdue.edu [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States)

    2014-09-12

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor{sup flox/flox} mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor{sup flox/flox} mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function.

  17. Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

    Science.gov (United States)

    Biron, Eric; Bédard, François

    2016-07-01

    The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 100-K Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    Ovink, R.

    2012-09-18

    This report documents the process used to identify source area target analytes in support of the 100-K Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

  19. 100-F Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    Ovink, R.

    2012-09-18

    This report documents the process used to identify source area target analytes in support of the 100-F Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

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

    Science.gov (United States)

    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.

  1. New gene targets for glucagon-like peptide-1 during embryonic development and in undifferentiated pluripotent cells.

    Science.gov (United States)

    Sanz, Carmen; Blázquez, Enrique

    2011-09-01

    In humans, glucagon-like peptide (GLP-1) functions during adult life as an incretin hormone with anorexigenic and antidiabetogenic properties. Also, the therapeutic potential of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and in bolstering the maintenance of human mesenchymal stem cell (hMSC) stores by promoting the proliferation and cytoprotection of hMSC seems to be relevant. Since these observations suggest a role for GLP-1 during developmental processes, the aim of the present work was to characterize GLP-1 in early development as well as its gene targets in mouse embryonic stem (mES) cells. Mouse embryos E6, E8, and E10.5 and pluripotent mES were used for the inmunodetection of GLP-1 and GLP-1 receptor. Quantitative real-time PCR was used to determine the expression levels of GLP-1R in several tissues from E12.5 mouse embryos. Additionally, GLP-1 gene targets were studied in mES by multiple gene expression analyses. GLP-1 and its receptors were identified in mES and during embryonic development. In pluripotent mES, GLP-1 modified the expression of endodermal, ectodermal, and mesodermal gene markers as well as sonic hedgehog, noggin, members of the fibroblast and hepatic growth factor families, and others involved in pancreatic development. Additionally, GLP-1 promoted the expression of the antiapoptotic gene bcl2 and at the same time reduced proapoptotic caspase genes. Our results indicate that apart from the effects and therapeutic benefits of GLP-1 in adulthood, it may have additional gene targets in mES cells during embryonic life. Furthermore, the pathophysiological implications of GLP-1 imbalance in adulthood may have a counterpart during development.

  2. Target assignment for security officers to K targets (TASK)

    International Nuclear Information System (INIS)

    Rowland, J.R.; Shelton, K.W.; Stunkel, C.B.

    1983-02-01

    A probabilistic algorithm is developed to provide an optimal Target Assignment for Security officers to K targets (TASK) using a maximin criterion. Under the assumption of only a limited number (N) of security officers, the TASK computer model determines deployment assignments which maximize the system protection against sabotage by an adversary who may select any link in the system, including the weakest, for the point of attack. Applying the TASK model to a hypothetical nuclear facility containing a nine-level building reveals that aggregate targets covering multiple vital areas should be utilized to reduce the number of possible target assignments to a value equal to or only slightly larger than N. The increased probability that a given aggregate target is covered by one or more security officers offsets the slight decrease in interruption probability due to its occurring earlier in the adversary's path. In brief, the TASK model determines the optimal maximin deployment strategy for limited numbers of security officers and calculates a quantitative measure of the resulting system protection

  3. Development of a hydrogen and deuterium polarized gas target for application in storage rings. Annual report, February 1, 1986-January 31, 1987

    International Nuclear Information System (INIS)

    Haeberli, W.

    1986-01-01

    Insertion of an internal polarized gas target into storage rings for protons, antiprotons or electrons would permit interesting new experiments, particularly if the circulating beam is polarized as well. The purpose of the present project is the development of a polarized gas target, based on injection of polarized hydrogen or deuterium atoms into a storage cell in order to build up the required target thickness. A method has been developed and tested, which permits measurement of the target polarization under realistic conditions (i.e., in the presence of an intense ion beam) without the need for a large accelerator. First measurements with an oxidized aluminum cell have been made. It is proposed to study wall depolarization in storage cells and to search for suitable wall conditions (wall material, coating, temperature, vacuum conditions) to permit eventual construction of a polarized gas target for a storage ring

  4. Preliminary study of mercury target structure

    Energy Technology Data Exchange (ETDEWEB)

    Kaminaga, Masanori; Haga, Katsuhiro; Hino, Ryutaro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Kumasaka, Katsuyuki; Uchida, Shoji; Nakagawa, Toshi; Mori, Seiji; Nishikawa, Akira

    1997-11-01

    Development of a proton accelerator based neutron source (1.5 GeV, 5.3 mA (for neutron source 3.3 mA), thermal power 8 MW) is currently conducted by the Special Task Force for Neutron Science Initiative, JAERI. Preliminary design studies and related R and D of a solid metal target for the first stage (1.5 GeV, 1 mA) and a liquid metal target for both the first and second stages (1.5 GeV, 3.3 mA) are conducted by the Target Group to develop both solid and liquid metal target systems. A few kinds of target structures have been investigated in FY 1996 and the preliminary results for the target structures are described in this paper. Investigation results of alternative materials for the target container are also described in this paper. (author)

  5. Prognostic Value of Molecular Markers and Implication for Molecular Targeted Therapies in Nasopharyngeal Carcinoma: An Update in an Era of New Targeted Molecules Development.

    Science.gov (United States)

    Liu, Mu-Tai; Chen, Mu-Kuan; Huang, Chia-Chun; Huang, Chao-Yuan

    2015-02-01

    The aim of the study was to evaluate the prognostic significance of molecular biomarkers which could provide information for more accurate prognostication and development of novel therapeutic strategies for nasopharyngeal carcinoma (NPC). NPC is a unique malignant epithelial carcinoma of head and neck region, with an intimate association with the Epstein-Barr virus (EBV). Currently, the prediction of NPC prognosis is mainly based on the clinical TNM staging; however, NPC patients with the same clinical stage often present different clinical outcomes, suggesting that the TNM stage is insufficient to precisely predict the prognosis of this disease. In this review, we give an overview of the prognostic value of molecular markers in NPC and discuss potential strategies of targeted therapies for treatment of NPC. Molecular biomarkers, which play roles in abnormal proliferation signaling pathways (such as Wnt/β-catenin pathway), intracellular mitogenic signal aberration (such as hypoxia-inducible factor (HIF)-1α), receptor-mediated aberrations (such as vascular endothelial growth factor (VEGF)), tumor suppressors (such as p16 and p27 activity), cell cycle aberrations (such as cyclin D1 and cyclin E), cell adhesion aberrations (such as E-cadherin), apoptosis dysregualtion (such as survivin) and centromere aberration (centromere protein H), are prognostic markers for NPC. Plasma EBV DNA concentrations and EBV-encoded latent membrane proteins are also prognostic markers for NPC. Implication of molecular targeted therapies in NPC was discussed. Such therapies could have potential in combination with different cytotoxic agents to combat and eradicate tumor cells. In order to further improve overall survival for patients with loco-regionally advanced NPC, the development of innovative strategies, including prognostic molecular markers and molecular targeted agents is needed.

  6. Physical measurements of inertial-fusion targets

    International Nuclear Information System (INIS)

    Weinstein, B.W.

    1981-01-01

    Measurement of inertial-fusion targets has stimulated the development of many new techniques and instruments. This paper reviews the basis for selected target measurement requirements and the development of optical interferometry, optical scattering, microradiography and scanning electron microscopy as applied to target measurement. We summarize the resolution and speed which have been achieved to date, and describe several systems in which these are traded off to fill specific measurement applications. We point out the extent to which present capabilities meet the requirements for target measurement and the key problems which remain to be solved

  7. Overexpression of miR-19b Impairs Cardiac Development in Zebrafish by Targeting ctnnb1

    Directory of Open Access Journals (Sweden)

    Mengmeng Li

    2014-07-01

    Full Text Available Background: MicroRNAs are broadly accepted as crucial regulators of cardiovascular development, and dysregulation of their expression has been linked to cardiac disease. MicroRNA cluster miR-17-92 has been implicated in cardiac development and function, yet its defined mechanisms of action in this context are uncertain. Here, we focused on miR-19b, a key component of the miR-17-92 cluster proven to induce cardiomyocyte proliferation in vitro. We aimed to identify the biological significance of miR-19b in cardiac development and its underlying molecular mechanism of action in vivo. Methods: We micro-injected zebrafish embryos with different concentrations (0, 2, 4 and 8 μm of miR-19b mimics or a negative control, and assessed the embryo malformation rate, mortality rate, hatching rate and heart abnormalities at 72 hours post-fertilization (72 hpf. Results: We found that overexpression of miR-19b impacted left-right symmetry and cardiac development of zebrafish embryos, characterized by pericardial edema, slower heart rate and cardiac looping defects in a dose-dependent manner. Moreover, several important signaling molecules in the Wnt signaling pathway were abnormally expressed, suggesting that overexpression of miR-19b induces the inhibition of the Wnt signaling pathway by directly targeting ctnnb1. Interestingly, the deformed cardiac phenotype was partially rescued by treatment with the GSK3β inhibitor lithium chloride. Conclusion: Our findings suggest that miR-19b regulates laterality development and heart looping in zebrafish embryos by targeting ctnnb1.

  8. Motor development in individuals with congenital adrenal hyperplasia: strength, targeting, and fine motor skill.

    Science.gov (United States)

    Collaer, Marcia L; Brook, Charles G D; Conway, Gerard S; Hindmarsh, Peter C; Hines, Melissa

    2009-02-01

    This study investigated early androgen influence on the development of human motor and visuomotor characteristics. Participants, ages 12-45 years, were individuals with congenital adrenal hyperplasia (CAH), a disorder causing increased adrenal androgen production before birth (40 females, 29 males) and their unaffected relatives (29 females, 30 males). We investigated grip strength and visuomotor targeting tasks on which males generally outperform females, and fine motor pegboard tasks on which females generally outperform males. Physical characteristics (height and weight) were measured to explore whether body parameters could explain differences in motor skills. Females with CAH were stronger and showed better targeting than unaffected females and showed reduced fine visuomotor skill on one pegboard measure, with no difference on the other. Males with CAH were weaker than unaffected males in grip strength but did not differ on the targeting or pegboard measures. Correction for body size could not explain the findings for females, but suggests that the reduced strength of males with CAH may relate to their smaller stature. Further, the targeting advantage in females with CAH persisted following adjustment for their greater strength. Results in females support the hypothesis that androgen may masculinize, or promote, certain motor characteristics at which males excel, and contribute to defeminization of certain fine motor characteristics at which females excel. Thus, these data suggest that organizational effects of androgens on behavior during prenatal life may extend to motor characteristics and may contribute to general sex differences in motor-related behaviors; however, alternative explanations based on activational influences of androgen or altered experiential factors cannot be excluded without further study.

  9. High resolution measurements and study of the neutron inelastic scattering reaction on 56Fe

    International Nuclear Information System (INIS)

    Dupont, E.

    1998-01-01

    High resolution measures of neutrons inelastic scattering cross section, have been performed on 56 Fe from 862 KeV to 3 MeV. The time of flight method has been used on the GELINA source of the IRMM in Geel (Belgium). Four barium fluoride scintillators, placed around the samples, recorded the gamma rays emissions coming from the iron and the boron. A study of the correlations between the partial elastic and inelastic lengths has been performed taking into account first transmission measures realized at Geel. (A.L.B.)

  10. Polarized targets and beams

    International Nuclear Information System (INIS)

    Meyer, W.

    1985-01-01

    First the experimental situation of the single-pion photoproduction and the photodisintegration of the deuteron is briefly discussed. Then a description of the Bonn polarization facilities is given. The point of main effort is put on the polarized target which plays a vital role in the program. A facility for photon induced double polarization experiments at ELSA will be presented in section 4. Properties of a tensor polarized deuteron target are discussed in section 5. The development in the field of polarized targets, especially on new target materials, enables a new generation of polarized target experiments with (polarized) electrons. Some comments on the use of a polarized target in combination with electron beams will be discussed in section 6. Electron deuteron scattering from a tensor polarized deuteron target is considered and compared with other experimental possibilities. (orig./HSI)

  11. Arabidopsis EMB1990 Encoding a Plastid-Targeted YlmG Protein Is Required for Chloroplast Biogenesis and Embryo Development

    Directory of Open Access Journals (Sweden)

    Hongyu Chen

    2018-02-01

    Full Text Available In higher plants, embryo development originated from fertilized egg cell is the first step of the life cycle. The chloroplast participates in many essential metabolic pathways, and its function is highly associated with embryo development. However, the mechanisms and relevant genetic components by which the chloroplast functions in embryogenesis are largely uncharacterized. In this paper, we describe the Arabidopsis EMB1990 gene, encoding a plastid-targeted YlmG protein which is required for chloroplast biogenesis and embryo development. Loss of the EMB1990/YLMG1-1 resulted in albino seeds containing abortive embryos, and the morphological development of homozygous emb1990 embryos was disrupted after the globular stage. Our results showed that EMB1990/YLMG1-1 was expressed in the primordia and adaxial region of cotyledon during embryogenesis, and the encoded protein was targeted to the chloroplast. TEM observation of cellular ultrastructure showed that chloroplast biogenesis was impaired in emb1990 embryo cells. Expression of certain plastid genes was also affected in the loss-of-function mutants, including genes encoding core protein complex subunits located in the thylakoid membrane. Moreover, the tissue-specific genes of embryo development were misexpressed in emb1990 mutant, including genes known to delineate cell fate decisions in the SAM (shoot apical meristem, cotyledon and hypophysis. Taken together, we propose that the nuclear-encoded YLMG1-1 is targeted to the chloroplast and required for normal plastid gene expression. Hence, YLMG1-1 plays a critical role in Arabidopsis embryogenesis through participating in chloroplast biogenesis.

  12. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1996 - September 30, 1997

    International Nuclear Information System (INIS)

    Gibson, J.

    1998-03-01

    This report documents the technical activities of the period October 1, 1996 through September 30, 1997. During this period, GA and their partner Schafer Corporation were assigned 13 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct open-quotes Onsite Supportclose quotes at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). Over 700 gold-plated hohlraum mandrels were fabricated and delivered to LLNL, LANL and SNLA. More than 1600 glass and plastic target capsules were produced for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). Nearly 2000 various target foils and films were delivered for Naval Research Lab (NRL) and UR/LLE in FY97. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. This project is part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. During FY97, significant progress was made in the design and component testing of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA. This included major design changes, reduction in equipment, and process simplifications. This report summarizes and documents the technical progress made on these tasks

  13. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1996--September 30, 1997

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, J. [ed.

    1998-03-01

    This report documents the technical activities of the period October 1, 1996 through September 30, 1997. During this period, GA and their partner Schafer Corporation were assigned 13 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct {open_quotes}Onsite Support{close_quotes} at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). Over 700 gold-plated hohlraum mandrels were fabricated and delivered to LLNL, LANL and SNLA. More than 1600 glass and plastic target capsules were produced for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). Nearly 2000 various target foils and films were delivered for Naval Research Lab (NRL) and UR/LLE in FY97. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D{sub 2} or deuterium-tritium (DT) fuel. This project is part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. During FY97, significant progress was made in the design and component testing of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA. This included major design changes, reduction in equipment, and process simplifications. This report summarizes and documents the technical progress made on these tasks.

  14. One target, different effects: a comparison of distinct therapeutic antibodies against the same targets.

    Science.gov (United States)

    Shim, Hyunbo

    2011-10-31

    To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-α, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

  15. The development of uranium foil farication technology utilizing twin roll method for Mo-99 irradiation target

    CERN Document Server

    Kim, C K; Park, H D

    2002-01-01

    MDS Nordion in Canada, occupying about 75% of global supply of Mo-99 isotope, has provided the irradiation target of Mo-99 using the rod-type UAl sub x alloys with HEU(High Enrichment Uranium). ANL (Argonne National Laboratory) through co-operation with BATAN in Indonesia, leading RERTR (Reduced Enrichment for Research and Test Reactors) program substantially for nuclear non-proliferation, has designed and fabricated the annular cylinder of uranium targets, and successfully performed irradiation test, in order to develop the fabrication technology of fission Mo-99 using LEU(Low Enrichment Uranium). As the uranium foils could be fabricated in laboratory scale, not in commercialized scale by hot rolling method due to significant problems in foil quality, productivity and economic efficiency, attention has shifted to the development of new technology. Under these circumstances, the invention of uranium foil fabrication technology utilizing twin-roll casting method in KAERI is found to be able to fabricate LEU or...

  16. Mast Cell Targeted Chimeric Toxin Can Be Developed as an Adjunctive Therapy in Colon Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Shan Wang

    2016-03-01

    Full Text Available The association of colitis with colorectal cancer has become increasingly clear with mast cells being identified as important inflammatory cells in the process. In view of the relationship between mast cells and cancer, we studied the effect and mechanisms of mast cells in the development of colon cancer. Functional and mechanistic insights were gained from ex vivo and in vivo studies of cell interactions between mast cells and CT26 cells. Further evidence was reversely obtained in studies of mast cell targeted Fcε-PE40 chimeric toxin. Experiments revealed mast cells could induce colon tumor cell proliferation and invasion. Cancer progression was found to be related to the density of mast cells in colonic submucosa. The activation of MAPK, Rho-GTPase, and STAT pathways in colon cancer cells was triggered by mast cells during cell-to-cell interaction. Lastly, using an Fcε-PE40 chimeric toxin we constructed, we confirmed the promoting effect of mast cells in development of colon cancer. Mast cells are a promoting factor of colon cancer and thus also a potential therapeutic target. The Fcε-PE40 chimeric toxin targeting mast cells could effectively prevent colon cancer in vitro and in vivo. Consequently, these data may demonstrate a novel immunotherapeutic approach for the treatment of tumors.

  17. Development of a NiO target for the production of {sup 11}C at ISAC/TRIUMF

    Energy Technology Data Exchange (ETDEWEB)

    Bricault, Pierre G.; Ames, Friedhelm; Dombsky, Marik; Kunz, Peter; Lassen, Jens; Mjøs, Anders; Wong, John

    2016-01-01

    High intensity {sup 11}C beams are necessary for the investigation of the formation of {sup 12}C via the nuclear reaction {sup 11}C(p, γ){sup 12}N → {sup 12}C + e{sup +} + ν. The production of intense carbon beams on-line is quite challenging due to the thermodynamic properties and chemical reactivity of carbon at high temperatures. A previous attempt, using a medical isotope cyclotron production method in batch mode, was not conclusive. The intensity obtained was at least one order of magnitude too low for a direct proton capture experiment using the DRAGON facility at ISAC/TRIUMF. Producing a {sup 11}C beams using the ISOL method requires a target capable of efficiently releasing the carbon isotopes. NiO has been selected as a target material because most of the nickel carbides are not stable at high temperature. The development of carbon beams using a composite NiO/Ni target on-line is described.

  18. More than just openness: developing and validating a measure of targeted parent-child communication about alcohol.

    Science.gov (United States)

    Miller-Day, Michelle; Kam, Jennifer A

    2010-06-01

    Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication-targeted parent-child communication about alcohol-and comparing the efficacy of targeted parent-child communication about alcohol in predicting positive expectancies of alcohol use and recent alcohol use. The predictive power of general openness in parent-child communication and frequency of communication about alcohol also were assessed. Students in fifth and sixth grade (N = 1,407) from 29 public schools completed surveys. Targeted parent-child communication about alcohol was negatively associated with both outcomes. Frequency and general openness were only negatively associated with positive expectancies regarding alcohol. Implications of these findings for the etiology and prevention of substance use are discussed.

  19. Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA-transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy.

    Science.gov (United States)

    Hung, Chien-Fu; Xu, Xuequn; Li, Linhong; Ma, Ying; Jin, Qiu; Viley, Angelia; Allen, Cornell; Natarajan, Pachai; Shivakumar, Rama; Peshwa, Madhusudan V; Emens, Leisha A

    2018-04-02

    CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to "on-target off-tumor" toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK cells may permit prospective control of "on-target off-tumor" toxicity. To develop a commercial product for solid tumors, mesothelin was selected as an antigen target based on its association with poor prognosis and overexpression in multiple solid cancers. It was hypothesized that selecting, activating, and expanding cells ex vivo prior to mRNA CAR transfection would not be necessary, thus simplifying the complexity and cost of manufacturing. Now, the development of anti-human mesothelin mRNA CAR transfected peripheral blood lymphocytes (CARMA-hMeso) is reported, demonstrating the manufacture and cryopreservation of multiple cell aliquots for repeat administrations from a single human leukapheresis. A rapid, automated, closed system for cGMP-compliant transfection of mRNA CAR in up to 20 × 10 9 peripheral blood lymphocytes was developed. Here we show that CARMA-hMeso cells recognize and lyse tumor cells in a mesothelin-specific manner. Expression of CAR was detectable over approximately 7 days in vitro, with a progressive decline of CAR expression that appears to correlate with in vitro cell expansion. In a murine ovarian cancer model, a single intraperitoneal injection of CARMA-hMeso resulted in the dose-dependent inhibition of tumor growth and improved survival of mice. Furthermore, repeat weekly intraperitoneal administrations of the optimal CARMA-hMeso dose further prolonged disease control and survival

  20. Simultaneous quantification of tumor uptake for targeted and non-targeted liposomes and their encapsulated contents by ICP-MS

    Science.gov (United States)

    Cheng, Zhiliang; Zaki, Ajlan Al; Hui, James Z; Tsourkas, Andrew

    2012-01-01

    Liposomes are intensively being developed for biomedical applications including drug and gene delivery. However, targeted liposomal delivery in cancer treatment is a very complicated multi-step process. Unfavorable liposome biodistribution upon intravenous administration and membrane destabilization in blood circulation could result in only a very small fraction of cargo reaching the tumors. It would therefore be desirable to develop new quantitative strategies to track liposomal delivery systems to improve the therapeutic index and decrease systemic toxicity. Here, we developed a simple and non-radiative method to quantify the tumor uptake of targeted and non-targeted control liposomes as well as their encapsulated contents simultaneously. Specifically, four different chelated lanthanide metals were encapsulated or surface-conjugated onto tumor-targeted and non-targeted liposomes, respectively. The two liposome formulations were then injected into tumor-bearing mice simultaneously and their tumor delivery was determined quantitatively via inductively coupled plasma-mass spectroscopy (ICP-MS), allowing for direct comparisons. Tumor uptake of the liposomes themselves and their encapsulated contents were consistent with targeted and non-targeted liposome formulations that were injected individually. PMID:22882145

  1. Must developing countries commit quantified targets? Time flexibility and equity in climate change mitigation

    International Nuclear Information System (INIS)

    Sugiyama, Taishi; Deshun, Liu

    2004-01-01

    Equity and efficiency dimensions of global time flexibility in GHG emission reduction are analyzed with an integrated assessment model. Global time flexibility is justifiable to some extent as found in previous studies by Wigley et al. Nevertheless, it does not necessarily serve as a rationale to delay emission reduction commitment and efforts of developed countries as they suggested. The time flexibility can be saved for developing countries, and it must be so in equity consideration; early reduction by developed countries eases burden of developing countries in both time and emission quantity dimensions. This equity-oriented argument is robust against time and spatial efficiency consideration, since the apparent benefits that might accrue to developed countries from delaying reductions will by no means be transferred to far distant future developing countries for mitigation of and adaptation to climate change. The analysis thus support entry into force of the Kyoto Protocol without participation of key low income developing countries such as China and India with legally binding quantified targets in the First Commitment Period from 2008 to 2012

  2. How can China reach its CO2 intensity reduction targets by 2020? A regional allocation based on equity and development

    International Nuclear Information System (INIS)

    Yi Wenjing; Zou Lele; Guo Jie; Wang Kai; Wei Yiming

    2011-01-01

    In late 2009, the Chinese government committed to cut its carbon dioxide emissions per unit of gross domestic product (GDP) by 40% to 45% of 2005 levels by 2020. This has raised the issue of how to allocate the CO 2 reduction target regionally to meet the national reduction target. To meet this objective, the following aspects may be taken into consideration: equity principles, 'common but differentiated responsibilities'; intensity reduction target fulfillment; and economic difference and reduction potential among provinces. This paper selects per capita GDP, accumulated fossil fuel related CO 2 emissions and energy consumption per unit of industrial added value as indicators for emission reduction capacity, responsibility and potential, respectively. Based on these three indicators, a comprehensive index is developed and an intensity allocation model constructed. As decision makers may have different preferences when allocating the reduction burden, we allocate different weights to the indicators, analyzing the results using cluster analysis. The following aspects may also be considered together with the national regional development strategy to determine how to share the burden: the reduction potential of various regions; implementation potential of the plans; and promotion of a highly efficient low carbon economic development model. - Research highlights: → We compiled a comprehensive index using per capita GDP, accumulated fossil fuel related CO 2 emissions and energy consumption per unit of industrial added value as indicators for emission reduction capacity, responsibility and potential, respectively. → National CO 2 intensity reduction target is allocated according to different index values of provinces. → Equity principles were taken into account when allocating the target.

  3. Development of a Near-Field Bistatic Synthetic Aperture Radar for Complex Target Reconstruction

    Directory of Open Access Journals (Sweden)

    David G. Johnson

    2012-01-01

    Full Text Available This paper begins with a description of the design, construction, and characterization of a small electromagnetic anechoic chamber, developed specifically to house a bistatic ISAR system for the analysis of rock samples. Particular emphasis is given to the practicalities of construction, with the intention of assisting those in a similar position, wishing to build an anechoic chamber on a tight budget. The second part of the paper outlines efficient algorithms that may be applied to the tomographic and topographic reconstruction of complex targets within the viewing geometry of this ISAR system.

  4. Development of Na/sup 123/I pharmaceutical from antimony target

    Energy Technology Data Exchange (ETDEWEB)

    Yongjian, L.; Qixun, S.; Dequn, S. (Shanghai Inst. of Nuclear Research, Academia Sinica, Shanghai (China))

    A new method for the production of Na/sup 123/I is described. It is produced by the /sup 121/Sb(..cap alpha..,2n)/sup 123/I nuclear reaction and using a natural antimony target prepared by electroplating in a bath of antimony oxide and hydrofluoric acid. The target is irradiated with 32MeV ..cap alpha..-beams then transferred to a dry distillation apparatus and the iodide evolved and absorbed in NaOH. Quality control is by paper chromatography.

  5. Development of fisetin-loaded folate functionalized pluronic micelles for breast cancer targeting.

    Science.gov (United States)

    Pawar, Atmaram; Singh, Srishti; Rajalakshmi, S; Shaikh, Karimunnisa; Bothiraja, C

    2018-01-15

    The natural flavonoid fisetin (FS) has shown anticancer properties but its in-vivo administration remains challenging due to its poor aqueous solubility. The aim of the study was to develop FS loaded pluronic127 (PF)-folic acid (FA) conjugated micelles (FS-PF-FA) by the way of increasing solubility, bioavailability and active targetability of FS shall increase its therapeutic efficacy. FA-conjugated PF was prepared by carbodiimide crosslinker chemistry. FS-PF-FA micelles were prepared by thin-film hydration method and evaluated in comparison with free FS and FS loaded PF micelles (FS-PF). The smooth surfaces with spherical in shape of FS-PF-PF micelles displayed smaller in size (103.2 ± 6.1 nm), good encapsulation efficiency (82.50 ± 1.78%), zeta potential (-26.7 ± 0.44 mV) and sustained FS release. Bioavailability of FS from FS-PF-PF micelles was increased by 6-fold with long circulation time, slower plasma elimination and no sign of tissue toxicity as compared to free FS. Further, the FS-PF-FA micelles demonstrated active targeting effect on folate overexpressed human breast cancer MCF-7 cells. The concentration of the drug needed for growth inhibition of 50% of cells in a designed time period (GI50) was 14.3 ± 1.2 µg/ml for FS while it was greatly decreased to 9.8 ± 0.78 µg/ml, i.e. a 31.46% decrease for the FS-PF. Furthermore, the GI50 value for FS-PF-FA was 4.9 ± 0.4 µg/ml, i.e. a 65.737% decrease compared to FS and 50% decrease compare to FS-PF. The results indicate that the FS-PF-FA micelles have the potential to be applied for targeting anticancer drug delivery.

  6. Development of AN Active 238UF6 Gas Target

    Science.gov (United States)

    Eckardt, C.; Enders, J.; Freudenberger, M.; Göök, A.; von Neumann-Cosel, P.; Oberstedt, A.; Oberstedt, S.

    2014-09-01

    Detailed studies of the fission process, e.g., the search for parity nonconservation (PNC) effects, the energy dependence of fission modes or the population of fission isomers, depend on high quality data, therefore requiring high luminosities. An active gas target containing uranium may overcome the deterioration of energy and angular resolution caused by large solid target thicknesses. A single Frisch-grid ionization chamber has been built to test a mixture of standard counting gases (e.g., argon) with depleted uranium hexafluoride (238UF6), utilizing a triple alpha source to evaluate signal quality and drift velocity. For mass fractions of up to 4 percent of 238U the drift velocity increases with rising UF6 content, while a good signal quality and energy resolution is preserved.

  7. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/.

  8. A role for fragment-based drug design in developing novel lead compounds for central nervous system targets

    Directory of Open Access Journals (Sweden)

    Michael J. Wasko

    2015-09-01

    Full Text Available Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacologic screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening, which employs computer models of the target protein to narrow the search for possible leads. A variant of virtual screening is fragment-based drug design, an emerging in silico lead discovery method that introduces low molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for growing the lead candidate. Current efforts in virtual fragment-based drug design within central nervous system (CNS targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor binding pocket using the fragment as a scaffold. This process places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies.

  9. A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets.

    Science.gov (United States)

    Wasko, Michael J; Pellegrene, Kendy A; Madura, Jeffry D; Surratt, Christopher K

    2015-01-01

    Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), an emerging in silico lead discovery method that introduces low-molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for "growing" the lead candidate. Current efforts in virtual FBDD within central nervous system (CNS) targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor-binding pocket using the fragment as a scaffold. This process not only places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies.

  10. Polymeric micelles for drug targeting.

    Science.gov (United States)

    Mahmud, Abdullah; Xiong, Xiao-Bing; Aliabadi, Hamidreza Montazeri; Lavasanifar, Afsaneh

    2007-11-01

    Polymeric micelles are nano-delivery systems formed through self-assembly of amphiphilic block copolymers in an aqueous environment. The nanoscopic dimension, stealth properties induced by the hydrophilic polymeric brush on the micellar surface, capacity for stabilized encapsulation of hydrophobic drugs offered by the hydrophobic and rigid micellar core, and finally a possibility for the chemical manipulation of the core/shell structure have made polymeric micelles one of the most promising carriers for drug targeting. To date, three generations of polymeric micellar delivery systems, i.e. polymeric micelles for passive, active and multifunctional drug targeting, have arisen from research efforts, with each subsequent generation displaying greater specificity for the diseased tissue and/or targeting efficiency. The present manuscript aims to review the research efforts made for the development of each generation and provide an assessment on the overall success of polymeric micellar delivery system in drug targeting. The emphasis is placed on the design and development of ligand modified, stimuli responsive and multifunctional polymeric micelles for drug targeting.

  11. EFTTRA, a European collaboration for the development of fuels and targets for the transmutation

    International Nuclear Information System (INIS)

    Babelot, J.F.; Muehling, G.; Prunier, C.; Rome, M.

    1994-12-01

    In the frame of the research programmes on the transmutation of long lived nuclides, many experimental or theoretical investigations have to be carried out within European collaborations, owing mainly to the costs of such studies. Therefore, a group named 'Experimental Feasibility of Targets for Transmutation' (EFTTRA), has been formed, with participants from CEA (France). ECN (The Netherlands), EDF (France), KFK (Germany) and ITU (European Commission), to organise joint experiments for the study of materials for the transmutation. So far, it was decided to focus the work on the transmutation of 99 Tc (metal), of 129 I (compound), and of Am (in an inert matrix). Irradiations will take place in parallel in the Phenix fast reactor in France, and in the high flux thermal reactor HFR in the Netherlands. These experiments, together with the related post-irradiation examinations, constitute the first phase of the EFTTRA collaboration. In subsequent phases, EFTTRA will contribute to the development of fuels and targets. (orig.)

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

    Science.gov (United States)

    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.

  13. A blow-in windowless gas target

    International Nuclear Information System (INIS)

    Sagara, K.; Motoshima, A.; Fujita, T.; Akiyoshi, H.; Nishimori, N.

    1996-01-01

    A new-type windowless gas target has been developed to realize a dense target with a low gas flow rate. The target is similar to the conventional differentially pumped windowless gas target except that the target gas is blown into the target region from both the side holes of the beam entrance and exit. Due to the gas-confining action caused by the blown-in gas, the target thickness is about twice increased and the target density sharply falls in the holes. Most of the target gas is at rest and the density is uniform. The gas flow rate is the same as that of the conventional target and is about an order of magnitude lower than that of the dense gas-jet target. (orig.)

  14. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    Feng Jiang

    2015-10-01

    Full Text Available Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX, are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

  15. Developments of 207Pb, 208Pb and 209Bi target wheels in the synthesis of 107Ns, 108Hs and 109Mt

    International Nuclear Information System (INIS)

    Folger, H.; Hartmann, W.; Hessberger, F.P.; Hofmann, S.; Klemm, J.; Muenzenberg, G.; Ninov, V.; Schmidt, K.H.; Schoett, H.J.; Thalheimer, W.; Armbruster, P.

    1993-05-01

    The developments of 207 Pb, 208 Pb and 209 Bi target wheels and their applications in heavy-ion fusion reactions are reviewed. In both, fabrication and use, the centers of the evaporator or accelerator beams are focussed at wheel radii of 155 mm to specially shaped frames which generate very homogeneous target layers and very constant reaction and counting rates in the experiment. Target areas of up to ∼98% of a wheel's circumference of 974 mm can be provided. The preparation procedures for necessary C backings and protecting layers of C are described, and details are given for the developments of high-vacuum evaporations of 207 Pb, 208 Pb and 209 Bi with deposition yields of 35-55% from tantalum crucibles. The applications of the target wheels in heavy-ion fusion reactions with beams of 54 Cr and 58 Fe at energies near the Coulomb barrier and intensities of ∼10 12 particles/s are mentioned. The target parameters for the production runs of the new chemical elements 107 Ns, 108 Hs and 109 Mt are included. (orig.)

  16. Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

    Directory of Open Access Journals (Sweden)

    Sara L White

    Full Text Available All obese women are categorised as being of equally high risk of gestational diabetes (GDM whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337 developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria. A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios provided an area under the curve of 0.71 (95%CI 0.68-0.74. This increased to 0.77 (95%CI 0.73-0.80 with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c, fructosamine, adiponectin, sex hormone binding globulin, triglycerides, but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81. Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described

  17. Development of an odour-baited insecticidal target system for the suppression of adults of the new world screwworm fly

    International Nuclear Information System (INIS)

    Allsopp, R.

    1992-02-01

    To provide a rapidly deployable supplemental means of effectively suppressing screwworms, the parameters needed to develop an odour-baited insecticidal target system were established. Electro-antennograph studies indicated the relative attractancy of swormlure component, identified candidate attractants and established that 4-methyl phenol and dimethyl sulphide more strongly attract male than female flies. Wind tunnel studies showed that the swormlure stimulates upwind flight and prolonged searching. By means of electric nets it was shown that screwworms fly directly to the target and land without circling. Black is the most effective colour for targets. The optimal size of the target was not identified, but those of 0.25 m 2 were found to be as effective as much larger ones. Targets are effective only when baited with swormlure. Excellent control of the rate of release of the attractant mixture was achieved by placing it in 120 micron thick polyethylene sachets with the exception that dimethyl disulphide must be dispensed separately form 1 mm thick polyethylene sachets. Of the insecticides tested when applied to black cloth targets, deltamethrin proved to be the most effective. Refs, figs and tabs

  18. Target for production of X-rays

    Energy Technology Data Exchange (ETDEWEB)

    Korenev, S.A. E-mail: sergey_korenev@steris.com

    2004-10-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented.

  19. Target for production of X-rays

    International Nuclear Information System (INIS)

    Korenev, S.A.

    2004-01-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented

  20. Target for production of X-rays

    Science.gov (United States)

    Korenev, S. A.

    2004-09-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented.

  1. Neutral Beam Source and Target Plasma for Development of a Local Electric Field Fluctuation Diagnostic

    Science.gov (United States)

    Bakken, M. R.; Burke, M. G.; Fonck, R. J.; Lewicki, B. T.; Rhodes, A. T.; Winz, G. R.

    2016-10-01

    A new diagnostic measuring local E-> (r , t) fluctuations is being developed for plasma turbulence studies in tokamaks. This is accomplished by measuring fluctuations in the separation of the π components in the Hα motional Stark spectrum. Fluctuations in this separation are expected to be Ẽ / ẼEMSE 10-3EMSE 10-3 . In addition to a high throughput, high speed spectrometer, the project requires a low divergence (Ω 0 .5°) , 80 keV, 2.5 A H0 beam and a target plasma test stand. The beam employs a washer-stack arc ion source to achieve a high species fraction at full energy. Laboratory tests of the ion source demonstrate repeatable plasmas with Te 10 eV and ne 1.6 ×1017 m-3, sufficient for the beam ion optics requirements. Te and ne scalings of the ion source plasma are presented with respect to operational parameters. A novel three-phase resonant converter power supply will provide 6 mA/cm2 of 80 keV H0 at the focal plane for pulse lengths up to 15 ms, with low ripple δV / 80 keV 0.05 % at 280 kHz. Diagnostic development and validation tests will be performed on a magnetized plasma test stand with 0.5 T field. The test chamber will utilize a washer-stack arc source to produce a target plasma comparable to edge tokamak plasmas. A bias-plate with programmable power supply will be used to impose Ẽ within the target plasma. Work supported by US DOE Grant DE-FG02-89ER53296.

  2. Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella

    NARCIS (Netherlands)

    Mengesha, Asferd; Dubois, Ludwig; Lambin, Philippe; Landuyt, Willy; Chiu, Roland K; Wouters, Bradly G; Theys, Jan

    To increase the potential of attenuated Salmonella as gene delivery vectors for cancer treatment, we developed a hypoxia-inducible promoter system to limit gene expression specifically to the tumor. This approach is envisaged to not only increase tumor specificity, but also to target those cells

  3. Properties of Protein Drug Target Classes

    Science.gov (United States)

    Bull, Simon C.; Doig, Andrew J.

    2015-01-01

    Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID

  4. Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

    Science.gov (United States)

    Burt, T; MacLeod, D; Lee, K; Santoro, A; DeMasi, D K; Hawk, T; Feinglos, M; Rowland, M; Noveck, R J

    2017-09-01

    Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  5. Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Eduardo Laborda

    2017-10-01

    Full Text Available The treatment of patients with acute myeloid leukemia (AML with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR-engineered T-cells (CAR-T-cells, a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs, and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.

  6. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1994--September 30, 1995

    International Nuclear Information System (INIS)

    Hoppe, M.

    1996-05-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities of the period October 1, 1994 through September 30, 1995. During this period, GA was assigned 15 tasks in support of the Inertial Confinement Fusion program and its laboratories. A portion of the effort on these tasks included providing direct ''Onsite Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). The ICF program is anticipating experiments at the National Ignition Facility (NIF) and the OMEGA Upgrade. Both facilities will require capsules containing layered D 2 or deuterium-tritium (D-T) fuel. The authors are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Progress has been made on ways to both create viable layers and to characterize them. They continued engineering, assembly and testing of equipment for a cryogenic target handling system for University of Rochester's Laboratory for Laser Energetics (UR/LLE) that will fill, transport, layer, and characterize targets filled with cryogenic fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments. This report summarizes and documents the technical progress made on these tasks

  7. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1994--September 30, 1995

    Energy Technology Data Exchange (ETDEWEB)

    Hoppe, M. [ed.

    1996-05-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities of the period October 1, 1994 through September 30, 1995. During this period, GA was assigned 15 tasks in support of the Inertial Confinement Fusion program and its laboratories. A portion of the effort on these tasks included providing direct ``Onsite Support`` at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). The ICF program is anticipating experiments at the National Ignition Facility (NIF) and the OMEGA Upgrade. Both facilities will require capsules containing layered D{sub 2} or deuterium-tritium (D-T) fuel. The authors are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Progress has been made on ways to both create viable layers and to characterize them. They continued engineering, assembly and testing of equipment for a cryogenic target handling system for University of Rochester`s Laboratory for Laser Energetics (UR/LLE) that will fill, transport, layer, and characterize targets filled with cryogenic fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments. This report summarizes and documents the technical progress made on these tasks.

  8. Variation in psychosocial influences according to the dimensions and content of children's unusual experiences: potential routes for the development of targeted interventions.

    Science.gov (United States)

    Ruffell, Tamatha; Azis, Matilda; Hassanali, Nedah; Ames, Catherine; Browning, Sophie; Bracegirdle, Karen; Corrigall, Richard; Laurens, Kristin R; Hirsch, Colette; Kuipers, Elizabeth; Maddox, Lucy; Jolley, Suzanne

    2016-03-01

    The psychosocial processes implicated in the development and maintenance of psychosis differ according to both the dimensional attributes (conviction, frequency, associated distress, adverse life impact) and the content or type (e.g. grandiosity, hallucinations, paranoia) of the psychotic symptoms experienced. This has informed the development of 'targeted' cognitive behavioural therapy for psychosis (CBTp): interventions focusing on specific psychological processes in the context of particular symptom presentations. In adults, larger effect sizes for change in primary outcomes are typically reported in trials of targeted interventions, compared to those for trials of generic CBTp approaches with multiple therapeutic foci. We set out to test the theoretical basis for developing targeted CBTp interventions for young people with distressing psychotic-like, or unusual, experiences (UEs). We investigated variations in the psychosocial processes previously associated with self-reported UE severity (reasoning, negative life events, emotional problems) according to UE dimensional attributes and content/type (using an established five-factor model) in a clinically referred sample of 72 young people aged 8-14 years. Regression analyses revealed associations of conviction and grandiosity with reasoning; of frequency, and hallucinations and paranoia, with negative life events; and of distress/adverse life impact, and paranoia and hallucinations, with emotional problems. We conclude that psychological targets for intervention differ according to particular characteristics of childhood UEs in much the same way as for psychotic symptoms in adults. The development of targeted interventions is therefore indicated, and tailoring therapy according to presentation should further improve clinical outcomes for these young people.

  9. Vascular targeting with peptide libraries

    Energy Technology Data Exchange (ETDEWEB)

    Pasqualini, R. [La Jolla Cancer Research Center The Burnham Inst., La Jolla CA (United States)

    1999-06-01

    The authors have developed an 'in vivo' selection system in which phage capable of selective homing to different tissues are recovered from a phage display peptide library following intravenous administration. Using this strategy, they have isolate several organ and tumor-homing peptides. They have shown that each of those peptides binds of different receptors that are selectively expressed on the vasculature of the target tissue. The tumor-homing peptides bind to receptors that are up regulated in tumor angiogenic vasculature. Targeted delivery of doxorubicin to angiogenic vasculature using these peptides in animals models decrease toxicity and increased the therapeutic efficacy of the drug. Vascular targeting may facilitate the development of other treatment strategies that rely on inhibition of angio genesis and lead to advances to extend the potential for targeting of drugs, genes and radionuclides in the context of many diseases.

  10. Turmeric (Curcuma longa): miRNAs and their regulating targets are involved in development and secondary metabolite pathways.

    Science.gov (United States)

    Singh, Noopur; Sharma, Ashok

    Turmeric has been used as a therapeutic herb over centuries in traditional medicinal systems due to the presence of several secondary metabolite compounds. microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression. miRNAs have been demonstrated to play an active role in secondary metabolism regulation. The present work was focused on the identification of the miRNAs involved in the regulation of secondary metabolite and development process of turmeric. Eighteen miRNA families were identified for turmeric. Sixteen miRNA families were observed to regulate 238 target transcripts. LncRNAs targets of the putative miRNA candidates were also predicted. Our results indicated their role in binding, reproduction, stress, and other developmental processes. Gene annotation and pathway analysis illustrated the biological function of the targets regulated by the putative miRNAs. The miRNA-mediated gene regulatory network also revealed co-regulated targets that were regulated by two or more miRNA families. miR156 and miR5015 were observed to be involved in rhizome development. miR5021 showed regulation for terpenoid backbone biosynthesis and isoquinoline alkaloid biosynthesis pathways. The flavonoid biosynthesis pathway was observed to be regulated by miR2919. The analysis revealed the probable involvement of three miRNAs (miR1168.2, miR156b and miR1858) in curcumin biosynthesis. Other miRNAs were found to be involved in the growth and developmental process of turmeric. Phylogenetic analysis of selective miRNAs was also performed. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

  11. A false-alarm aware methodology to develop robust and efficient multi-scale infrared small target detection algorithm

    Science.gov (United States)

    Moradi, Saed; Moallem, Payman; Sabahi, Mohamad Farzan

    2018-03-01

    False alarm rate and detection rate are still two contradictory metrics for infrared small target detection in an infrared search and track system (IRST), despite the development of new detection algorithms. In certain circumstances, not detecting true targets is more tolerable than detecting false items as true targets. Hence, considering background clutter and detector noise as the sources of the false alarm in an IRST system, in this paper, a false alarm aware methodology is presented to reduce false alarm rate while the detection rate remains undegraded. To this end, advantages and disadvantages of each detection algorithm are investigated and the sources of the false alarms are determined. Two target detection algorithms having independent false alarm sources are chosen in a way that the disadvantages of the one algorithm can be compensated by the advantages of the other one. In this work, multi-scale average absolute gray difference (AAGD) and Laplacian of point spread function (LoPSF) are utilized as the cornerstones of the desired algorithm of the proposed methodology. After presenting a conceptual model for the desired algorithm, it is implemented through the most straightforward mechanism. The desired algorithm effectively suppresses background clutter and eliminates detector noise. Also, since the input images are processed through just four different scales, the desired algorithm has good capability for real-time implementation. Simulation results in term of signal to clutter ratio and background suppression factor on real and simulated images prove the effectiveness and the performance of the proposed methodology. Since the desired algorithm was developed based on independent false alarm sources, our proposed methodology is expandable to any pair of detection algorithms which have different false alarm sources.

  12. MicroRNA-275 and its target Vitellogenin-2 are crucial in ovary development and blood digestion of Haemaphysalis longicornis.

    Science.gov (United States)

    Hao, Jiawei; Luo, Jin; Chen, Ze; Ren, Qiaoyun; Guo, Jinxia; Liu, Xiaocui; Chen, Qiuyu; Wu, Feng; Wang, Zhen; Luo, Jianxun; Yin, Hong; Wang, Hui; Liu, Guangyuan

    2017-05-22

    The hard tick Haemaphysalis longicornis is widely distributed in eastern Asia, New Zealand and Australia and is considered the major vector of Theileria and Babesia, harmful parasites to humans and animals. Female ticks need successful blood meals to complete the life-cycle. Therefore, elucidation of the underlying molecular mechanisms of H. longicornis development and reproduction is considered important for developing control strategies against the tick and tick-borne pathogens. Luciferase assays were used to identify the targets of micro RNA miR-275 in vitro. RNAi of Vitellogenin (Vg) was used in phenotype rescue experiments of ticks with miR-275 inhibition, and these analyses were used to identify the authentic target of miR-275 in vivo. The expression of miR-275 in different tissues and developmental stages of ticks was assessed by real-time PCR. To elucidate the functions of miR-275 in female ticks, we injected a miR-275 antagomir into female ticks and observed the phenotypic changes. Statistical analyses were performed with GraphPad5 using Student's t-test. In this study, we identified Vg-2 as an authentic target of miR-275 both in vitro and in vivo by luciferase assays and phenotype rescue experiments. miR-275 plays the regulatory role in a tissue-specific manner and differentially in developmental stages. Silencing of miR-275 resulted in blood digestion problems, substantially impaired ovary development and significantly reduced egg mass (P development. These findings improve the molecular understanding of tick development and reproduction.

  13. New type of metal targets

    International Nuclear Information System (INIS)

    Bukharov, A.V.; Ankudinov, V.B.; Ogorodnikov, V.P.; Marukhin, Y.A.

    2014-01-01

    Now the technologies based on interaction of high-intensity beams with substance of a target are being intensively developed. As a target it is possible to use the new type of monodisperse metal targets. The principal advantages of new targets type are: target cooling isn't required; there is no induced activity: the target can be used many times; small dispersion on the speed, the size and interaction points with a beam. The basis of a target is the jet of molten metal, following in the vacuum chamber .Under the influence of the special disturbance superimposed on the liquid jet, the jet disintegrated into identical drops. In the vacuum chamber the drops freeze and form into the solid granules. It is possible to receive monodisperse targets from different metals, alloys and salts (diameter of targets is from 30 .m to 1.5 mm). Dispersion by the sizes and speed is less than 1%. The technique allows to receive not only continuous targets, but also hollow targets with dispersion on thickness of wall within 1...2%.

  14. Development of whole-building energy design targets for commercial buildings: Phase 1, Planning: Volume 1, Final report

    Energy Technology Data Exchange (ETDEWEB)

    Crawley, D.B.; Briggs, R.S.; Jones, J.W.; Seaton, W.W.; Kaufman, J.E.; Deringer, J.J.; Kennett, E.W.

    1987-04-01

    This report describes background research for preparation of a plan for development of whole-building energy targets for new commercial buildings. The lead laboratory for this program is the Pacific Northwest Laboratory. A wide variety of expertise and resources from industry, academia, other government entities, and other DOE laboratories are used in planning, reviewing and conducting research activities. Cooperative and complementary research development, and technology transfer activities with other interested organizations are actively pursued.

  15. A New Development in Audiovisual Translation Studies: Focus on Target Audience Perception

    Directory of Open Access Journals (Sweden)

    John Denton

    2013-03-01

    Full Text Available Audiovisual translation is now a well-established sub-discipline of Translation Studies (TS: a position that it has reached over the last twenty years or so. Italian scholars and professionals in the field have made a substantial contribution to this successful development, a brief overview of which will be given in the first part of this article, inevitably concentrating on dubbing in the Italian context. Special attention will be devoted to the question of target audience perception, an area where researchers in the University of Bologna at Forlì have excelled. The second part of the article applies the methodology followed by the above mentioned researchers in a case study of how Italian end users perceive the dubbed version of the British film The History Boys (2006, which contains a plethora of culture-specific verbal and visual references to the English education system. The aim of the study was to ascertain: a whether translation/adaptation allows the transmission in this admittedly constrained medium of all the intended culture-bound issues, only too well known to the source audience, and, if so, to what extent, and b whether the target audience respondents to the e-questionnaire used were aware that they were missing information. The linked, albeit controversial, issue of quality assessment will also be addressed.

  16. 40 CFR 35.9020 - Planning targets.

    Science.gov (United States)

    2010-07-01

    ... STATE AND LOCAL ASSISTANCE Financial Assistance for the National Estuary Program § 35.9020 Planning targets. The EPA Assistant Administrator for Water develops planning targets each year to help each... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Planning targets. 35.9020 Section 35...

  17. Drug target identification in protozoan parasites.

    Science.gov (United States)

    Müller, Joachim; Hemphill, Andrew

    2016-08-01

    Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

  18. Development, evaluation, and application of sediment quality targets for assessing and managing contaminated sediments in Tampa Bay, Florida

    Science.gov (United States)

    MacDonald, D.D.; Carr, R.S.; Eckenrod, D.; Greening, H.; Grabe, S.; Ingersoll, C.G.; Janicki, S.; Janicki, T.; Lindskoog, R.A.; Long, E.R.; Pribble, R.; Sloane, G.; Smorong, D.E.

    2004-01-01

    Tampa Bay is a large, urban estuary that is located in west central Florida. Although water quality conditions represent an important concern in this estuary, information from numerous sources indicates that sediment contamination also has the potential to adversely affect aquatic organisms, aquatic-dependent wildlife, and human health. As such, protecting relatively uncontaminated areas of the bay from contamination and reducing the amount of toxic chemicals in contaminated sediments have been identified as high-priority sediment management objectives for Tampa Bay. To address concerns related to sediment contamination in the bay, an ecosystem-based framework for assessing and managing sediment quality conditions was developed that included identification of sediment quality issues and concerns, development of ecosystem goals and objectives, selection of ecosystem health indicators, establishment of metrics and targets for key indicators, and incorporation of key indicators, metrics, and targets into watershed management plans and decision-making processes. This paper describes the process that was used to select and evaluate numerical sediment quality targets (SQTs) for assessing and managing contaminated sediments. These SQTs included measures of sediment chemistry, whole-sediment and pore-water toxicity, and benthic invertebrate community structure. In addition, the paper describes how the SQTs were used to develop site-specific concentration-response models that describe how the frequency of adverse biological effects changes with increasing concentrations of chemicals of potential concern. Finally, a key application of the SQTs for defining sediment management areas is discussed.

  19. Target identification using Zernike moments and neural networks

    Science.gov (United States)

    Azimi-Sadjadi, Mahmood R.; Jamshidi, Arta A.; Nevis, Andrew J.

    2001-10-01

    The development of an underwater target identification algorithm capable of identifying various types of underwater targets, such as mines, under different environmental conditions pose many technical problems. Some of the contributing factors are: targets have diverse sizes, shapes and reflectivity properties. Target emplacement environment is variable; targets may be proud or partially buried. Environmental properties vary significantly from one location to another. Bottom features such as sand, rocks, corals, and vegetation can conceal a target whether it is partially buried or proud. Competing clutter with responses that closely resemble those of the targets may lead to false positives. All the problems mentioned above contribute to overly difficult and challenging conditions that could lead to unreliable algorithm performance with existing methods. In this paper, we developed and tested a shape-dependent feature extraction scheme that provides features invariant to rotation, size scaling and translation; properties that are extremely useful for any target classification problem. The developed schemes were tested on an electro-optical imagery data set collected under different environmental conditions with variable background, range and target types. The electro-optic data set was collected using a Laser Line Scan (LLS) sensor by the Coastal Systems Station (CSS), located in Panama City, Florida. The performance of the developed scheme and its robustness to distortion, rotation, scaling and translation was also studied.

  20. Targeting Splicing in Prostate Cancer

    OpenAIRE

    Effrosyni Antonopoulou; Michael Ladomery

    2018-01-01

    Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA, KLF6, BCL2L2, ERG, and AR. We discuss opportunities to develop novel therapies that target specific splice isoforms, or that target the machinery of splicing. Therapeutic approaches include the development of small molecule inhibitors of splice factor kinases, splice isoform speci...

  1. ENTERPRISE RESOURCE STRATEGIC PLANNING: TARGET CHOICE TECHNIQUES

    Directory of Open Access Journals (Sweden)

    A. S. Lankin

    2011-01-01

    Full Text Available Choice of the targets is one of most important elements of the resource planning system. Particular feature of the strategic planning is development of future alternatives for the enterprise. Main resource strategic planning cycle elements: examination of principal external and internal environment components; forming the company mission; development of long-term targets; concretization of the long-term targets through short-term aims; examination of strategies and final choice.

  2. Intra‐Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

    Science.gov (United States)

    MacLeod, D; Lee, K; Santoro, A; DeMasi, DK; Hawk, T; Feinglos, M; Rowland, M; Noveck, RJ

    2017-01-01

    Abstract Intra‐Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first‐in‐human (FIH) testing of new molecular entities (NMEs). ITM combines intra‐target drug delivery and “microdosing,” the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic‐level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18F‐fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well‐tolerated. Results are consistent with ITM proof‐of‐concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach. PMID:28689370

  3. Targeting Virus-host Interactions of HIV Replication.

    Science.gov (United States)

    Weydert, Caroline; De Rijck, Jan; Christ, Frauke; Debyser, Zeger

    2016-01-01

    Cellular proteins that are hijacked by HIV in order to complete its replication cycle, form attractive new targets for antiretroviral therapy. In particular, the protein-protein interactions between these cellular proteins (cofactors) and viral proteins are of great interest to develop new therapies. Research efforts have led to the validation of different cofactors and some successes in therapeutic applications. Maraviroc, the first cofactor inhibitor approved for human medicinal use, provided a proof of concept. Furthermore, compounds developed as Integrase-LEDGF/p75 interaction inhibitors (LEDGINs) have advanced to early clinical trials. Other compounds targeting cofactors and cofactor-viral protein interactions are currently under development. Likewise, interactions between cellular restriction factors and their counteracting HIV protein might serve as interesting targets in order to impair HIV replication. In this respect, compounds targeting the Vif-APOBEC3G interaction have been described. In this review, we focus on compounds targeting the Integrase- LEDGF/p75 interaction, the Tat-P-TEFb interaction and the Vif-APOBEC3G interaction. Additionally we give an overview of currently discovered compounds presumably targeting cellular cofactor-HIV protein interactions.

  4. Development of a high-density gas-jet target for nuclear astrophysics and reaction studies with rare isotope beams. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Uwe, Greife [Colorado School of Mines, Golden, CO (United States)

    2014-08-12

    The purpose of this project was to develop a high-density gas jet target that will enable a new program of transfer reaction studies with rare isotope beams and targets of hydrogen and helium that is not currently possible and will have an important impact on our understanding of stellar explosions and of the evolution of nuclear shell structure away from stability. This is the final closeout report for the project.

  5. Development of a high-density gas-jet target for nuclear astrophysics and reaction studies with rare isotope beams. Final Report

    International Nuclear Information System (INIS)

    Uwe, Greife

    2014-01-01

    The purpose of this project was to develop a high-density gas jet target that will enable a new program of transfer reaction studies with rare isotope beams and targets of hydrogen and helium that is not currently possible and will have an important impact on our understanding of stellar explosions and of the evolution of nuclear shell structure away from stability. This is the final closeout report for the project.

  6. GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

    Science.gov (United States)

    Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

    2009-11-01

    G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.

  7. China's energy efficiency target 2010

    International Nuclear Information System (INIS)

    Yang Ming

    2008-01-01

    The Chinese government has set an ambitious target: reducing China's energy intensity by 20%, or 4.36% each year between 2006 and 2010 on the 2005 level. Real data showed that China missed its target in 2006, having reduced its energy intensity only by 1.3%. The objective of this study is to evaluate the feasibility and potential of the Chinese to achieve the target. This paper presents issues of macro-economy, population migration, energy savings, and energy efficiency policy measures to achieve the target. A top-down approach was used to analyse the relationship between the Chinese economic development and energy demand cycles and to identify the potentials of energy savings in sub-sectors of the Chinese economy. A number of factors that contribute to China's energy intensity are identified in a number of energy-intensive sectors. This paper concludes that China needs to develop its economy at its potential GDP growth rate; strengthen energy efficiency auditing, monitoring and verification; change its national economy from a heavy-industry-dominated mode to a light industry or a commerce-dominated mode; phase out inefficient equipment in industrial sectors; develop mass and fast railway transportation; and promote energy-efficient technologies at the end use. This paper transfers key messages to policy makers for designing their policy to achieve China's energy efficiency target

  8. REVIEW APPROACHES ECONOMIC DEVELOPMENT OF THE TERRITORY OF THE ARCTIC ZONE OF THE RUSSIAN FEDERATION, PRESENTED IN THE FORM OF TARGET SUBSPACE

    Directory of Open Access Journals (Sweden)

    N. I. Didenko

    2015-01-01

    Full Text Available This paper presents a conceptual idea of the organization of management of development of the Arctic area of the Russian Federation in the form of a set of target subspace. Among the possible types of target subspace comprising the Arctic zone of the Russian Federation, allocated seven subspace: basic city mobile Camps, site production of mineral resources, recreational area, fishing area, the Northern Sea Route, infrastructure protection safe existence in the Arctic. The task of determining the most appropriate theoretical approach for the development of each target subspaces. To this end, the theoretical approaches of economic growth and development of the theory of "economic base» (Economic Base Theory; resource theory (Staple Theory; Theory sectors (Sector Theory; theory of growth poles (Growth Pole Theory; neoclassical theory (Neoclassical Growth Theory; theory of inter-regional trade (Interregional Trade Theory; theory of the commodity cycle; entrepreneurial theory (Entrepreneurship Theories.

  9. Novel targets for ATM-deficient malignancies

    Science.gov (United States)

    Winkler, Johannes; Hofmann, Kay; Chen, Shuhua

    2014-01-01

    Conventional chemo- and radiotherapies for the treatment of cancer target rapidly dividing cells in both tumor and non-tumor tissues and can exhibit severe cytotoxicity in normal tissue and impair the patient's immune system. Novel targeted strategies aim for higher efficacy and tumor specificity. The role of ATM protein in the DNA damage response is well known and ATM deficiency frequently plays a role in tumorigenesis and development of malignancy. In addition to contributing to disease development, ATM deficiency also renders malignant cells heavily dependent on other pathways that cooperate with the ATM-mediated DNA damage response to ensure tumor cell survival. Disturbing those cooperative pathways by inhibiting critical protein components allows specific targeting of tumors while sparing healthy cells with normal ATM status. We review druggable candidate targets for the treatment of ATM-deficient malignancies and the mechanisms underlying such targeted therapies. PMID:27308314

  10. ANL progress in developing a target and process for converting CNEA Mo-99 production to LEU

    International Nuclear Information System (INIS)

    Vandegrift, G.F.; Gelis, A.; Aase, S.; Bakel, A.; Freiberg, E.; Conner, C.

    2002-01-01

    The primary mission of the Reduced Enrichment in Research and Test Reactors (RERTR) Program is to facilitate the conversion of research and test reactor fuel and targets from high-enriched uranium (HEU) to low-enriched uranium (LEU). One of the current goals at Argonne National Laboratory (ANL) is to convert 99 Mo production at Argentine Commission Nacional de Energia Atomica (CNEA) from HEU to LEU targets. Specifically addressed in this paper is ANL R and D related to this conversion: (1) designing a prototype production vessel for digesting irradiated LEU foils in alkaline solutions, (2) developing means to improve digestion efficiency, and (3) modifying ion-exchange processes used in the CNEA recovery and purification of 99 Mo to deal with the lower volumes generated from LEU-foil digestion. (author)

  11. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Science.gov (United States)

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  12. Cancer Drug Development: New Targets for Cancer Treatment.

    Science.gov (United States)

    Curt

    1996-01-01

    cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of

  13. Neutron resonance analysis for nuclear safeguards and security applications

    Science.gov (United States)

    Paradela, Carlos; Heyse, Jan; Kopecky, Stefan; Schillebeeckx, Peter; Harada, Hideo; Kitatani, Fumito; Koizumi, Mitsuo; Tsuchiya, Harufumi

    2017-09-01

    Neutron-induced reactions can be used to study the properties of nuclear materials of interest in the fields of nuclear safeguards and security. The elemental and isotopic composition of these materials can be determined by using the presence of resonance structures. This idea is the basis of two non-destructive analysis techniques which have been developed at the GELINA neutron time-of-flight facility at JRC-Geel: Neutron Resonance Capture Analysis (NRCA) and Neutron Resonance Transmission Analysis (NRTA). A combination of NRTA and NRCA has been proposed for the characterisation of particle-like debris of melted fuel formed in severe nuclear accidents. In this work, we present a quantitative validation of the NRTA technique which was used to determine the areal densities of Pu enriched reference samples used for safeguards applications. Less than 2% bias has been obtained for the fissile isotopes, with well-known total cross sections.

  14. Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Kim JS

    2013-11-01

    Full Text Available Jae Sik Kim,1 Sang Don Lee,2 Sang Jin Lee,3 Moon Kee Chung21Department of Urology, The Catholic University of Korea Incheon St Mary's Hospital, Incheon, 2Pusan National University Yangsan Hospital and Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 3Genitourinary Cancer Branch, National Cancer Center, Goyang, KoreaBackground: To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating oncolytic adenovirus (Ad equipped with mRFP(monomeric red fluorescence protein/ttk (modified herpes simplex virus thymidine kinase This construct was then further modified to express both mRFP/ttk and a soluble form of cytokine FLT3L (fms-related tyrosine kinase 3 ligand simultaneously.Methods: To construct the recombinant oncolytic adenovirus, E1a and E4 genes, which are necessary for adenovirus replication, were controlled by the prostate-specific enhancer sequence (PSES targeting prostate cancer cells expressing prostate-specific antigen (PSA and prostate-specific membrane antigen (PSMA. Simultaneously, it expressed the mRFP/ttk fusion protein in order to be able to elicit the cytotoxic effect.Results: The Ad5/35PSES.mRFP/ttk chimeric recombinant adenovirus was generated successfully. When replication of Ad5/35PSES.mRFP/ttk was evaluated in prostate cancer cell lines under fluorescence microscopy, red fluorescence intensity increased more in LNCaP cells, suggesting that the mRFP/ttk fusion protein was folded functionally. In addition, the replication assay including wild-type adenovirus as a positive control showed that PSES-positive cells (LNCaP and CWR22rv permitted virus replication but not PSES-negative cells (DU145 and PC3. Next, we evaluated the killing activity of this recombinant adenovirus. The Ad5/35PSES.mRFP/ttk killed LNCaP and CWR22rv more effectively. Unlike PSES-positive cells, DU145 and PC3 were resistant to killing by this recombinant

  15. TBC2target: A Resource of Predicted Target Genes of Tea Bioactive Compounds

    Directory of Open Access Journals (Sweden)

    Shihua Zhang

    2018-02-01

    Full Text Available Tea is one of the most popular non-alcoholic beverages consumed worldwide. Numerous bioactive constituents of tea were confirmed to possess healthy benefits via the mechanisms of regulating gene expressions or protein activities. However, a complete interacting profile between tea bioactive compounds (TBCs and their target genes is lacking, which put an obstacle in the study of healthy function of tea. To fill this gap, we developed a database of target genes of TBCs (TBC2target, http://camellia.ahau.edu.cn/TBC2target based on a pharmacophore mapping approach. In TBC2target, 6,226 interactions between 240 TBCs and 673 target genes were documented. TBC2target contains detailed information about each interacting entry, such as TBC, CAS number, PubChem CID, source of compound (e.g., green, black, compound type, target gene(s of TBC, gene symbol, gene ID, ENSEMBL ID, PDB ID, TBC bioactivity and the reference. Using the TBC-target associations, we constructed a bipartite network and provided users the global network and local sub-network visualization and topological analyses. The entire database is free for online browsing, searching and downloading. In addition, TBC2target provides a BLAST search function to facilitate use of the database. The particular strengths of TBC2target are the inclusion of the comprehensive TBC-target interactions, and the capacity to visualize and analyze the interacting networks, which may help uncovering the beneficial effects of tea on human health as a central resource in tea health community.

  16. TBC2target: A Resource of Predicted Target Genes of Tea Bioactive Compounds.

    Science.gov (United States)

    Zhang, Shihua; Zhang, Liang; Wang, Yijun; Yang, Jian; Liao, Mingzhi; Bi, Shoudong; Xie, Zhongwen; Ho, Chi-Tang; Wan, Xiaochun

    2018-01-01

    Tea is one of the most popular non-alcoholic beverages consumed worldwide. Numerous bioactive constituents of tea were confirmed to possess healthy benefits via the mechanisms of regulating gene expressions or protein activities. However, a complete interacting profile between tea bioactive compounds (TBCs) and their target genes is lacking, which put an obstacle in the study of healthy function of tea. To fill this gap, we developed a database of target genes of TBCs (TBC2target, http://camellia.ahau.edu.cn/TBC2target) based on a pharmacophore mapping approach. In TBC2target, 6,226 interactions between 240 TBCs and 673 target genes were documented. TBC2target contains detailed information about each interacting entry, such as TBC, CAS number, PubChem CID, source of compound (e.g., green, black), compound type, target gene(s) of TBC, gene symbol, gene ID, ENSEMBL ID, PDB ID, TBC bioactivity and the reference. Using the TBC-target associations, we constructed a bipartite network and provided users the global network and local sub-network visualization and topological analyses. The entire database is free for online browsing, searching and downloading. In addition, TBC2target provides a BLAST search function to facilitate use of the database. The particular strengths of TBC2target are the inclusion of the comprehensive TBC-target interactions, and the capacity to visualize and analyze the interacting networks, which may help uncovering the beneficial effects of tea on human health as a central resource in tea health community.

  17. The Development of a 3D LADAR Simulator Based on a Fast Target Impulse Response Generation Approach

    Science.gov (United States)

    Al-Temeemy, Ali Adnan

    2017-09-01

    A new laser detection and ranging (LADAR) simulator has been developed, using MATLAB and its graphical user interface, to simulate direct detection time of flight LADAR systems, and to produce 3D simulated scanning images under a wide variety of conditions. This simulator models each stage from the laser source to data generation and can be considered as an efficient simulation tool to use when developing LADAR systems and their data processing algorithms. The novel approach proposed for this simulator is to generate the actual target impulse response. This approach is fast and able to deal with high scanning requirements without losing the fidelity that accompanies increments in speed. This leads to a more efficient LADAR simulator and opens up the possibility for simulating LADAR beam propagation more accurately by using a large number of laser footprint samples. The approach is to select only the parts of the target that lie in the laser beam angular field by mathematically deriving the required equations and calculating the target angular ranges. The performance of the new simulator has been evaluated under different scanning conditions, the results showing significant increments in processing speeds in comparison to conventional approaches, which are also used in this study as a point of comparison for the results. The results also show the simulator's ability to simulate phenomena related to the scanning process, for example, type of noise, scanning resolution and laser beam width.

  18. Feasibility study on fission moly target development

    International Nuclear Information System (INIS)

    Kim, Byung Ku; Kim, Seong Nyun; Shon, Dong Seong; Choi, Chang Beom; Lee, Jae Kuk; Park, Jin Ho; Jeong, Won Myung; Jeon, Kwan Sik; You, Jae Hyung; Kang, Kyung Chul; Ahn, Jong Hwan; Ju, Po Kuk

    1996-01-01

    A multi-purpose research reactor, HANARO has been operated on the beginning of 1995 and can be utilized for production of various radioisotopes. And a R and D program for fission Mo production was established, and the technical and economical feasibility study has been performed for fission Mo production in Korea. In this study the process for fission Mo production was recommended as follows; 1. Target : UO 2 of annulus type. 2. Separation and purification : Nitric acid dissolution → Alumina adsorption → Benzoin oxime precipitation → Alumina adsorption. And more desirable plan for steady supply of fission Mo were suggested in following viewpoints; 1. Technical collaboration with foreign company. 2. Backup supply system. 3. Marketing arrangement. (Author)

  19. Relationship between Attitude toward Target Language Culture Instruction and Pragmatic Comprehension Development

    Science.gov (United States)

    Rafieyan, Vahid; Majid, Norazman Bin Abdul; Eng, Lin Siew

    2013-01-01

    Familiarity with the cultural features of the target language society and interest in learning those cultural features are the key factors to determine language learners' level of pragmatic comprehension. To investigate this issue, this study attempted to assess the relationship between attitude toward incorporating target language culture into…

  20. Fabrication of cryogenic inertial-confinement-fusion targets using target free-fall technique. Report No. 2-82

    International Nuclear Information System (INIS)

    Kim, K.; Murphy, M.J.

    1982-04-01

    Techniques for fabricating cryogenic inertial confinement fusion targets (i.e., spherical shells containing a uniform layer of DT ice) are investigated using target free-fall concept. Detection and characterization of the moving targets are effected by optoelectronic means, of which the principal is an RF ac-interferometer. This interferometer system demonstrates, for the first time, the speed capabilities of the phase-modulation ac-interferometry. New techiques developed for handling, holding, launching, and transporting targets are also described. Results obtained at both room and cryogenic temperatures are presented

  1. Development of lithium target system in engineering validation and engineering design activity of the international fusion materials irradiation facility (IFMIF/EVEDA)

    International Nuclear Information System (INIS)

    Wakai, Eiichi; Kondo, Hiroo; Sugimoto, Masayoshi; Ida, Mizuho; Kanemura, Takuji; Watanabe, Kazuyoshi; Fujishiro, Kouji; Edao, Yuuki; Niitsuma, Shigeto; Kimura, Haruyuki; Fukada, Satoshi; Hiromoto, Tetsushi; Shigeharu, Satoshi; Yagi, Jyuro; Furukawa, Tomohiro; Hirakawa, Yasushi; Suzuki, Akihiro; Terai, Takayuki; Horiike, Hiroshi; Hoashi, Eiji; Suzuki, Sachiko; Yamaoka, Nobuo; Serizawa, Hisashi; Kawahito, Yosuke; Tsuji, Yoshiyuki; Furuya, Kazuyuki; Takeo, Fumio

    2012-01-01

    Engineering validation and engineering design activity (EVEDA) for the international fusion materials irradiation facility (IFMIF) has been conducted since 2007. Research and development of the Lithium target facility is an important part of this activity. We constructed a world largest liquid Lithium test loop with a capacity of 5000 L in 2010 and successfully completed the first stage validation tests (functional tests of components and Lithium flow test (flow velocity 15 m/s at the target). In the present article, recent results of the EVEDA activity for the Lithium target facility and related technologies on liquid Lithium are reviewed. (author)

  2. Community-based oral health promotion practices targeted at children and adolescents in Finland--developing an assessment tool.

    Science.gov (United States)

    Blomqvist, Pia; Ojala, Ellinoora; Kettunen, Tarja; Poskiparta, Marita; Kasila, Kirsti

    2014-06-01

    To develop an assessment tool for evaluating oral health promotion practices and to evaluate community-based oral health promotion practices targeted at children and adolescents with this tool. A theoretical framework about health promotion planning, implementation and evaluation was made on the basis of a literature review. Then, information about Finnish community-based oral health promotion practices (n=12) targeted at children and adolescents was collected using semi-structured interviews. Also, related documents, for example action plans and reports, were collected when available. Next, an assessment tool based on the theoretical framework was developed, and the recorded and transcribed interview data and other documents were evaluated with this tool. The assessment tool proved to be practical: it pointed out the strengths and weaknesses of the practices. The tool revealed strengths in the implementation and deficiencies in the planning and evaluation of oral health promotion practices. One-quarter of the 12 practices assessed could be considered 'good practices'. There is a need to improve the planning and evaluation of oral health promotion practices. The assessment tool developed in this study might be useful for practitioners both in the field of oral health promotion and general health promotion. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Role of Chemokine Network in the Development and Progression of Ovarian Cancer: A Potential Novel Pharmacological Target

    Directory of Open Access Journals (Sweden)

    Federica Barbieri

    2010-01-01

    Full Text Available Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.

  4. Mechanisms of developing post-traumatic stress disorder: new targets for drug development and other potential interventions.

    Science.gov (United States)

    Wimalawansa, Sunil J

    2014-01-01

    amygdala and hippocampus, which are characteristics of patients with PTSD. Considering these abnormalities, neuroendocrine system needs to be considered as a key target for new drug development for prevention and treatment of PTSD.

  5. The biology of Mur ligases as an antibacterial target.

    Science.gov (United States)

    Kouidmi, Imène; Levesque, Roger C; Paradis-Bleau, Catherine

    2014-10-01

    With antibiotic resistance mechanisms increasing in diversity and spreading among bacterial pathogens, the development of new classes of antibacterial agents against judiciously chosen targets is a high-priority task. The biochemical pathway for peptidoglycan biosynthesis is one of the best sources of antibacterial targets. Within this pathway are the Mur ligases, described in this review as highly suitable targets for the development of new classes of antibacterial agents. The amide ligases MurC, MurD, MurE and MurF function with the same catalytic mechanism and share conserved amino acid regions and structural features that can conceivably be exploited for the design of inhibitors that simultaneously target more than one enzyme. This would provide multi-target antibacterial weapons with minimized likelihood of target-mediated resistance development. © 2014 John Wiley & Sons Ltd.

  6. HomoTarget: a new algorithm for prediction of microRNA targets in Homo sapiens.

    Science.gov (United States)

    Ahmadi, Hamed; Ahmadi, Ali; Azimzadeh-Jamalkandi, Sadegh; Shoorehdeli, Mahdi Aliyari; Salehzadeh-Yazdi, Ali; Bidkhori, Gholamreza; Masoudi-Nejad, Ali

    2013-02-01

    MiRNAs play an essential role in the networks of gene regulation by inhibiting the translation of target mRNAs. Several computational approaches have been proposed for the prediction of miRNA target-genes. Reports reveal a large fraction of under-predicted or falsely predicted target genes. Thus, there is an imperative need to develop a computational method by which the target mRNAs of existing miRNAs can be correctly identified. In this study, combined pattern recognition neural network (PRNN) and principle component analysis (PCA) architecture has been proposed in order to model the complicated relationship between miRNAs and their target mRNAs in humans. The results of several types of intelligent classifiers and our proposed model were compared, showing that our algorithm outperformed them with higher sensitivity and specificity. Using the recent release of the mirBase database to find potential targets of miRNAs, this model incorporated twelve structural, thermodynamic and positional features of miRNA:mRNA binding sites to select target candidates. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Prediction of potential drug targets based on simple sequence properties

    Directory of Open Access Journals (Sweden)

    Lai Luhua

    2007-09-01

    Full Text Available Abstract Background During the past decades, research and development in drug discovery have attracted much attention and efforts. However, only 324 drug targets are known for clinical drugs up to now. Identifying potential drug targets is the first step in the process of modern drug discovery for developing novel therapeutic agents. Therefore, the identification and validation of new and effective drug targets are of great value for drug discovery in both academia and pharmaceutical industry. If a protein can be predicted in advance for its potential application as a drug target, the drug discovery process targeting this protein will be greatly speeded up. In the current study, based on the properties of known drug targets, we have developed a sequence-based drug target prediction method for fast identification of novel drug targets. Results Based on simple physicochemical properties extracted from protein sequences of known drug targets, several support vector machine models have been constructed in this study. The best model can distinguish currently known drug targets from non drug targets at an accuracy of 84%. Using this model, potential protein drug targets of human origin from Swiss-Prot were predicted, some of which have already attracted much attention as potential drug targets in pharmaceutical research. Conclusion We have developed a drug target prediction method based solely on protein sequence information without the knowledge of family/domain annotation, or the protein 3D structure. This method can be applied in novel drug target identification and validation, as well as genome scale drug target predictions.

  8. Study Identifies New Lymphoma Treatment Target

    Science.gov (United States)

    NCI researchers have identified new therapeutic targets for diffuse large B-cell lymphoma. Drugs that hit these targets are under clinical development and the researchers hope to begin testing them in clinical trials of patients with DLBCL.

  9. Developments in target micro-Doppler signatures analysis: radar imaging, ultrasound and through-the-wall radar

    OpenAIRE

    Clemente, C.; Balleri, A.; Woodbridge, K.; Soraghan, J. J.

    2013-01-01

    Target motions, other than the main bulk translation of the target, induce Doppler modulations around the main Doppler shift that form what is commonly called a target micro-Doppler signature. Radar micro-Doppler signatures are generally both target and action speci c and hence can be used to classify and recognise targets as well as to identify possible threats. In recent years, research into the use of micro-Doppler signatures for target classi cation to address many defence and security ch...

  10. A rotating target wheel system for gammasphere

    International Nuclear Information System (INIS)

    Greene, J. P.

    1999-01-01

    A description is given for a low-mass, rotating target wheel to be used within the Gammasphere target chamber. This system was developed for experiments employing high beam currents in order to extend lifetimes of targets using low-melting point target material. The design is based on a previously successful implementation of rotating target wheels for the Argonne Positron Experiment (APEX) as well as the Fragment Mass Analyser (FMA) at ATLAS (Argonne Tandem Linac Accelerator System). A brief history of these rotating target wheel systems is given as well as a discussion on target preparation and performance

  11. The Bering Autonomous Target Detection

    DEFF Research Database (Denmark)

    Jørgensen, John Leif; Denver, Troelz; Betto, Maurizio

    2003-01-01

    An autonomous asteroid target detection and tracking method has been developed. The method features near omnidirectionality and focus on high speed operations and completeness of search of the near space rather than the traditional faint object search methods, employed presently at the larger...... telescopes. The method has proven robust in operation and is well suited for use onboard spacecraft. As development target for the method and the associated instrumentation the asteroid research mission Bering has been used. Onboard a spacecraft, the autonomous detection is centered around the fully...... autonomous star tracker the Advanced Stellar Compass (ASC). One feature of this instrument is that potential targets are registered directly in terms of date, right ascension, declination, and intensity, which greatly facilitates both tracking search and registering. Results from ground and inflight tests...

  12. Application of target costing in machining

    Science.gov (United States)

    Gopalakrishnan, Bhaskaran; Kokatnur, Ameet; Gupta, Deepak P.

    2004-11-01

    In today's intensely competitive and highly volatile business environment, consistent development of low cost and high quality products meeting the functionality requirements is a key to a company's survival. Companies continuously strive to reduce the costs while still producing quality products to stay ahead in the competition. Many companies have turned to target costing to achieve this objective. Target costing is a structured approach to determine the cost at which a proposed product, meeting the quality and functionality requirements, must be produced in order to generate the desired profits. It subtracts the desired profit margin from the company's selling price to establish the manufacturing cost of the product. Extensive literature review revealed that companies in automotive, electronic and process industries have reaped the benefits of target costing. However target costing approach has not been applied in the machining industry, but other techniques based on Geometric Programming, Goal Programming, and Lagrange Multiplier have been proposed for application in this industry. These models follow a forward approach, by first selecting a set of machining parameters, and then determining the machining cost. Hence in this study we have developed an algorithm to apply the concepts of target costing, which is a backward approach that selects the machining parameters based on the required machining costs, and is therefore more suitable for practical applications in process improvement and cost reduction. A target costing model was developed for turning operation and was successfully validated using practical data.

  13. Test of a High Power Target Design

    CERN Multimedia

    2002-01-01

    %IS343 :\\\\ \\\\ A high power tantalum disc-foil target (RIST) has been developed for the proposed radioactive beam facility, SIRIUS, at the Rutherford Appleton Laboratory. The yield and release characteristics of the RIST target design have been measured at ISOLDE. The results indicate that the yields are at least as good as the best ISOLDE roll-foil targets and that the release curves are significantly faster in most cases. Both targets use 20 -25 $\\mu$m thick foils, but in a different internal geometry.\\\\ \\\\Investigations have continued at ISOLDE with targets having different foil thickness and internal geometries in an attempt to understand the release mechanisms and in particular to maximise the yield of short lived isotopes. A theoretical model has been developed which fits the release curves and gives physical values of the diffusion constants.\\\\ \\\\The latest target is constructed from 2 $\\mu$m thick tantalum foils (mass only 10 mg) and shows very short release times. The yield of $^{11}$Li (half-life of ...

  14. The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite is a Dual-Stage Target for Drug Development

    Science.gov (United States)

    Herman, Jonathan D.; Pepper, Lauren R.; Cortese, Joseph F.; Estiu, Guillermina; Galinsky, Kevin; Zuzarte-Luis, Vanessa; Derbyshire, Emily R.; Ribacke, Ulf; Lukens, Amanda K.; Santos, Sofia A.; Patel, Vishal; Clish, Clary B.; Sullivan, William J.; Zhou, Huihao; Bopp, Selina E.; Schimmel, Paul; Lindquist, Susan; Clardy, Jon; Mota, Maria M.; Keller, Tracy L.; Whitman, Malcolm; Wiest, Olaf; Wirth, Dyann F.; Mazitschek, Ralph

    2015-01-01

    The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for the development of the next-generation of antimalarial drugs. Using an integrated chemogenomics approach that combined drug-resistance selection, whole genome sequencing and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses, and represents a promising lead for the development of dual-stage next generation antimalarials. PMID:25995223

  15. Formulation, Development, and In Vitro Evaluation of a CD22 Targeted Liposomal System Containing a Non-Cardiotoxic Anthracycline for B Cell Malignancies

    Directory of Open Access Journals (Sweden)

    Nivesh K. Mittal

    2018-04-01

    Full Text Available Doxorubicin cardiotoxicity has led to the development of superior chemotherapeutic agents such as AD 198. However, depletion of healthy neutrophils and thrombocytes from AD 198 therapy must be limited. This can be done by the development of a targeted drug delivery system that delivers AD 198 to the malignant cells. The current research highlights the development and in vitro analysis of targeted liposomes containing AD 198. The best lipids were identified and optimized for physicochemical effects on the liposomal system. Physiochemical characteristics such as size, ζ-potential, and dissolution were also studied. Active targeting to CD22 positive cells was achieved by conjugating anti-CD22 Fab’ to the liposomal surface. Size and ζ-potential of the liposomes was between 115 and 145 nm, and −8 to−15 mV. 30% drug was released over 72 h. Higher cytotoxicity was observed in CD22+ve Daudi cells compared to CD22−ve Jurkat cells. The route of uptake was a clathrin- and caveolin-independent pathway. Intracellular localization of the liposomes was in the endolysosomes. Upon drug release, apoptotic pathways were activated partly by the regulation of apoptotic and oncoproteins such as caspase-3 and c-myc. It was observed that the CD22 targeted drug delivery system was more potent and specific compared to other untargeted formulations.

  16. Study of the potential of low carbon energy development and its contribution to realize the reduction target of carbon intensity in China

    International Nuclear Information System (INIS)

    Li Hongqiang; Wang Limao; Shen Lei; Chen Fengnan

    2012-01-01

    Appraising low carbon energy potential in China and studying its contribution to China's target of cutting CO 2 emissions by 40–45% per unit of GDP by 2020 is crucial for taking countermeasures against climate change and identifying low carbon energy development strategies. This paper presents two scenarios and evaluates the development potential for low carbon energy and its various sources. Based on the evaluation, we analyze how low carbon energy contributes to achieving China's national target of carbon intensity reduction. We draw several conclusions from the analysis. First, low carbon energy will contribute 9.74% (minimum) to 24.42% (maximum) toward the 2020 carbon intensity target under three economic development schemes. Second, the contribution will decrease when the GDP growth rate increases. Third, to maintain the same contribution with high GDP growth rates, China should not only strengthen its investment and policy stimulation for low carbon energy but also simultaneously optimize economic structures and improve carbon productivity. - Highlights: ► Low carbon energy can substitute at least 659.5 Mtce of fossil energy in 2020. ► Potential of hydropower ranks first among all low carbon energy sources in 2020. ► Low carbon energy will contribute at least 9.47% to reach carbon target in 2020. ► China should formulate and implement comprehensive measures to cut carbon emission.

  17. Structural insights into drug development strategy targeting EGFR T790M/C797S.

    Science.gov (United States)

    Zhu, Su-Jie; Zhao, Peng; Yang, Jiao; Ma, Rui; Yan, Xiao-E; Yang, Sheng-Yong; Yang, Jing-Wen; Yun, Cai-Hong

    2018-03-02

    Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.

  18. Development of a plasma assisted ITER level controlled heat source and observation of novel micro/nanostructures produced upon exposure of tungsten targets

    Energy Technology Data Exchange (ETDEWEB)

    Aomoa, N.; Sarmah, Trinayan; Sah, Puspalata [CIMPLE-PSI Laboratory, Centre of Plasma Physics-Institute for Plasma Research, Sonapur 782 402 Assam (India); Chaudhuri, P.; Khirwarker, S.; Ghosh, J. [Institute for Plasma Research, Gandhinagar 382428 Gujarat (India); Satpati, B. [Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700 064 (India); Kakati, M., E-mail: mayurkak@rediffmail.com [CIMPLE-PSI Laboratory, Centre of Plasma Physics-Institute for Plasma Research, Sonapur 782 402 Assam (India); De Temmerman, G. [ITER Organization, Route de Vinon-sur-Verdon, CS 90 046 Saint Paul Lez Durance, Cedex (France)

    2016-05-15

    Highlights: • Developed a plasma assisted ITER level high heat flux device for material testing. • The beam deposits over 10 MW/m{sup 2} flux uniformly over a remote material target. • Hopper micro-crystals were growing while exposing Plansee tungsten in the device. • CIMPLE-PSI being developed for exact reproduction of Tokomak Divertor conditions. - Abstract: This paper reports on the development of a simple, low-cost, segmented plasma torch assisted high-heat flux device for material testing, which can simulate the extreme heat flux expected in future fusion devices. Calorimetric measurements confirmed uniform heat deposition by the well collimated argon plasma beam over a target surface with power fluxes in excess of 10 MW/m{sup 2} during high current, high gas flow rate operations. To understand the outcome of possible melting of first wall material in an ITER like machine, an Plansee tungsten target was exposed in this device, which witnessed growth of micrometer level Hopper crystals and their aggregation to vertical grains in central exposed region. Increase in viscosity of the metal during high under-cooling is believed to have lead to the skeletal patterns, observed for the first time for tungsten here. Transmission electron microscopy confirmed that re-solidified grains on the target actually had crystalline substructures in the nanometer level. This laboratory is in the process of developing an exact linear Tokamak Divertor simulator, where a magnetized hydrogen/helium collimated plasma jet will be produced at higher vacuum, for plasma material interaction studies with direct relevance to modern plasma fusion machines.

  19. Graphite target for the spiral project

    International Nuclear Information System (INIS)

    Putaux, J.C.; Ducourtieux, M.; Ferro, A.; Foury, P.; Kotfila, L.; Mueller, A.C.; Obert, J.; Pauwels, N.; Potier, J.C.; Proust, J.; Loiselet, M.

    1996-01-01

    A study of the thermal and physical properties of graphite targets for the SPIRAL project is presented. The main objective is to develop an optimized set-up both mechanically and thermally resistant, presenting good release properties (hot targets with thin slices). The results of irradiation tests concerning the mechanical and thermal resistance of the first prototype of SPIRAL target with conical geometry are presented. The micro-structural properties of the graphite target is also studied, in order to check that the release properties are not deteriorated by the irradiation. Finally, the results concerning the latest pilot target internally heated by an electrical current are shown. (author)

  20. Possible approaches to fast quality control of IFE targets

    International Nuclear Information System (INIS)

    Koresheva, E.R.; Nikitenko, A.I.; Aleksandrova, I.V.; Bazdenkov, S.V.; Belolipetskiy, A.A.; Chtcherbakov, V.I.; Osipov, I.E.

    2006-01-01

    In recent years, research into the development of reliable methods and techniques for characterization and quality control of ICF/IFE targets has been carried out very actively. This is motivated by the need to provide the means for precise and accurate knowledge of cryogenic target parameters. On the other hand, particular emphasis should be paid to the fact that fuelling of a commercial power plant requires ∼6 targets each second. This indicates that the development of fast quality control techniques is of critical importance as well. Therefore, in this report we discuss the issues underlying the construction of different algorithms for characterization and quality control of ICF/IFE targets. Among them are: (a) algorithm banks and their structure, (b) algorithm testing, (c) target reconstruction experiments. The algorithm bank incorporates the algorithms for two stages of target production: the stage of fuel layering technique development (motionless target) and the stage of cryogenic target delivery (injected target). In the first case an inverse algorithm for individual target characterization (3D target reconstruction) and two threshold algorithms for fast control of target quality are presented. They are based on tomographic information processing methods. Experimentally, tomographic data acquisition is carried out by a hundred projections microtomograph. The spatial resolution of the optical system of the microtomograph is 1 μm for 490 nm wavelength, the accuracy of target angular positioning is ±1.5-2.5 min. In the second case we describe the algorithm based on Fourier transform holography for ultra fast target characterization during its injection. The performed computer experiments have demonstrated much promise of this approach in the following directions: recognition of the target imperfections in both low- and high- harmonics; quality control of both a single target and a target batch; simultaneous control of both an injected target quality and

  1. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  2. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  3. Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

    Science.gov (United States)

    Stewart, Keri S.; Kleinerman, Eugenie S.

    2011-01-01

    Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM) cell participation in vascular development have identified VEGF, SDF-1α, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway. PMID:21785569

  4. Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

    Science.gov (United States)

    Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

    2015-07-01

    BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.

  5. Treating rheumatoid arthritis to target

    DEFF Research Database (Denmark)

    Smolen, Josef S; Aletaha, Daniel; Bijlsma, Johannes W J

    2010-01-01

    BACKGROUND: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA). OBJECTIVE: /st> To develop recommendations for achieving optimal therapeutic outcomes in RA. METHODS....... Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow...

  6. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael

    2010-01-01

    Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug......-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments....... In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We...

  7. Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.

    Science.gov (United States)

    Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T

    2017-04-01

    Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

  8. Targeting autophagy in cancer management – strategies and developments

    International Nuclear Information System (INIS)

    Ozpolat, Bulent; Benbrook, Doris M

    2015-01-01

    Autophagy is a highly regulated catabolic process involving lysosomal degradation of intracellular components, damaged organelles, misfolded proteins, and toxic aggregates, reducing oxidative stress and protecting cells from damage. The process is also induced in response to various conditions, including nutrient deprivation, metabolic stress, hypoxia, anticancer therapeutics, and radiation therapy to adapt cellular conditions for survival. Autophagy can function as a tumor suppressor mechanism in normal cells and dysregulation of this process (ie, monoallelic Beclin-1 deletion) may lead to malignant transformation and carcinogenesis. In tumors, autophagy is thought to promote tumor growth and progression by helping cells to adapt and survive in metabolically-challenged and harsh tumor microenvironments (ie, hypoxia and acidity). Recent in vitro and in vivo studies in preclinical models suggested that modulation of autophagy can be used as a therapeutic modality to enhance the efficacy of conventional therapies, including chemo and radiation therapy. Currently, more than 30 clinical trials are investigating the effects of autophagy inhibition in combination with cytotoxic chemotherapies and targeted agents in various cancers. In this review, we will discuss the role, molecular mechanism, and regulation of autophagy, while targeting this process as a novel therapeutic modality, in various cancers

  9. Development of new releasing agents for preparation of thin self-supporting target films

    Energy Technology Data Exchange (ETDEWEB)

    Sugai, I; Takaku, S; Hasegawa, T [Tokyo Univ., Tanashi (Japan). Inst. for Nuclear Study

    1978-06-01

    Several kinds of materials were examined for the usefulness as releasing agents in the preparation of various thin self-supporting target films for use in nuclear reaction experiments. NaCl, BaCl/sub 2/, KCl, CsI, Teepol, glucose, KIO/sub 3/, mica, nitrocellulose of Formvar was deposited onto glass plates as the release agent by vacuum evaporation or dipping method. The obtained target film was tested on impurities from the release agent by using nuclear reactions. The relative effectiveness of each release agent was also considered from ease in the stripping of target films.

  10. Development of new releasing agents for preparation of thin self-supporting target films

    International Nuclear Information System (INIS)

    Sugai, Isao; Takaku, Seisaku; Hasegawa, Takeo

    1978-01-01

    Several kinds of materials were examined for the usefulness as releasing agents in the preparation of various thin self-supporting target films for use in nuclear reaction experiments. NaCl, BaCl 2 , KCl, CsI, Teepol, glucose, KIO 3 , mica, nitrocellulose of Formvar was deposited onto glass plates as the release agent by vacuum evaporation or dipping method. The obtained target film was tested on impurities from the release agent by using nuclear reactions. The relative effectiveness of each release agent was also considered from ease in the stripping of target films. (auth.)

  11. Target-ion source unit ionization efficiency measurement by method of stable ion beam implantation

    CERN Document Server

    Panteleev, V.N; Fedorov, D.V; Moroz, F.V; Orlov, S.Yu; Volkov, Yu.M

    The ionization efficiency is one of the most important parameters of an on-line used target-ion source system exploited for production of exotic radioactive beams. The ionization efficiency value determination as a characteristic of a target-ion source unit in the stage of its normalizing before on-line use is a very important step in the course of the preparation for an on-line experiment. At the IRIS facility (Petersburg Nuclear Physics Institute, Gatchina) a reliable and rather precise method of the target-ion source unit ionization efficiency measurement by the method of stable beam implantation has been developed. The method worked out exploits an off-line mass-separator for the implantation of the ion beams of selected stable isotopes of different elements into a tantalum foil placed inside the Faraday cup in the focal plane of the mass-separator. The amount of implanted ions has been measured with a high accuracy by the current integrator connected to the Faraday cup. After the implantation of needed a...

  12. National Ignition Facility Target Chamber

    International Nuclear Information System (INIS)

    Wavrik, R W; Cox, J R; Fleming, P J

    2000-01-01

    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 two 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

  13. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  14. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  15. TargetSpy: a supervised machine learning approach for microRNA target prediction.

    Science.gov (United States)

    Sturm, Martin; Hackenberg, Michael; Langenberger, David; Frishman, Dmitrij

    2010-05-28

    Virtually all currently available microRNA target site prediction algorithms require the presence of a (conserved) seed match to the 5' end of the microRNA. Recently however, it has been shown that this requirement might be too stringent, leading to a substantial number of missed target sites. We developed TargetSpy, a novel computational approach for predicting target sites regardless of the presence of a seed match. It is based on machine learning and automatic feature selection using a wide spectrum of compositional, structural, and base pairing features covering current biological knowledge. Our model does not rely on evolutionary conservation, which allows the detection of species-specific interactions and makes TargetSpy suitable for analyzing unconserved genomic sequences.In order to allow for an unbiased comparison of TargetSpy to other methods, we classified all algorithms into three groups: I) no seed match requirement, II) seed match requirement, and III) conserved seed match requirement. TargetSpy predictions for classes II and III are generated by appropriate postfiltering. On a human dataset revealing fold-change in protein production for five selected microRNAs our method shows superior performance in all classes. In Drosophila melanogaster not only our class II and III predictions are on par with other algorithms, but notably the class I (no-seed) predictions are just marginally less accurate. We estimate that TargetSpy predicts between 26 and 112 functional target sites without a seed match per microRNA that are missed by all other currently available algorithms. Only a few algorithms can predict target sites without demanding a seed match and TargetSpy demonstrates a substantial improvement in prediction accuracy in that class. Furthermore, when conservation and the presence of a seed match are required, the performance is comparable with state-of-the-art algorithms. TargetSpy was trained on mouse and performs well in human and drosophila

  16. TargetSpy: a supervised machine learning approach for microRNA target prediction

    Directory of Open Access Journals (Sweden)

    Langenberger David

    2010-05-01

    Full Text Available Abstract Background Virtually all currently available microRNA target site prediction algorithms require the presence of a (conserved seed match to the 5' end of the microRNA. Recently however, it has been shown that this requirement might be too stringent, leading to a substantial number of missed target sites. Results We developed TargetSpy, a novel computational approach for predicting target sites regardless of the presence of a seed match. It is based on machine learning and automatic feature selection using a wide spectrum of compositional, structural, and base pairing features covering current biological knowledge. Our model does not rely on evolutionary conservation, which allows the detection of species-specific interactions and makes TargetSpy suitable for analyzing unconserved genomic sequences. In order to allow for an unbiased comparison of TargetSpy to other methods, we classified all algorithms into three groups: I no seed match requirement, II seed match requirement, and III conserved seed match requirement. TargetSpy predictions for classes II and III are generated by appropriate postfiltering. On a human dataset revealing fold-change in protein production for five selected microRNAs our method shows superior performance in all classes. In Drosophila melanogaster not only our class II and III predictions are on par with other algorithms, but notably the class I (no-seed predictions are just marginally less accurate. We estimate that TargetSpy predicts between 26 and 112 functional target sites without a seed match per microRNA that are missed by all other currently available algorithms. Conclusion Only a few algorithms can predict target sites without demanding a seed match and TargetSpy demonstrates a substantial improvement in prediction accuracy in that class. Furthermore, when conservation and the presence of a seed match are required, the performance is comparable with state-of-the-art algorithms. TargetSpy was trained on

  17. Targeting Employment Expansion, Economic Growth and Development in Sub-Saharan Africa: Outlines of an Alternative Economic Programme for the Region

    OpenAIRE

    James Heintz; Robert Pollin

    2008-01-01

    This paper outlines the elements of a development-targeted economic framework aimed at creating decent employment opportunities as a strategy for realizing core human development goals in Africa. Four policy areas form the core of the paper: monetary policy and inflation, exchange rate policy, development finance and financial sector reforms, and public investment and fiscal policy. This paper draws heavily on three large UNDP-sponsored studies of employment-oriented economic policies in Keny...

  18. Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development.

    Science.gov (United States)

    Kim, Seonwook; Yang, Lihua; Kim, Seongu; Lee, Richard G; Graham, Mark J; Berliner, Judith A; Lusis, Aldons J; Cai, Lei; Temel, Ryan E; Rateri, Debra L; Lee, Sangderk

    2017-01-01

    The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model. Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin II (AngII, 1,000ng/kg/min) for the last 4 weeks of ASO administration. We confirmed that the HB-EGF ASO administration significantly downregulated HB-EGF expression in multiple tissues including the liver. Importantly, the HB-EGF ASO administration significantly suppressed development of aortic aneurysms including thoracic and abdominal types. Interestingly, the HB-EGF ASO administration induced a remarkable anti-hyperlipidemic effect by suppressing very low density lipoprotein (VLDL) level in the blood. Mechanistically, the HB-EGF targeting suppressed hepatic VLDL secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate. This result suggested that the HB-EGF targeting induced protection against aneurysm development through anti-hyperlipidemic effects. Suppression of hepatic VLDL production process appears to be a key mechanism for the anti-hyperlipidemic effects by the HB-EGF targeting.

  19. Modified egg as a nutritional supplement during peak brain development: a new target for fortification.

    Science.gov (United States)

    Shapira, Niva

    2009-01-01

    Though eggs have the unique capacity, like breastmilk, to concentrate essential nutrients required for early growth and brain development of offspring - i.e. n-3 PUFA, increasingly deficient and sources contaminated - cholesterol and allergy concerns often exclude them from perinatal recommendations. Egg's potential contribution of key nutrients required for peak brain development are re-evaluated vis-à-vis fortification, accessibility, and risks. Contributions of standard (USDA) and fortified (selected market-available) egg compositions to perinatal requirements for critical brain-supporting nutrients were compared to human and cow milks, and risks and recommendations evaluated. Standard egg has already higher concentrations/kcal of iron, selenium, zinc, choline, vitamins B12 and E, and essential amino acids (plus taurine) than human milk. Fortified egg could further yield significant n-3 PUFA % recommendations for pregnancy-lactation (total n-3 69.6-75.0% [DRI=1400-1300 mg/day]), including DHA (120.1-129.3%, mostly approximately 80% [calculated DRI=140-130 mg/day]), plus antioxidant vitamins A (9.0-15.2%) and E (51.6-65.3%), and minerals iodine (33.6-44.5%) and selenium (33.7-39.3%); % recommendations for children (1-3 y) even more. Cholesterol, important for nerve membranes and learning, may not be generally contraindicated in childbearing-aged women (approximately 10.5% hypercholesterolemia), and early-life egg exposure may increase tolerance. Egg-inclusive perinatal nutrition programs have shown significant contributions. Eggs, especially target-fortified, may provide a unique nutritional supplement for peak brain development continously during pregnancy, nursing, and infancy (from 6 months), especially vs. insufficiencies. Missing nutritional opportunities by egg exclusion vs. concerns of hypercholesterolemia or allergy could be addressed individually, rather than as general recommendations, warranting further research and targeted egg design.

  20. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  1. Development of behavioral parameters and ERPs in a novel-target visual detection paradigm in children, adolescents and young adults.

    Science.gov (United States)

    Rojas-Benjumea, María Ángeles; Sauqué-Poggio, Ana María; Barriga-Paulino, Catarina I; Rodríguez-Martínez, Elena I; Gómez, Carlos M

    2015-07-04

    The present study analyzes the development of ERPs related to the process of selecting targets based on their novelty. One hundred and sixty-seven subjects from 6 to 26 years old were recorded with 30 electrodes during a visual target novelty paradigm. Behavioral results showed good performance in children that improved with age: a decrease in RTs and errors and an increase in the d' sensitivity parameter with age were obtained. In addition, the C response bias parameter evolved from a conservative to a neutral bias with age. Fronto-polar Selection Positivity (FSP) was statistically significant in all the age groups when standards and targets were compared. There was a statistically significant difference in the posterior Selection Negativity (SN) between the target and standard conditions in all age groups. The P3a component obtained was statistically significant in the emergent adult (18-21 years) and young adult (22-26 years) groups. The modulation of the P3b component by novel targets was statistically significant in all the age groups, but it decreased in amplitude with age. Peak latencies of the FSP and P3b components decreased with age. The results reveal differences in the ERP indexes for the cognitive evaluation of the stimuli presented, depending on the age of the subjects. The ability of the target condition to induce the modulation of the studied components would depend on the posterior-anterior gradient of cortex maturation and on the gradient of maturation of the low to higher order association areas.

  2. The History of Target-Controlled Infusion

    NARCIS (Netherlands)

    Struys, Michel M. R. F.; De Smet, Tom; Glen, John (Iain) B.; Vereecke, Hugo E. M.; Absalom, Anthony R.; Schnider, Thomas W.

    Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted (target) drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical

  3. The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening.

    Science.gov (United States)

    Xia, Jie; Hsieh, Jui-Hua; Hu, Huabin; Wu, Song; Wang, Xiang Simon

    2017-06-26

    Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment. Continuing from it, in the present work we attempted to incorporate knowledge collected from diverse protein-ligand interfaces of multiple crystal structures of the same target to build PF ensembles (PFEs). Toward this end, we first constructed a comprehensive data set to meet the requirements of ensemble modeling and validation. This set contains 10 diverse targets, 118 well-prepared X-ray structures of protein-ligand complexes, and large benchmarking actives/decoys sets. Notably, we designed a unique workflow of two-layer classifiers based on the concept of ensemble learning and applied it to the construction of PFEs for all of the targets. Through extensive benchmarking studies, we demonstrated that (1) coupling PFE with Chemgauss4 significantly improves the early enrichment of Chemgauss4 itself and (2) PFEs show greater consistency in boosting early enrichment and larger overall enrichment than our prior PFs. In addition, we analyzed the pairwise topological similarities among cognate ligands used to construct PFEs and found that it is the higher chemical diversity of the cognate ligands that leads to the improved performance of PFEs. Taken together, the results so far prove that the incorporation of knowledge from diverse protein-ligand interfaces by ensemble modeling is able to enhance the screening competence of SBVS scoring functions.

  4. [Target volume margins for lung cancer: internal target volume/clinical target volume].

    Science.gov (United States)

    Jouin, A; Pourel, N

    2013-10-01

    The aim of this study was to carry out a review of margins that should be used for the delineation of target volumes in lung cancer, with a focus on margins from gross tumour volume (GTV) to clinical target volume (CTV) and internal target volume (ITV) delineation. Our review was based on a PubMed literature search with, as a cornerstone, the 2010 European Organisation for Research and Treatment of Cancer (EORTC) recommandations by De Ruysscher et al. The keywords used for the search were: radiotherapy, lung cancer, clinical target volume, internal target volume. The relevant information was categorized under the following headings: gross tumour volume definition (GTV), CTV-GTV margin (first tumoural CTV then nodal CTV definition), in field versus elective nodal irradiation, metabolic imaging role through the input of the PET scanner for tumour target volume and limitations of PET-CT imaging for nodal target volume definition, postoperative radiotherapy target volume definition, delineation of target volumes after induction chemotherapy; then the internal target volume is specified as well as tumoural mobility for lung cancer and respiratory gating techniques. Finally, a chapter is dedicated to planning target volume definition and another to small cell lung cancer. For each heading, the most relevant and recent clinical trials and publications are mentioned. Copyright © 2013. Published by Elsevier SAS.

  5. Energy deposition in a thin copper target downstream and off-axis of a proton-radiography target

    International Nuclear Information System (INIS)

    Greene, G.A.; Finfrock, C.C.; Snead, C.L.; Hanson, A.L.; Murray, M.M.

    2002-01-01

    A series of proton energy-deposition experiments was conducted to measure the energy deposited in a copper target located downstream and off-axis of a high-energy proton-radiography target. The proton/target interactions involved low-intensity bunches of protons at 24 GeV/c onto a spherical target consisting of concentric shells of tungsten and copper. The energy-deposition target was placed at five locations downstream of the proton-radiography target, off-axis of the primary beam transport, and was either unshielded or shielded by 5 or 10 cm of lead. Maximum temperature rises measured in the energy-deposition target due to single bunches of 5x10 10 protons on the proton-radiography target were approximately 20 mK per bunch. The data indicated that the scattered radiation was concentrated close to the primary transport axis of the beam line. The energy deposited in the energy-deposition target was reduced by moving the target radially away from the primary transport axis. Placing lead shielding in front of the target further reduced the energy deposition. The measured temperature rises of the energy-deposition target were empirically correlated with the distance from the source, the number of protons incident on the proton-radiography target, the thickness of the lead shielding, and the angle of the energy-deposition target off-axis of the beam line from the proton-radiography target. The correlation of the experimental data that was developed provides a starting point for the evaluation of the shielding requirements for devices downstream of proton-radiography targets such as superconducting magnets

  6. Addressing key science and technology issues for IFE chambers, target fabrication and target injection

    International Nuclear Information System (INIS)

    Meier, W.R.; Goodin, D.T.; Nobile, A.

    2003-01-01

    Significant progress has been made in the development of high repetition rate chambers, target fabrication and injection for inertial fusion energy (IFE) for both heavy ion and laser drivers. Research is being conducted in a coordinated manner by national laboratories, universities and industry. This paper provides an overview of U.S. research activities and discusses how interface considerations (such as beam propagation and target survival during injection) impact design choices. (author)

  7. Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

    Science.gov (United States)

    Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

    2018-01-01

    Introduction Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted. PMID:28271910

  8. Project Plan Remote Target Fabrication Refurbishment Project

    International Nuclear Information System (INIS)

    Bell, Gary L.; Taylor, Robin D.

    2009-01-01

    In early FY2009, the DOE Office of Science - Nuclear Physics Program reinstated a program for continued production of 252 Cf and other transcurium isotopes at the Radiochemical Engineering Development Center (REDC) at Oak Ridge National Laboratory (ORNL). The FY2009 major elements of the workscope are as follows: (1) Recovery and processing of seven transuranium element targets undergoing irradiation at the High Flux Isotope Reactor (HFIR) at ORNL; (2) Development of a plan to manufacture new targets for irradiation beginning in early- to mid-FY10 to supply irradiated targets for processing Campaign 75 (TRU75); and (3) Refurbishment of the target manufacturing equipment to allow new target manufacture in early FY10 The 252 Cf product from processing Campaign 74 (recently processed and currently shipping to customers) is expected to supply the domestic demands for a period of approximately two years. Therefore it is essential that new targets be introduced for irradiation by the second quarter of FY10 (HFIR cycle 427) to maintain supply of 252 Cf; the average irradiation period is ∼10 HFIR cycles, requiring about 1.5 calendar years. The strategy for continued production of 252 Cf depends upon repairing and refurbishing the existing pellet and target fabrication equipment for one additional target production campaign. This equipment dates from the mid-1960s to the late 1980s, and during the last target fabrication campaign in 2005- 2006, a number of component failures and operations difficulties were encountered. It is expected that following the target fabrication and acceptance testing of the targets that will supply material for processing Campaign 75 a comprehensive upgrade and replacement of the remote hot-cell equipment will be required prior to subsequent campaigns. Such a major refit could start in early FY 2011 and would take about 2 years to complete. Scope and cost estimates for the repairs described herein were developed, and authorization for the work

  9. Neutron resonance spectroscopy for the characterization of materials and objects

    International Nuclear Information System (INIS)

    Schillebeeckx, P; Borella, A; Emiliani, F; Kopecky, S; Lampoudis, C; Gorini, G; Cippo, E Perelli; Kockelmann, W; Rhodes, N J; Schooneveld, E M; Moxon, M; Postma, H; Van Beveren, C

    2012-01-01

    The resonance structure in neutron induced reaction cross sections can be used to determine the elemental compositions of materials or objects. The occurrence of resonances is the basis of neutron resonance capture analysis (NRCA) and neutron resonance transmission analysis (NRTA). NRCA and NRTA are fully non-destructive methods to determine the bulk elemental composition without the need of any sample preparation and resulting in a negligible residual activity. They have been applied to determine the elemental composition of archaeological objects and to characterize reference materials used for cross section measurements. For imaging applications a position sensitive neutron detector has been developed within the ANCIENT CHARM project. The detector is based on a 10 × 10 array of 6 Li-glass scintillators mounted on a pitch of 2.5 mm, resulting in a 25 × 25 mm 2 active area. The detector has been tested at the time-of-flight facility GELINA and used at the ISIS spallation source to study cultural heritage objects.

  10. Neutron resonance spectroscopy for the characterization of materials and objects

    Science.gov (United States)

    Schillebeeckx, P.; Borella, A.; Emiliani, F.; Gorini, G.; Kockelmann, W.; Kopecky, S.; Lampoudis, C.; Moxon, M.; Perelli Cippo, E.; Postma, H.; Rhodes, N. J.; Schooneveld, E. M.; Van Beveren, C.

    2012-03-01

    The resonance structure in neutron induced reaction cross sections can be used to determine the elemental compositions of materials or objects. The occurrence of resonances is the basis of neutron resonance capture analysis (NRCA) and neutron resonance transmission analysis (NRTA). NRCA and NRTA are fully non-destructive methods to determine the bulk elemental composition without the need of any sample preparation and resulting in a negligible residual activity. They have been applied to determine the elemental composition of archaeological objects and to characterize reference materials used for cross section measurements. For imaging applications a position sensitive neutron detector has been developed within the ANCIENT CHARM project. The detector is based on a 10 × 10 array of 6Li-glass scintillators mounted on a pitch of 2.5 mm, resulting in a 25 × 25 mm2 active area. The detector has been tested at the time-of-flight facility GELINA and used at the ISIS spallation source to study cultural heritage objects.

  11. HPPD: ligand- and target-based virtual screening on a herbicide target.

    Science.gov (United States)

    López-Ramos, Miriam; Perruccio, Francesca

    2010-05-24

    Hydroxyphenylpyruvate dioxygenase (HPPD) has proven to be a very successful target for the development of herbicides with bleaching properties, and today HPPD inhibitors are well established in the agrochemical market. Syngenta has a long history of HPPD-inhibitor research, and HPPD was chosen as a case study for the validation of diverse ligand- and target-based virtual screening approaches to identify compounds with inhibitory properties. Two-dimensional extended connectivity fingerprints, three-dimensional shape-based tools (ROCS, EON, and Phase-shape) and a pharmacophore approach (Phase) were used as ligand-based methods; Glide and Gold were used as target-based. Both the virtual screening utility and the scaffold-hopping ability of the screening tools were assessed. Particular emphasis was put on the specific pitfalls to take into account for the design of a virtual screening campaign in an agrochemical context, as compared to a pharmaceutical environment.

  12. Climate and energy targets of the European Union

    International Nuclear Information System (INIS)

    Stolwijk, H.; Veenendaal, P.

    2007-01-01

    Attention is paid to two important parts of the targets for climate and energy which were determined by the European Council in March 2007 for the year 2020: (1) the impact of the emission reduction target and the correlations with the sustainable development targets; and (2) the obstacles for the European Union on the way to thar 20% renewable energy target [nl

  13. Evaluation of stable tungsten isotopes in the resolved resonance region

    Directory of Open Access Journals (Sweden)

    Schillebeeckx P.

    2013-03-01

    Full Text Available In the last decade benchmark experiments and simulations, together with newly obtained neutron cross section data, have pointed out deficiencies in evaluated data files of W isotopes. The role of W as a fundamental structural material in different nuclear applications fully justifies a new evaluation of 182, 183, 184, 186W neutron resonance parameters. In this regard transmission and capture cross section measurements on natural and enriched tungsten samples were performed at the GELINA facility of the EC-JRC-IRMM. A resonance parameter file used as input in the resonance shape analysis was prepared based on the available literature and adjusted in first instance to transmission data.

  14. Rexin-G, a targeted genetic medicine for cancer.

    Science.gov (United States)

    Gordon, Erlinda M; Hall, Frederick L

    2010-05-01

    Rexin-G, a tumor-targeted retrovector bearing a cytocidal cyclin G1 construct, is the first targeted gene therapy vector to gain fast track designation and orphan drug priorities for multiple cancer indications in the US. This review describes the major milestones in the clinical development of Rexin-G: from the molecular cloning and characterization of the human cyclin G1 proto-oncogene in 1994, to the design of the first knockout constructs and genetic engineering of the targeted delivery system from 1995 to 1997, through the initial proofs-of-concept, molecular pharmacology and toxicology studies of Rexin-G in preclinical cancer models from 1997 to 2001, to the pioneering clinical studies in humans from 2002 to 2004, which--together with the advancements in bioprocess development of high-potency clinical grade vectors circa 2005 - 2006--led to the accelerated approval of Rexin-G for all solid tumors by the Philippine FDA in 2007 and the rapid progression of clinical studies from 2007 to 2009 to the cusp of pivotal Phase III trials in the US. In recording the development of Rexin-G as a novel form of targeted biological therapy, this review also highlights important aspects of vector design engineering which served to overcome the physiological barriers to gene delivery as it addresses the key regulatory issues involved in the development of a targeted gene therapy product. Progressive clinical development of Rexin-G demonstrates the potential safety and efficacy of targeted genetic medicine, while validating the design engineering of the molecular biotechnology platform.

  15. Development and application of a quantitative multiplexed small GTPase activity assay using targeted proteomics.

    Science.gov (United States)

    Zhang, Cheng-Cheng; Li, Ru; Jiang, Honghui; Lin, Shujun; Rogalski, Jason C; Liu, Kate; Kast, Juergen

    2015-02-06

    Small GTPases are a family of key signaling molecules that are ubiquitously expressed in various types of cells. Their activity is often analyzed by western blot, which is limited by its multiplexing capability, the quality of isoform-specific antibodies, and the accuracy of quantification. To overcome these issues, a quantitative multiplexed small GTPase activity assay has been developed. Using four different binding domains, this assay allows the binding of up to 12 active small GTPase isoforms simultaneously in a single experiment. To accurately quantify the closely related small GTPase isoforms, a targeted proteomic approach, i.e., selected/multiple reaction monitoring, was developed, and its functionality and reproducibility were validated. This assay was successfully applied to human platelets and revealed time-resolved coactivation of multiple small GTPase isoforms in response to agonists and differential activation of these isoforms in response to inhibitor treatment. This widely applicable approach can be used for signaling pathway studies and inhibitor screening in many cellular systems.

  16. Development of LEU targets for 99Mo production and their chemical processing status 1989

    International Nuclear Information System (INIS)

    Vandegrift, G.F.; Kwok, J.D.; Chamberlain, D.B.; Hoh, J.C.; Streets, E.W.; Vogler, S.; Thresh, H.R.; Domagala, R.F.; Wiencek, T.C.; Matos, J.E.

    1991-01-01

    Most of the world's supply of Tc-99m for medical purposes is currently produced from Mo-99 derived from the fissioning of high enriched uranium (HEU). Substitution of low enriched uranium (LEU) silicide fuel for the HEU alloy and aluminide fuels used in current target designs will allow equivalent Mo-99 yields with no change in target geometries. Substitution of uranium metal will also allow the substitution of LEU for HEU. Efforts performed in 1989 focused on (1) fabrication of a uranium metal target by Hot Isostatic Pressing uranium metal foil to zirconium, (2) experimental investigation of the dissolution step for U 3 Si 2 targets, allowing us to present a conceptual design for the dissolution process and equipment, and (3) investigation of the procedures used to reclaim irradiated uranium from Mo-production targets, allowing us to further analyze the waste and by-product problems associated with the substitution of LEU for HEU. (orig.)

  17. Concepts for fabrication of inertial fusion energy targets

    Energy Technology Data Exchange (ETDEWEB)

    Nobile, A. (Arthur), Jr.; Hoffer, J. K. (James K.); Gobby, P. L. (Peter L.); Steckle, W. P. (Warren P.), Jr.; Goodin, D. T. (Daniel T.); Besenbruch, G. E. (Gottfried E.); Schultz, K. R. (Kenneth R.)

    2001-01-01

    Future inertial fusion energy (IFE) power plants will have a Target Fabrication Facility (TFF) that must produce approximately 500,000 targets per day. To achieve a relatively low cost of electricity, the cost to produce these targets will need to be less than approximately $0.25 per target. In this paper the status on the development of concepts for a TFF to produce targets for a heavy ion fusion (HIF) reactor, such as HYLIFE II, and a laser direct drive fusion reactor such as Sombrero, is discussed. The baseline target that is produced in the HIF TFF is similar to the close-coupled indirect drive target designed by Callahan-Miller and Tabak at Lawrence Livermore Laboratory. This target consists of a cryogenic hohlraum that is made of a metal case and a variety of metal foams and metal-doped organic foams. The target contains a DT-filled CH capsule. The baseline direct drive target is the design developed by Bodner and coworkers at Naval Research Laboratory. HIF targets can be filled with DT before or after assembly of the capsule into the hohlraum. Assembly of targets before filling allows assembly operations to be done at room temperature, but tritium inventories are much larger due to the large volume that the hohlraum occupies in the fill system. Assembly of targets cold after filling allows substantial reduction in tritium inventory, but this requires assembly of targets at cryogenic temperature. A model being developed to evaluate the tritium inventories associated with each of the assembly and fill options indicates that filling targets before assembling the capsule into the hohlraum, filling at temperatures as high as possible, and reducing dead-volumes in the fill system as much as possible offers the potential to reduce tritium inventories to acceptable levels. Use of enhanced DT ice layering techniques, such as infrared layering can reduce tritium inventories significantly by reducing the layering time and therefore the number of capsules being layered

  18. Development and evaluation of targeted psychological skills training for oncology nurses in managing stressful patient and family encounters.

    Science.gov (United States)

    Traeger, Lara; Park, Elyse R; Sporn, Nora; Repper-DeLisi, Jennifer; Convery, Mary Susan; Jacobo, Michelle; Pirl, William F

    2013-07-01

    To reduce workplace stress by developing a brief psychological skills training for nurses and to evaluate program feasibility, acceptability, and preliminary efficacy in decreasing burnout and stress. Intervention development and evaluation. Outpatient chemotherapy unit at a comprehensive cancer center. 26 infusion nurses and oncology social workers. Focus groups were conducted with nurses. Results informed the development and evaluation of training for nurses. Participants completed the Maslach Burnout Inventory and Perceived Stress Scale post-training. Burnout and stress. Focus groups indicated strong commitment among nurses to psychosocial care and supported the idea that relationships with patients and families were sources of reward and stress. Stressors included factors that interfered with psychosocial care such as difficult family dynamics, patient behaviors and end-of-life care issues. Psychological skills training was developed to address these stressors. Evaluations suggested that the program was feasible and acceptable to nurses. At two months, participants showed reductions in emotional exhaustion (p = 0.02) and stress (p = 0.04). Psychological skills training for managing difficult encounters showed feasibility, acceptability, and potential benefit in reducing emotional exhaustion and stress. Brief training that targets sources of clinical stress may be useful for nurses in outpatient chemotherapy units. Specific stressors in relationships with patients and families present challenges to nurses' therapeutic use of self. Targeted psychological skills training may help nurses problem-solve difficult encounters while taking care of themselves. System-level strategies are needed to support and promote training participation.

  19. Polarized targets at triangle universities nuclear laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Seely, M.L. [North Carolina State Univ., Raleigh, NC (United States); Gould, C.R. [North Carolina State Univ., Raleigh, NC (United States); Haase, D.G. [North Carolina State Univ., Raleigh, NC (United States); Huffman, P.R. [Triangle Universities Nuclear Laboratory, Durham, NC 27708 (United States); Keith, C.D. [North Carolina State Univ., Raleigh, NC (United States); Roberson, N.R. [Triangle Universities Nuclear Laboratory, Durham, NC 27708 (United States); Tornow, W. [Triangle Universities Nuclear Laboratory, Durham, NC 27708 (United States); Wilburn, W.S. [Triangle Universities Nuclear Laboratory, Durham, NC 27708 (United States)

    1995-03-01

    A summary of the polarized and aligned nuclear targets which have been constructed and used at the Triangle Universities Nuclear Laboratory is given. Statically polarized targets, typically operating at a temperature of 12 mK and a magnetic field of 7 T, have provided significant nuclear polarization in {sup 1}H, {sup 3}He, {sup 27}Al, {sup 93}Nb and {sup 165}Ho. A rotating, aligned {sup 165}Ho target is also in use. A {sup 3}He melting curve thermometer has been developed for use in statically polarized targets. A dynamically polarized proton target is under construction. ((orig.))

  20. Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Hongguang Sun

    2014-01-01

    Full Text Available Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

  1. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

    Directory of Open Access Journals (Sweden)

    Ronald E. See

    2011-06-01

    Full Text Available Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches.

  2. Application of monitoring and targeting to energy management

    Energy Technology Data Exchange (ETDEWEB)

    Gotel, D G; Hale, D K

    1989-01-01

    This general guide has been prepared to show how monitoring and targeting can control energy use and improve the efficiency with which energy is used in different sectors of the national economy. It is based on the results of work carried out, under the Energy Efficiency Office Monitoring and Targeting Programme, on the development of practical energy management systems for use in manufacturing industry, commerce and the public sector. The principles of monitoring and targeting are described together with the steps which have to be taken to set up monitoring and targeting as an integral part of an existing management organization. Procedures are given for monitoring energy use, defining standards and targets, reporting results and reviewing progress. These procedures which have been developed and tested in working environments are illustrated with examples of their practical application. Finally, an account is given of the improvements of performance in the use of energy and the other benefits which can be gained through energy monitoring and targeting.

  3. Vision-Based Target Finding and Inspection of a Ground Target Using a Multirotor UAV System.

    Science.gov (United States)

    Hinas, Ajmal; Roberts, Jonathan M; Gonzalez, Felipe

    2017-12-17

    In this paper, a system that uses an algorithm for target detection and navigation and a multirotor Unmanned Aerial Vehicle (UAV) for finding a ground target and inspecting it closely is presented. The system can also be used for accurate and safe delivery of payloads or spot spraying applications in site-specific crop management. A downward-looking camera attached to a multirotor is used to find the target on the ground. The UAV descends to the target and hovers above the target for a few seconds to inspect the target. A high-level decision algorithm based on an OODA (observe, orient, decide, and act) loop was developed as a solution to address the problem. Navigation of the UAV was achieved by continuously sending local position messages to the autopilot via Mavros. The proposed system performed hovering above the target in three different stages: locate, descend, and hover. The system was tested in multiple trials, in simulations and outdoor tests, from heights of 10 m to 40 m. Results show that the system is highly reliable and robust to sensor errors, drift, and external disturbance.

  4. Multi-laboratory evaluations of the performance of Catellicoccus marimammalium PCR assays developed to target gull fecal sources

    Science.gov (United States)

    Sinigalliano, Christopher D.; Ervin, Jared S.; Van De Werfhorst, Laurie C.; Badgley, Brian D.; Ballestée, Elisenda; Bartkowiaka, Jakob; Boehm, Alexandria B.; Byappanahalli, Muruleedhara N.; Goodwin, Kelly D.; Gourmelon, Michèle; Griffith, John; Holden, Patricia A.; Jay, Jenny; Layton, Blythe; Lee, Cheonghoon; Lee, Jiyoung; Meijer, Wim G.; Noble, Rachel; Raith, Meredith; Ryu, Hodon; Sadowsky, Michael J.; Schriewer, Alexander; Wang, Dan; Wanless, David; Whitman, Richard; Wuertz, Stefan; Santo Domingo, Jorge W.

    2013-01-01

    Here we report results from a multi-laboratory (n = 11) evaluation of four different PCR methods targeting the 16S rRNA gene of Catellicoccus marimammalium originally developed to detect gull fecal contamination in coastal environments. The methods included a conventional end-point PCR method, a SYBR® Green qPCR method, and two TaqMan® qPCR methods. Different techniques for data normalization and analysis were tested. Data analysis methods had a pronounced impact on assay sensitivity and specificity calculations. Across-laboratory standardization of metrics including the lower limit of quantification (LLOQ), target detected but not quantifiable (DNQ), and target not detected (ND) significantly improved results compared to results submitted by individual laboratories prior to definition standardization. The unit of measure used for data normalization also had a pronounced effect on measured assay performance. Data normalization to DNA mass improved quantitative method performance as compared to enterococcus normalization. The MST methods tested here were originally designed for gulls but were found in this study to also detect feces from other birds, particularly feces composited from pigeons. Sequencing efforts showed that some pigeon feces from California contained sequences similar to C. marimammalium found in gull feces. These data suggest that the prevalence, geographic scope, and ecology of C. marimammalium in host birds other than gulls require further investigation. This study represents an important first step in the multi-laboratory assessment of these methods and highlights the need to broaden and standardize additional evaluations, including environmentally relevant target concentrations in ambient waters from diverse geographic regions.

  5. A modular platform for targeted RNAi therapeutics.

    Science.gov (United States)

    Kedmi, Ranit; Veiga, Nuphar; Ramishetti, Srinivas; Goldsmith, Meir; Rosenblum, Daniel; Dammes, Niels; Hazan-Halevy, Inbal; Nahary, Limor; Leviatan-Ben-Arye, Shani; Harlev, Michael; Behlke, Mark; Benhar, Itai; Lieberman, Judy; Peer, Dan

    2018-03-01

    Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs 1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting 4-8 , their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.

  6. A modular platform for targeted RNAi therapeutics

    Science.gov (United States)

    Kedmi, Ranit; Veiga, Nuphar; Ramishetti, Srinivas; Goldsmith, Meir; Rosenblum, Daniel; Dammes, Niels; Hazan-Halevy, Inbal; Nahary, Limor; Leviatan-Ben-Arye, Shani; Harlev, Michael; Behlke, Mark; Benhar, Itai; Lieberman, Judy; Peer, Dan

    2018-01-01

    Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting4-8, their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.

  7. Realistic, achievable and effective targets and timetables

    International Nuclear Information System (INIS)

    Hambley, M.G.

    1997-01-01

    The current status of U.S. policy regarding climate change, and the U.S. perspective on targets and timetables were discussed. U.S. policy is based on four particular points: (1) legally binding, multi-year emissions budgets, (2) focus on medium, not short-term targets, (3) maximum flexibility offered to parties to reach whatever targets are agreed upon, and (4) a proposal concerning developing countries. It was strongly suggested that if the December 1997 conference in Kyoto is to succeed, developing countries would have to have a role in negotiations. Greenhouse gas emissions and climate change are global issues, and can only be solved by global action

  8. Achieving the Renewable Energy Target for Jamaica

    Directory of Open Access Journals (Sweden)

    Abdullahi Olabode ABDULKADRI

    2014-05-01

    Full Text Available ieving the Renewable Energy Target for Jamaica Abstract: The high cost of energy in Jamaica, one of the highest in the Caribbean region, is usually cited as a hindrance to industrial development and efficiency, especially in the manufacturing sector. High energy cost is also considered to be a national energy security issue and the government is taking steps to ensure adequate supply of energy at affordable prices. In the current National Development Plan, the government has set a target for renewable energy sources to supply 20% of the country's energy need by the year 2030. Using a linear programing model of energy planning, we examine how realistically this target could be achieved. Our findings indicate that the 20% renewable energy target is technically achievable with the optimal plan showing a mixture of wind power, hydropower and bagasse power but no solar power. However, when the timeline for investment in new generating capacities that will ensure the attainment of the target is considered, it becomes highly improbable that the target will be met. This study fills the gap that exists in evidence-based analysis of energy policy in Jamaica.

  9. Detection of Moving Targets Using Soliton Resonance Effect

    Science.gov (United States)

    Kulikov, Igor K.; Zak, Michail

    2013-01-01

    The objective of this research was to develop a fundamentally new method for detecting hidden moving targets within noisy and cluttered data-streams using a novel "soliton resonance" effect in nonlinear dynamical systems. The technique uses an inhomogeneous Korteweg de Vries (KdV) equation containing moving-target information. Solution of the KdV equation will describe a soliton propagating with the same kinematic characteristics as the target. The approach uses the time-dependent data stream obtained with a sensor in form of the "forcing function," which is incorporated in an inhomogeneous KdV equation. When a hidden moving target (which in many ways resembles a soliton) encounters the natural "probe" soliton solution of the KdV equation, a strong resonance phenomenon results that makes the location and motion of the target apparent. Soliton resonance method will amplify the moving target signal, suppressing the noise. The method will be a very effective tool for locating and identifying diverse, highly dynamic targets with ill-defined characteristics in a noisy environment. The soliton resonance method for the detection of moving targets was developed in one and two dimensions. Computer simulations proved that the method could be used for detection of singe point-like targets moving with constant velocities and accelerations in 1D and along straight lines or curved trajectories in 2D. The method also allows estimation of the kinematic characteristics of moving targets, and reconstruction of target trajectories in 2D. The method could be very effective for target detection in the presence of clutter and for the case of target obscurations.

  10. Validation, optimisation, and application data in support of the development of a targeted selected ion monitoring assay for degraded cardiac troponin T

    Directory of Open Access Journals (Sweden)

    Alexander S. Streng

    2016-06-01

    Full Text Available Cardiac troponin T (cTnT fragmentation in human serum was investigated using a newly developed targeted selected ion monitoring assay, as described in the accompanying article: “Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T” [1]. This article presents data describing aspects of the validation and optimisation of this assay. The data consists of several figures, an excel file containing the results of a sequence identity search, and a description of the raw mass spectrometry (MS data files, deposited in the ProteomeXchange repository with id PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD003187.

  11. A Plutonium Ceramic Target for MASHA

    International Nuclear Information System (INIS)

    Wilk, P A; Shaughnessy, D A; Moody, K J; Kenneally, J M; Wild, J F; Stoyer, M A; Patin, J B; Lougheed, R W; Ebbinghaus, B B; Landingham, R L; Oganessian, Y T; Yeremin, A V; Dmitriev, S N

    2004-01-01

    We are currently developing a plutonium ceramic target for the MASHA mass separator. The MASHA separator will use a thick plutonium ceramic target capable of tolerating temperatures up to 2000 C. Promising candidates for the target include oxides and carbides, although more research into their thermodynamic properties will be required. Reaction products will diffuse out of the target into an ion source, where they will then be transported through the separator to a position-sensitive focal-plane detector array. Experiments on MASHA will allow us to make measurements that will cement our identification of element 114 and provide for future experiments where the chemical properties of the heaviest elements are studied

  12. Generation and compression of a target plasma for magnetized target fusion

    International Nuclear Information System (INIS)

    Kirkpatrick, R.C.; Lindemuth, I.R.; Sheehey, P.T.

    1998-01-01

    This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). Magnetized target fusion (MTF) is intermediate between the two very different approaches to fusion: inertial and magnetic confinement fusion (ICF and MCF). Results from collaboration with a Russian MTF team on their MAGO experiments suggest they have a target plasma suitable for compression to provide an MTF proof of principle. This LDRD project had tow main objectives: first, to provide a computational basis for experimental investigation of an alternative MTF plasma, and second to explore the physics and computational needs for a continuing program. Secondary objectives included analytic and computational support for MTF experiments. The first objective was fulfilled. The second main objective has several facets to be described in the body of this report. Finally, the authors have developed tools for analyzing data collected on the MAGO and LDRD experiments, and have tested them on limited MAGO data

  13. Identifying Drug-Target Interactions with Decision Templates.

    Science.gov (United States)

    Yan, Xiao-Ying; Zhang, Shao-Wu

    2018-01-01

    During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can

  14. Drug-Target Interactions: Prediction Methods and Applications.

    Science.gov (United States)

    Anusuya, Shanmugam; Kesherwani, Manish; Priya, K Vishnu; Vimala, Antonydhason; Shanmugam, Gnanendra; Velmurugan, Devadasan; Gromiha, M Michael

    2018-01-01

    Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development.

    Science.gov (United States)

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-10-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and expression of chondrogenic genes, including Indian hedgehog (Ihh), a critical mediator of mechanotransduction. Conversely, cyclic loading (1 Hz, 5% matrix deformation) of embryonic chicken growth plate chondrocytes in 3-dimensional (3D) collagen scaffolding induced sustained activation of mTOR. Mechanical activation of mTOR occurred in serum-free medium, indicating that it is independent of growth factor or nutrients. Treatment of chondrocytes with Rapa abolished mechanical activation of cell proliferation and Ihh gene expression. Cyclic loading of chondroprogenitor cells deficient in SH2-containing protein tyrosine phosphatase 2 (Shp2) further enhanced mechanical activation of mTOR, cell proliferation, and chondrogenic gene expression. This result suggests that Shp2 is an antagonist of mechanotransduction through inhibition of mTOR activity. Our data demonstrate that mechanical activation of mTOR is necessary for cell proliferation, chondrogenesis, and cartilage growth during bone development, and that mTOR is an essential mechanotransduction component modulated by Shp2 in the cytoplasm. © FASEB.

  16. Treat-to-target in systemic lupus erythematosus

    DEFF Research Database (Denmark)

    van Vollenhoven, Ronald F; Mosca, Marta; Bertsias, George

    2014-01-01

    guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology...

  17. Systematic Development of the YouRAction program, a computer-tailored Physical Activity promotion intervention for Dutch adolescents, targeting personal motivations and environmental opportunities

    Directory of Open Access Journals (Sweden)

    Prins Richard G

    2010-08-01

    Full Text Available Abstract Background Increasing physical activity (PA among adolescents is an important health promotion goal. PA has numerous positive health effects, but the majority of Dutch adolescents do not meet PA requirements. The present paper describes the systematic development of a theory-based computer-tailored intervention, YouRAction, which targets individual and environmental factors determining PA among adolescents. Design The intervention development was guided by the Intervention Mapping protocol, in order to define clear program objectives, theoretical methods and practical strategies, ensure systematic program planning and pilot-testing, and anticipate on implementation and evaluation. Two versions of YouRAction were developed: one that targets individual determinants and an extended version that also provides feedback on opportunities to be active in the neighbourhood. Key determinants that were targeted included: knowledge and awareness, attitudes, self-efficacy and subjective norms. The extended version also addressed perceived availability of neighbourhood PA facilities. Both versions aimed to increase levels of moderate-to-vigorous PA among adolescents. The intervention structure was based on self-regulation theory, comprising of five steps in the process of successful goal pursuit. Monitoring of PA behaviour and behavioural and normative feedback were used to increase awareness of PA behaviour; motivation was enhanced by targeting self-efficacy and attitudes, by means of various interactive strategies, such as web movies; the perceived environment was targeted by visualizing opportunities to be active in an interactive geographical map of the home environment; in the goal setting phase, the adolescents were guided in setting a goal and developing an action plan to achieve this goal; in the phase of active goal pursuit adolescents try to achieve their goal and in the evaluation phase the achievements are evaluated. Based on the results

  18. The Effects of Color Cues on Typically Developing Preschoolers' Speed of Locating a Target Line Drawing: Implications for Augmentative and Alternative Communication Display Design

    Science.gov (United States)

    Thistle, Jennifer J.; Wilkinson, Krista

    2009-01-01

    Purpose: This research examined how the presence of color in relation to a target within an augmentative and alternative communication array influenced the speed with which typically developing preschoolers located a target line drawing. Method: Fifteen children over the age of 4 years (from 4;2 [years;months] to 5;4) and 15 children under the age…

  19. Spallation source neutron target systems

    International Nuclear Information System (INIS)

    Russell, G.; Brown, R.; Collier, M.; Donahue, J.

    1996-01-01

    This is the final report for a two-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The project sought to design a next-generation spallation source neutron target system for the Manuel Lujan, Jr., Neutron Scattering Center (LANSCE) at Los Alamos. It has been recognized for some time that new advanced neutron sources are needed in the US if the country is to maintain a competitive position in several important scientific and technological areas. A recent DOE panel concluded that the proposed Advanced Neutron Source (a nuclear reactor at Oak Ridge National Laboratory) and a high-power pulsed spallation source are both needed in the near future. One of the most technically challenging designs for a spallation source is the target station itself and, more specifically, the target-moderator-reflector arrangement. Los Alamos has demonstrated capabilities in designing, building, and operating high-power spallation-neutron-source target stations. Most of the new design ideas proposed worldwide for target system design for the next generation pulsed spallation source have either been conceived and implemented at LANSCE or proposed by LANSCE target system designers. These concepts include split targets, flux-trap moderators, back scattering and composite moderators, and composite reflectors

  20. IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Wang, Liya; Wang, Y Andrew; Chen, Hongyu; Kooby, David; Yu, Qian; Lipowska, Malgorzata; Staley, Charles A; Mao, Hui; Yang, Lily

    2015-08-25

    Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

  1. Targets for the APEX experiment at ATLAS

    International Nuclear Information System (INIS)

    Greene, J.P.; Thomas, G.E.; Leonard, R.H.

    1994-01-01

    Targets of lead, tantalum, thorium and uranium have been produced for experiments with the APEX (Argonne Positron Experiment) apparatus at ATLAS (Argonne Tandem Linac Accelerator System). APEX is a device built at Argonne National Laboratory to investigate the anomalous positrons observed in collisions of very heavy ion beams on heavy targets. Both fixed and rotating targets have been used. The rotating target system involves a 4-quadrant wheel rotating at speeds up to 700 rpm with the position encoded into the data stream. In addition to the hundreds of targets produced for the heavy-ion reactions studied, a wide variety of targets were employed for beam diagnostics, detector calibration and target wheel development. The experiment used very heavy ion beams ( 238 U, 206 Pb and 208 Pb) from ATLAS and targets of 206 Pb, 208 Pb, 232 Th and 238 U produced in the laboratory

  2. Drug target ontology to classify and integrate drug discovery data.

    Science.gov (United States)

    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

  3. Bio-Guided Targeting for Preservative and Anti-Ageing Cosmetic Ingredient Development

    Directory of Open Access Journals (Sweden)

    Emilie Destandau

    2014-01-01

    Full Text Available To develop a new antioxidant, antibacterial and natural cosmetic ingredient without cytotoxicity to skin cells, bioactive molecules contained in Kalanchoe pinnata leaf methanolic extract were targeted using semi-preparative HPLC fractionation linked to biological activity tests. Chromatographic effluent was collected at the column outlet into a 96 deep-well microplate, filling successively all the wells. After freeze-drying, the microplate was ready to use for different biological tests such as antimicrobial activity on microorganisms, skin cell viability and antioxidant activity on human keratinocyte cells. The injection of only 2.64 mg of crude extract into the HPLC system reveals a good correlation between the chromatographic peaks and the different biological activities. One fraction is mainly of interest since good antibacterial and antioxidant activities without cytotoxicity are observed. The analysis of this fraction using mass spectrometry allows the identification of glycoside derivatives of quercetin, isorhamnetin and kaempferol. Thus, a correlation between biological activity and the presence of these flavonoids is obtained. This screening method allows a rapid fractionation associated with a biological activity evaluation and a first molecular identification, saving time by limiting sample treatments and solvent consumption.

  4. Targeting the latest hallmark of cancer: another attempt at 'magic bullet' drugs targeting cancers' metabolic phenotype.

    Science.gov (United States)

    Cuperlovic-Culf, M; Culf, A S; Touaibia, M; Lefort, N

    2012-10-01

    The metabolism of tumors is remarkably different from the metabolism of corresponding normal cells and tissues. Metabolic alterations are initiated by oncogenes and are required for malignant transformation, allowing cancer cells to resist some cell death signals while producing energy and fulfilling their biosynthetic needs with limiting resources. The distinct metabolic phenotype of cancers provides an interesting avenue for treatment, potentially with minimal side effects. As many cancers show similar metabolic characteristics, drugs targeting the cancer metabolic phenotype are, perhaps optimistically, expected to be 'magic bullet' treatments. Over the last few years there have been a number of potential drugs developed to specifically target cancer metabolism. Several of these drugs are currently in clinical and preclinical trials. This review outlines examples of drugs developed for different targets of significance to cancer metabolism, with a focus on small molecule leads, chemical biology and clinical results for these drugs.

  5. MicroRNAs responding to southern rice black-streaked dwarf virus infection and their target genes associated with symptom development in rice.

    Science.gov (United States)

    Xu, Donglin; Mou, Guiping; Wang, Kang; Zhou, Guohui

    2014-09-22

    Southern rice black-streaked dwarf virus (SRBSDV) is a recently emerged rice virus that has spread across Asia. This devastating virus causes rice plants to produce a variety of symptoms during different growth stages. MicroRNAs (miRNAs) comprise a large group of 21-24-nt RNA molecules that are important regulators of plant development processes and stress responses. In this study, we used microarray profiling to investigate rice miRNAs responding to SRBSDV infection at 3, 9, 15, and 20 days post-inoculation (dpi). Expression levels of 56 miRNAs were altered in SRBSDV-infected rice plants, with these changes classified into eight different regulation patterns according to their temporal expression dynamics. Fourteen miRNAs belonging to six families (miR164, R396, R530, R1846, R1858, and R2097) were significantly regulated at 20 dpi. We used RT-qPCR to search for expression level correlations between members of these families and their putative targets at 3, 9, and 15 dpi. Some members of the miR164, R396, R530, and R1846 families were found to be positively or negatively correlated with their respective targets during 3-15 days after SRBSDV infection, whereas in more cases the rice miRNAs were not in correlation with their targets along the post-inoculation period, suggesting that some additional factors may be involved in rice miRNA-target interactions. The reported functions of rice genes targeted by the miR164, R396, R530, R1846, and R1858 families indicated that these genes are associated with symptom development. These results provide insights into miRNA-mediated SRBSDV-rice interactions. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Targeted therapy using nanotechnology: focus on cancer.

    Science.gov (United States)

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication.

  7. a Plutonium Ceramic Target for Masha

    Science.gov (United States)

    Wilk, P. A.; Shaughnessy, D. A.; Moody, K. J.; Kenneally, J. M.; Wild, J. F.; Stoyer, M. A.; Patin, J. B.; Lougheed, R. W.; Ebbinghaus, B. B.; Landingham, R. L.; Oganessian, Yu. Ts.; Yeremin, A. V.; Dmitriev, S. N.

    2005-09-01

    We are currently developing a plutonium ceramic target for the MASHA mass separator. The MASHA separator will use a thick plutonium ceramic target capable of tolerating temperatures up to 2000 °C. Promising candidates for the target include oxides and carbides, although more research into their thermodynamic properties will be required. Reaction products will diffuse out of the target into an ion source, where they will then be transported through the separator to a position-sensitive focal-plane detector array. Experiments on MASHA will allow us to make measurements that will cement our identification of element 114 and provide for future experiments where the chemical properties of the heaviest elements are studied.

  8. Beyond the binding site: in vivo identification of tbx2, smarca5 and wnt5b as molecular targets of CNBP during embryonic development.

    Science.gov (United States)

    Armas, Pablo; Margarit, Ezequiel; Mouguelar, Valeria S; Allende, Miguel L; Calcaterra, Nora B

    2013-01-01

    CNBP is a nucleic acid chaperone implicated in vertebrate craniofacial development, as well as in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human muscle diseases. CNBP is highly conserved among vertebrates and has been implicated in transcriptional regulation; however, its DNA binding sites and molecular targets remain elusive. The main goal of this work was to identify CNBP DNA binding sites that might reveal target genes involved in vertebrate embryonic development. To accomplish this, we used a recently described yeast one-hybrid assay to identify DNA sequences bound in vivo by CNBP. Bioinformatic analyses revealed that these sequences are G-enriched and show high frequency of putative G-quadruplex DNA secondary structure. Moreover, an in silico approach enabled us to establish the CNBP DNA-binding site and to predict CNBP putative targets based on gene ontology terms and synexpression with CNBP. The direct interaction between CNBP and candidate genes was proved by EMSA and ChIP assays. Besides, the role of CNBP upon the identified genes was validated in loss-of-function experiments in developing zebrafish. We successfully confirmed that CNBP up-regulates tbx2b and smarca5, and down-regulates wnt5b gene expression. The highly stringent strategy used in this work allowed us to identify new CNBP target genes functionally important in different contexts of vertebrate embryonic development. Furthermore, it represents a novel approach toward understanding the biological function and regulatory networks involving CNBP in the biology of vertebrates.

  9. Beyond the binding site: in vivo identification of tbx2, smarca5 and wnt5b as molecular targets of CNBP during embryonic development.

    Directory of Open Access Journals (Sweden)

    Pablo Armas

    Full Text Available CNBP is a nucleic acid chaperone implicated in vertebrate craniofacial development, as well as in myotonic dystrophy type 2 (DM2 and sporadic inclusion body myositis (sIBM human muscle diseases. CNBP is highly conserved among vertebrates and has been implicated in transcriptional regulation; however, its DNA binding sites and molecular targets remain elusive. The main goal of this work was to identify CNBP DNA binding sites that might reveal target genes involved in vertebrate embryonic development. To accomplish this, we used a recently described yeast one-hybrid assay to identify DNA sequences bound in vivo by CNBP. Bioinformatic analyses revealed that these sequences are G-enriched and show high frequency of putative G-quadruplex DNA secondary structure. Moreover, an in silico approach enabled us to establish the CNBP DNA-binding site and to predict CNBP putative targets based on gene ontology terms and synexpression with CNBP. The direct interaction between CNBP and candidate genes was proved by EMSA and ChIP assays. Besides, the role of CNBP upon the identified genes was validated in loss-of-function experiments in developing zebrafish. We successfully confirmed that CNBP up-regulates tbx2b and smarca5, and down-regulates wnt5b gene expression. The highly stringent strategy used in this work allowed us to identify new CNBP target genes functionally important in different contexts of vertebrate embryonic development. Furthermore, it represents a novel approach toward understanding the biological function and regulatory networks involving CNBP in the biology of vertebrates.

  10. Ca-48 targets - Home and abroad!

    Science.gov (United States)

    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.

  11. Polarized gas targets for storage rings

    International Nuclear Information System (INIS)

    Holt, R.J.

    1990-01-01

    It is widely recognized that polarized gas targets in electron storage rings represent a new opportunity for precision nuclear physics studies. New developments in polarized target technology specific to internal applications will be discussed. In particular, polarized gas targets have been used in the VEPP-3 electron ring in Novosibirsk. A simple storage cell was used to increase the total target thickness by a factor of 15 over the simple gas jet target from an atomic beam source. Results from the initial phase of this project will be reported. In addition, the plans for increasing the luminosity by an additional order or magnitude will be presented. The application of this work to polarized hydrogen and deuterium targets for the HERA ring will be noted. The influence of beam-induced depolarization, a phenomena encountered in short-pulse electron storage rings, will be discussed. Finally, the performance tests of laser-driven sources will be presented. 8 refs., 12 figs., 1 tab

  12. High volume fabrication of laser targets using MEMS techniques

    International Nuclear Information System (INIS)

    Spindloe, C; Tomlinson, S; Green, J; Booth, N.; Tolley, M K; Arthur, G; Hall, F; Potter, R; Kar, S; Higginbotham, A

    2016-01-01

    The latest techniques for the fabrication of high power laser targets, using processes developed for the manufacture of Micro-Electro-Mechanical System (MEMS) devices are discussed. These laser targets are designed to meet the needs of the increased shot numbers that are available in the latest design of laser facilities. Traditionally laser targets have been fabricated using conventional machining or coarse etching processes and have been produced in quantities of 10s to low 100s. Such targets can be used for high complexity experiments such as Inertial Fusion Energy (IFE) studies and can have many complex components that need assembling and characterisation with high precision. Using the techniques that are common to MEMS devices and integrating these with an existing target fabrication capability we are able to manufacture and deliver targets to these systems. It also enables us to manufacture novel targets that have not been possible using other techniques. In addition, developments in the positioning systems that are required to deliver these targets to the laser focus are also required and a system to deliver the target to a focus of an F2 beam at 0.1Hz is discussed. (paper)

  13. Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling.

    Science.gov (United States)

    Vlot, Anna H C; de Witte, Wilhelmus E A; Danhof, Meindert; van der Graaf, Piet H; van Westen, Gerard J P; de Lange, Elizabeth C M

    2017-12-04

    Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

  14. A Holistic In silico Approach to Develop Novel Inhibitors Targeting ...

    African Journals Online (AJOL)

    Purpose: To design a dual inhibitor of natural origin capable of targeting ErbB1 and ErbB2 kinases for the treatment of lung cancer. Method: Advanced In silico drug designing techniques were explored in this study. Sequence and structure analysis of ErbB1 and ErbB2 was followed by three dimensional (3D) ...

  15. Genome-wide identification of KANADI1 target genes.

    Directory of Open Access Journals (Sweden)

    Paz Merelo

    Full Text Available Plant organ development and polarity establishment is mediated by the action of several transcription factors. Among these, the KANADI (KAN subclade of the GARP protein family plays important roles in polarity-associated processes during embryo, shoot and root patterning. In this study, we have identified a set of potential direct target genes of KAN1 through a combination of chromatin immunoprecipitation/DNA sequencing (ChIP-Seq and genome-wide transcriptional profiling using tiling arrays. Target genes are over-represented for genes involved in the regulation of organ development as well as in the response to auxin. KAN1 affects directly the expression of several genes previously shown to be important in the establishment of polarity during lateral organ and vascular tissue development. We also show that KAN1 controls through its target genes auxin effects on organ development at different levels: transport and its regulation, and signaling. In addition, KAN1 regulates genes involved in the response to abscisic acid, jasmonic acid, brassinosteroids, ethylene, cytokinins and gibberellins. The role of KAN1 in organ polarity is antagonized by HD-ZIPIII transcription factors, including REVOLUTA (REV. A comparison of their target genes reveals that the REV/KAN1 module acts in organ patterning through opposite regulation of shared targets. Evidence of mutual repression between closely related family members is also shown.

  16. Development Of A Hydrogen And Deuterium Polarized Gas Target For Application In Storage Rings

    International Nuclear Information System (INIS)

    Haeberli, Willy

    2009-01-01

    The exploration of spin degrees of freedom in nuclear and high-energy interactions requires the use of spin-polarized projectiles and/or spin-polarized targets. During the last two decades, the use of external beams from cyclotrons has to a large extent been supplanted by use of circulating beams stored in storage rings. In these experiments, the circulating particles pass millions of times through targets internal to the ring. Thus the targets need to be very thin to avoid beam loss by scattering out of the acceptance aperture of the ring.

  17. Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

    LENUS (Irish Health Repository)

    Storm, Janet

    2011-07-14

    Abstract Background Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target. Methods The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated. Results No growth defect under low and elevated oxygen tension, no up- or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10Δgdha parasite lines. Further, the fate of the carbon skeleton of [13C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of α-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites. Conclusions First, the data support the conclusion that D10Δgdha parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)-dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra

  18. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

    DEFF Research Database (Denmark)

    Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B

    2017-01-01

    transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1......Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global......-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both...

  19. Design of the MYRRHA Spallation Target Assembly

    International Nuclear Information System (INIS)

    Keijers, S.; Fernandez, R.; Stankovskiy, A.; Kennedy, G.; Van Tichelen, K.

    2015-01-01

    MYRRHA (Multi-purpose hybrid Research Reactor for High-tech Applications) is a multi-purpose research facility currently being developed at SCK.CEN. MYRRHA is based on the ADS (Accelerator Driven System) concept where a proton accelerator, a spallation target and a subcritical reactor are coupled. MYRRHA will demonstrate the ADS full concept by coupling these three components at a reasonable power level. As a flexible irradiation facility, the MYRRHA research reactor will be able to work in both critical and subcritical modes. In this way, MYRRHA will allow fuel developments for innovative reactor systems, material research for GEN IV and fusion reactors, and radioisotope production for medical and industrial applications. MYRRHA will be cooled by Lead Bismuth Eutectic (LBE) and will play an important role in the development of the Pb-alloys technology needed for the LFR (Lead Fast Reactor) GEN IV concept. This paper describes the evolution of the MYRRHA spallation target design. In the early phase of the MYRRHA project (XT-ADS), the target design was based on a dedicated spallation loop inside the primary reactor vessel. Within the core, the 3 central fuel assembly positions were occupied by the spallation target, which enabled a windowless design created by a free surface of LBE facing the proton beam. The windowless option was preferred because of high heat loads in combination with severe irradiation damage in the target region would result in unacceptably short lifetimes of a target window. The LBE in the loop served as spallation target and as target coolant, but was separated from the LBE cooling the reactor core. The loop was equipped with its own pump, heat exchanger and conditioning system. The change from cyclotron to linear accelerator allowed the increase in proton energy from 350 MeV to 600 MeV. This modification led to an important reduction of the specific heat load at the target level and an improvement of the neutronic performance. In addition to

  20. Brain tumor-targeted drug delivery strategies

    Directory of Open Access Journals (Sweden)

    Xiaoli Wei

    2014-06-01

    Full Text Available Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

  1. Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development.

    Science.gov (United States)

    Pu, Wenchen; Li, Jiao; Zheng, Yuanyuan; Shen, Xianyan; Fan, Xin; Zhou, Jian-Kang; He, Juan; Deng, Yulan; Liu, Xuesha; Wang, Chun; Yang, Shengyong; Chen, Qiang; Liu, Lunxu; Zhang, Guolin; Wei, Yu-Quan; Peng, Yong

    2018-01-30

    Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with the Pin1 inhibitor (API-1), a specific small molecule targeting Pin1 peptidyl-prolyl isomerase domain and inhibiting Pin1 cis-trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API-1-induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low exportin-5 (XPO5) phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated serine-proline motif of phosphorylated XPO5 and passivates phosphorylated XPO5. Pin1 inhibition by API-1 maintains the active conformation of phosphorylated XPO5 and restores XPO5-driven precursor miRNA nuclear-to-cytoplasm export, activating anticancer miRNA biogenesis and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Experimental evidence suggests that Pin1 inhibition by API-1 up-regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supporting API-1 as a drug candidate for HCC therapy, especially for Pin1-overexpressing, extracellular signal-regulated kinase-activated HCC. (Hepatology 2018). © 2018 by the American Association for the Study of Liver Diseases.

  2. Future Targets for Female Sexual Dysfunction.

    Science.gov (United States)

    Farmer, Melissa; Yoon, Hana; Goldstein, Irwin

    2016-08-01

    Female sexual function reflects a dynamic interplay of central and peripheral nervous, vascular, and endocrine systems. The primary challenge in the development of novel treatments for female sexual dysfunction is the identification and targeted modulation of excitatory sexual circuits using pharmacologic treatments that facilitate the synthesis, release, and/or receptor binding of neurochemicals, peptides, and hormones that promote female sexual function. To develop an evidence-based state-of-the-art consensus report that critically integrates current knowledge of the therapeutic potential for known molecular and cellular targets to facilitate the physiologic processes underlying female sexual function. State-of-the-art review representing the opinions of international experts developed in a consensus process during a 1-year period. Expert opinion was established by grading the evidence-based medical literature, intensive internal committee discussion, public presentation, and debate. Scientific investigation is urgently needed to expand knowledge and foster development of future treatments that maintain genital tissue integrity, enhance genital physiologic responsiveness, and optimize positive subjective appraisal of internal and external sexual cues. This article critically condenses the current knowledge of therapeutic manipulation of molecular and cellular targets within biological systems responsible for female sexual physiologic function. Future treatment targets include pharmacologic modulation of emotional learning circuits, restoration of normal tactile sensation, growth factor therapy, gene therapy, stem cell-based therapies, and regenerative medicine. Concurrent use of centrally and peripherally acting therapies could optimize treatment response. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  3. Target-Rich Environment

    Science.gov (United States)

    Perna, Mark C.

    2005-01-01

    Target marketing is defining school enrollment goals and then developing a strategic plan to accomplish those goals through the use of specific communication vehicles and community focus. It is critical to reach the right audience, with the right message, at the right time, for the right cost. In this brief article, the author describes several…

  4. Designing to target cost: one approach to design/construction integration

    DEFF Research Database (Denmark)

    Jørgensen, Bo

    2005-01-01

    One approach to a more integrated construction delivery process is the concept of ‘designing to target cost’ of which the first examples of application within a lean construction framework have recently been seen. This paper introduces the main principles of the design to target cost method...... and discusses the applicability of this approach to construction. The low degree of organizational and technical continuity from one construction project to the next limits the applicability of the design for target cost approach when compared to its origin in product development of mass manufactured artefacts....... It can be argued that design to target cost may also provide a frame for developing the supply chain towards better coordination and collaboration. Thus methods of design to target cost may serve to facilitate the development of a more integrated supply chain....

  5. Conductive cooling of high-power RIB targets

    International Nuclear Information System (INIS)

    Talbert, W.L.; Drake, D.M.; Wilson, M.T.; Lenz, J.W.; Hsu, H.-H.

    2002-01-01

    A short review is presented of target cooling approaches suggested for targets irradiated by intense high-energy proton beams to produce radioactive species for use in a broad range of physics studies. This work reports on conductive cooling approaches for operation at temperatures lower than effective for radiative cooling. The possibilities for conductive cooling are discussed, and a prototype test target is described. This target was constructed for an experiment, designed to validate the numerical analysis approaches, at the TRIUMF/ISAC facility. Fabrication issues and the results of the experiment are presented, followed by a discussion of the implications of the experiment outcome for future development of targets to produce intense beams of radioactive ions

  6. Market segmentation, targeting and positioning

    OpenAIRE

    Camilleri, Mark Anthony

    2017-01-01

    Businesses may not be in a position to satisfy all of their customers, every time. It may prove difficult to meet the exact requirements of each individual customer. People do not have identical preferences, so rarely does one product completely satisfy everyone. Many companies may usually adopt a strategy that is known as target marketing. This strategy involves dividing the market into segments and developing products or services to these segments. A target marketing strategy is focused on ...

  7. Camouflage target detection via hyperspectral imaging plus information divergence measurement

    Science.gov (United States)

    Chen, Yuheng; Chen, Xinhua; Zhou, Jiankang; Ji, Yiqun; Shen, Weimin

    2016-01-01

    Target detection is one of most important applications in remote sensing. Nowadays accurate camouflage target distinction is often resorted to spectral imaging technique due to its high-resolution spectral/spatial information acquisition ability as well as plenty of data processing methods. In this paper, hyper-spectral imaging technique together with spectral information divergence measure method is used to solve camouflage target detection problem. A self-developed visual-band hyper-spectral imaging device is adopted to collect data cubes of certain experimental scene before spectral information divergences are worked out so as to discriminate target camouflage and anomaly. Full-band information divergences are measured to evaluate target detection effect visually and quantitatively. Information divergence measurement is proved to be a low-cost and effective tool for target detection task and can be further developed to other target detection applications beyond spectral imaging technique.

  8. Preparation of targets by a centrifugal method

    International Nuclear Information System (INIS)

    Richaud, J.P.

    1979-01-01

    For β and γ in-beam spectroscopy measurements, a centrifugal technique has been developed to produce targets of powdered isotopic materials. Plastic or metallic backings and suitable organic solutions are described. With this method, targets in the range 1-50 mg/cm 2 have been obtained. (orig.)

  9. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

    Science.gov (United States)

    Narayanan, Ramesh; Dalton, James T.

    2016-01-01

    Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer. PMID:27918430

  10. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    2016-12-01

    Full Text Available Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER and human epidermal growth factor receptor (HER2 are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer.

  11. A QFD-Based Mathematical Model for New Product Development Considering the Target Market Segment

    Directory of Open Access Journals (Sweden)

    Liang-Hsuan Chen

    2014-01-01

    Full Text Available Responding to customer needs is important for business success. Quality function deployment provides systematic procedures for converting customer needs into technical requirements to ensure maximum customer satisfaction. The existing literature mainly focuses on the achievement of maximum customer satisfaction under a budgetary limit via mathematical models. The market goal of the new product for the target market segment is usually ignored. In this study, the proposed approach thus considers the target customer satisfaction degree for the target market segment in the model by formulating the overall customer satisfaction as a function of the quality level. In addition, the proposed approach emphasizes the cost-effectiveness concept in the design stage via the achievement of the target customer satisfaction degree using the minimal total cost. A numerical example is used to demonstrate the applicability of the proposed approach and its characteristics are discussed.

  12. The Pseudomonas syringae type III effector HopG1 targets mitochondria, alters plant development, and suppresses plant innate immunity

    Science.gov (United States)

    Block, Anna; Guo, Ming; Li, Guangyong; Elowsky, Christian; Clemente, Thomas E.; Alfano, James R.

    2009-01-01

    Summary The bacterial plant pathogen Pseudomonas syringae uses a type III protein secretion system to inject type III effectors into plant cells. Primary targets of these effectors appear to be effector-triggered immunity (ETI) and pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). The type III effector HopG1 is a suppressor of ETI that is broadly conserved in bacterial plant pathogens. Here we show that HopG1 from P. syringae pv. tomato DC3000 also suppresses PTI. Interestingly, HopG1 localizes to plant mitochondria, suggesting that its suppression of innate immunity may be linked to a perturbation of mitochondrial function. While HopG1 possesses no obvious mitochondrial signal peptide, its N-terminal two-thirds was sufficient for mitochondrial localization. A HopG1-GFP fusion lacking HopG1’s N-terminal 13 amino acids was not localized to the mitochondria reflecting the importance of the N-terminus for targeting. Constitutive expression of HopG1 in Arabidopsis thaliana, Nicotiana tabacum (tobacco) and Lycopersicon esculentum (tomato) dramatically alters plant development resulting in dwarfism, increased branching and infertility. Constitutive expression of HopG1 in planta leads to reduced respiration rates and an increased basal level of reactive oxygen species. These findings suggest that HopG1’s target is mitochondrial and that effector/target interaction promotes disease by disrupting mitochondrial functions. PMID:19863557

  13. Tracking Target and Spiral Waves

    DEFF Research Database (Denmark)

    Jensen, Flemming G.; Sporring, Jon; Nielsen, Mads

    2002-01-01

    A new algorithm for analyzing the evolution of patterns of spiral and target waves in large aspect ratio chemical systems is introduced. The algorithm does not depend on finding the spiral tip but locates the center of the pattern by a new concept, called the spiral focus, which is defined...... by the evolutes of the actual spiral or target wave. With the use of Gaussian smoothing, a robust method is developed that permits the identification of targets and spirals foci independently of the wave profile. Examples of an analysis of long image sequences from experiments with the Belousov......–Zhabotinsky reaction catalyzed by ruthenium-tris-bipyridyl are presented. Moving target and spiral foci are found, and the speed and direction of movement of single as well as double spiral foci are investigated. For the experiments analyzed in this paper it is found that the movement of a focus correlates with foci...

  14. A new transfer system for solid targets

    Science.gov (United States)

    Klug, J.; Buckley, K. R.; Zeisler, S. K.; Dodd, M.; Tsao, P.; Hoehr, C.; Economou, C.; Corsaut, J.; Appiah, J. P.; Kovacs, M. S.; Valliant, J. F.; Benard, F.; Ruth, T. J.; Schaffer, P.

    2012-12-01

    As part of a collaborative research project funded by Natural Resources Canada, TRIUMF has designed and manufactured solid target and solid target processing systems for the production of technetium-99m using small medical cyclotrons. The system described herein is capable of transporting the target from a hotcell, where the target is loaded and processed, to the cyclotron and back again. The versatility of the transfer system was demonstrated through the successful installation and operation on the ACSI TR 19 at the BC Cancer Agency, the GE PETtrace cyclotrons at Lawson Health Research (LHRI) and the Centre for Probe Development and Commercialization (CDPC).

  15. LIFE Target Fabrication Research Plan Sept 2008

    Energy Technology Data Exchange (ETDEWEB)

    Miles, R; Biener, J; Kucheyev, S; Montesanti, R; Satcher, J; Spadaccini, C; Rose, K; Wang, M; Hamza, A; Alexander, N; Brown, L; Hund, J; Petzoldt, R; Sweet, W; Goodin, D

    2008-11-10

    The target-system for the baseline LIFE fast-ignition target was analyzed to establish a preliminary estimate for the costs and complexities involved in demonstrating the technologies needed to build a prototype LIFE plant. The baseline fast-ignition target upon which this analysis was developed is shown in Figure 1.0-1 below. The LIFE target-system incorporates requirements for low-cost, high throughput manufacture, high-speed, high accuracy injection of the target into the chamber, production of sufficient energy from implosion and recovery and recycle of the imploded target material residue. None of these functions has been demonstrated to date. Existing target fabrication techniques which lead to current 'hot spot' target costs of {approx}$100,000 per target and at a production rate of 2/day are unacceptable for the LIFE program. Fabrication techniques normally used for low-cost, low accuracy consumer products such as toys must be adapted to the high-accuracy LIFE target. This will be challenge. A research program resulting is the demonstration of the target-cycle technologies needed for a prototype LIFE reactor is expected to cost {approx}$51M over the course of 5 years. The effort will result in targets which will cost an estimated $0.23/target at a rep-rate of 20 Hz or about 1.73M targets/day.

  16. Proceedings of the workshop on polarized targets in storage rings

    International Nuclear Information System (INIS)

    Holt, R.J.

    1984-08-01

    Polarization phenomena have played an increasingly important part in the study of nuclei and nucleons in recent years. Polarization studies have been hampered by the relatively few and rather fragile polarized targets which are presently available. The concept of polarized gas targets in storage rings opens a much wider range of possibilities than is available in the external target geometry. This novel method will represent a considerable advance in nuclear physics and will continue to receive much attention in plans for future facilities. An internal, polarized-target station is being planned for the cooler ring at the Indiana University Cyclotron Facility. Internal targets are compatible with recent designs of electron accelerators proposed by the Massachusetts Institute of Technology and the Southeastern Universities Research Association. The key to nuclear-science programs based on internal targets pivots on recent developments in polarized atomic beam methods, which include the more recent laser-driven polarized targets. The workshop drew together a unique group of physicists in the fields of high-energy, nuclear and atomic physics. The meeting was organized in a manner that stimulated discussion among the 58 participants and focused on developments in polarized target technology and the underlying atomic physics. An impressive array of future possibilities for polarized targets as well as current developments in polarized target technology were discussed at the workshop. Abstracts of individual items from the workshop were prepared separately for the data base

  17. Engineering liposomal nanoparticles for targeted gene therapy.

    Science.gov (United States)

    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.

  18. A quick reality check for microRNA target prediction.

    Science.gov (United States)

    Kast, Juergen

    2011-04-01

    The regulation of protein abundance by microRNA (miRNA)-mediated repression of mRNA translation is a rapidly growing area of interest in biochemical research. In animal cells, the miRNA seed sequence does not perfectly match that of the mRNA it targets, resulting in a large number of possible miRNA targets and varied extents of repression. Several software tools are available for the prediction of miRNA targets, yet the overlap between them is limited. Jovanovic et al. have developed and applied a targeted, quantitative approach to validate predicted miRNA target proteins. Using a proteome database, they have set up and tested selected reaction monitoring assays for approximately 20% of more than 800 predicted let-7 targets, as well as control genes in Caenorhabditis elegans. Their results demonstrate that such assays can be developed quickly and with relative ease, and applied in a high-throughput setup to verify known and identify novel miRNA targets. They also show, however, that the choice of the biological system and material has a noticeable influence on the frequency, extent and direction of the observed changes. Nonetheless, selected reaction monitoring assays, such as those developed by Jovanovic et al., represent an attractive new tool in the study of miRNA function at the organism level.

  19. Metallochaperone UreG serves as a new target for design of urease inhibitor: A novel strategy for development of antimicrobials.

    Directory of Open Access Journals (Sweden)

    Xinming Yang

    2018-01-01

    Full Text Available Urease as a potential target of antimicrobial drugs has received considerable attention given its versatile roles in microbial infection. Development of effective urease inhibitors, however, is a significant challenge due to the deeply buried active site and highly specific substrate of a bacterial urease. Conventionally, urease inhibitors are designed by either targeting the active site or mimicking substrate of urease, which is not efficient. Up to now, only one effective inhibitor-acetohydroxamic acid (AHA-is clinically available, but it has adverse side effects. Herein, we demonstrate that a clinically used drug, colloidal bismuth subcitrate, utilizes an unusual way to inhibit urease activity, i.e., disruption of urease maturation process via functional perturbation of a metallochaperone, UreG. Similar phenomena were also observed in various pathogenic bacteria, suggesting that UreG may serve as a general target for design of new types of urease inhibitors. Using Helicobacter pylori UreG as a showcase, by virtual screening combined with experimental validation, we show that two compounds targeting UreG also efficiently inhibited urease activity with inhibitory concentration (IC50 values of micromolar level, resulting in attenuated virulence of the pathogen. We further demonstrate the efficacy of the compounds in a mammalian cell infection model. This study opens up a new opportunity for the design of more effective urease inhibitors and clearly indicates that metallochaperones involved in the maturation of important microbial metalloenzymes serve as new targets for devising a new type of antimicrobial drugs.

  20. Metallochaperone UreG serves as a new target for design of urease inhibitor: A novel strategy for development of antimicrobials.

    Science.gov (United States)

    Yang, Xinming; Koohi-Moghadam, Mohamad; Wang, Runming; Chang, Yuen-Yan; Woo, Patrick C Y; Wang, Junwen; Li, Hongyan; Sun, Hongzhe

    2018-01-01

    Urease as a potential target of antimicrobial drugs has received considerable attention given its versatile roles in microbial infection. Development of effective urease inhibitors, however, is a significant challenge due to the deeply buried active site and highly specific substrate of a bacterial urease. Conventionally, urease inhibitors are designed by either targeting the active site or mimicking substrate of urease, which is not efficient. Up to now, only one effective inhibitor-acetohydroxamic acid (AHA)-is clinically available, but it has adverse side effects. Herein, we demonstrate that a clinically used drug, colloidal bismuth subcitrate, utilizes an unusual way to inhibit urease activity, i.e., disruption of urease maturation process via functional perturbation of a metallochaperone, UreG. Similar phenomena were also observed in various pathogenic bacteria, suggesting that UreG may serve as a general target for design of new types of urease inhibitors. Using Helicobacter pylori UreG as a showcase, by virtual screening combined with experimental validation, we show that two compounds targeting UreG also efficiently inhibited urease activity with inhibitory concentration (IC)50 values of micromolar level, resulting in attenuated virulence of the pathogen. We further demonstrate the efficacy of the compounds in a mammalian cell infection model. This study opens up a new opportunity for the design of more effective urease inhibitors and clearly indicates that metallochaperones involved in the maturation of important microbial metalloenzymes serve as new targets for devising a new type of antimicrobial drugs.

  1. Competitive Effects of Purchase-Based Targeted Advertising

    OpenAIRE

    Jianqiang Zhang; Weijun Zhong; Shue Mei

    2012-01-01

    This paper develops a two-period sales model to investigate the competitive effects of purchase-based targeted advertising. In the model, two competing firms gain consumer information during the first period sales, which allows them to target advertising based on consumer purchase history. Advertising is assumed to be persuasive in terms of consumer valuation enhancing and product differentiation increasing. The authors find that the firm’s ability to target can damage industry profits, con...

  2. Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages.

    Science.gov (United States)

    Qian, Yuan; Qiao, Sha; Dai, Yanfeng; Xu, Guoqiang; Dai, Bolei; Lu, Lisen; Yu, Xiang; Luo, Qingming; Zhang, Zhihong

    2017-09-26

    Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8 + T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8 + T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.

  3. Dynamics of target recognition by interstitial axon branching along developing cortical axons.

    Science.gov (United States)

    Bastmeyer, M; O'Leary, D D

    1996-02-15

    Corticospinal axons innervate their midbrain, hindbrain, and spinal targets by extending collateral branches interstitially along their length. To establish that the axon shaft rather than the axonal growth cone is responsible for target recognition in this system, and to characterize the dynamics of interstitial branch formation, we have studied this process in an in vivo-like setting using slice cultures from neonatal mice containing the entire pathway of corticospinal axons. Corticospinal axons labeled with the dye 1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (or Dil) were imaged using time-lapse video microscopy of their pathway overlying the basilar pons, their major hindbrain target. The axon shaft millimeters behind the growth cone exhibits several dynamic behaviors, including the de novo formation of varicosities and filopodia-like extensions, and a behavior that we term "pulsation," which is characterized by a variable thickening and thining of short segments of the axon. An individual axon can have multiple sites of branching activity, with many of the branches being transient. These dynamic behaviors occur along the portion of the axon shaft overlying the basilar pons, but not just caudal to it. Once the collaterals extend into the pontine neuropil, they branch further in the neuropil, while the parent axon becomes quiescent. Thus, the branching activity is spatially restricted to specific portions of the axon, as well as temporally restricted to a relatively brief time window. These findings provide definitive evidence that collateral branches form de novo along corticospinal axons and establish that the process of target recognition in this system is a property of the axon shaft rather than the leading growth cone.

  4. CTD² Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network* | Office of Cancer Genomics

    Science.gov (United States)

    The Cancer Target Discovery and Development (CTD2) Network aims to use functional genomics to accelerate the translation of high-throughput and high-content genomic and small-molecule data towards use in precision oncology.

  5. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  6. A method for comparing impacts with real targets to impacts onto the IAEA unyielding target

    International Nuclear Information System (INIS)

    Ammerman, D.J.

    1993-01-01

    A mathematically rigorous method is developed for relating impacts with yielding targets to lower velocity impacts with unyielding targets. The method correctly models the mechanics of the impact and the conversion of kinetic energy to strain energy. An important result shown by the example problem is that apparent target hardness depends on the stiffness of the impacting package. For a cask with impact limiters a 26.8 m/s impact onto hard soil results in equivalent forces as a 13.9 m/s impact onto an unyielding target. For the same cask without impact limiters a 26.8 m/s impact onto hard soil is equivalent to a 1.74 m/s impact onto an unyielding target. This is one reason why non-technical members of the public often have difficulty realizing the severity of the regulatory impact. For most people, objects such as trucks and bridge columns appear to be very hard, but to many radioactive material shipping packages these objects are relatively soft. The method discussed in this paper for relating impacts with yielding targets to lower velocity impacts with unyielding targets helps to explain how the regulatory impact accident provides a high degree of safety to the public. This methodology is relatively simple to use, and can be applied to the 'What if' scenarios brought up by interveners. (J.P.N.)

  7. Long-Lifetime Low-Scatter Neutron Polarization Target

    International Nuclear Information System (INIS)

    Richardson, Jonathan M.

    2004-01-01

    Polarized neutrons scattering is an important technology for characterizing magnetic and other materials. Polarized helium three (P-3He) is a novel technology for creating polarized beams and, perhaps more importantly, for the analysis of polarization in highly divergent scattered beams. Analysis of scattered beams requires specialized targets with complex geometries to ensure accurate results. Special materials and handling procedures are required to give the targets a long useful lifetime. In most cases, the targets must be shielded from stray magnetic fields from nearby equipment. SRL has developed and demonstrated hybrid targets made from glass and aluminum. We have also developed and calibrated a low-field NMR system for measuring polarization lifetimes. We have demonstrated that our low-field system is able to measure NMR signals in the presence of conducting (metallic) cell elements. We have also demonstrated a non-magnetic valve that can be used to seal the cells. We feel that these accomplishments in Phase I are sufficient to ensure a successful Phase II program. The commercial market for this technology is solid. There are over nine neutron scattering centers in the US and Canada and over 22 abroad. Currently, the US plans to build a new $1.4B scattering facility called the Spallation Neutron Source (SNS). The technology developed in this project will allow SRL to supply targets to both existing and future facilities. SRL is also involved with the application of P-3He to medical imaging

  8. Conceptual design studies for the liquid metal target META:LIC

    International Nuclear Information System (INIS)

    Class, A.G.; Fazio, C.; Fetzer, J.R.; Gordeev, S.

    2014-01-01

    When the construction of ESS (European Spallation Source) in Sweden was initiated, the target station concept selection group decided to reevaluate a variety of target designs to respect new developments in their selection process. The META:LIC (MEgawatt TArget:Lead bIsmuth Cooled) target concept was developed following an extensive analysis of existing and new proposed designs and reached the level of proof of principle within only 2 years. ESS selected META:LIC as comparative target option for licensing purposes during the design update phase of ESS. The present work describes the design motivation of META:LIC referring to properties and design features of other targets. Therefore, META:LIC design is an evolutionary target which incorporates the extensive experience of liquid metal targets. The modular LBE (Lead Bismuth Eutectic) target concept with focus on the target module is introduced. Both, a window target option for the start of operation and a windowless option with extended lifetime are foreseen. Thermohydraulic simulations show that adequate window cooling can be realized. The stability of the free surface in the windowless option has been shown. Robust target module instrumentation based on free surface levels and the MEGAPIE experience is proposed for target control. Since the META:LIC concept foresees a horizontal extraction for both moderators and target from the monolith a safety concept based on the SNS and JSNS experience is proposed

  9. Recent developments and on-line tests of uranium carbide targets for production of nuclides far from

    CERN Document Server

    V.N. Panteleev et al.

    The capacity of uranium carbide target materials of different structure and density for production of neutron-rich and heavy neutron-deficient isotopes have been investigated at the IRIS facility (PNPI) in the collaboration with Legnaro – GANIL – Orsay laboratories. The yields and release times of the species produced in the targets by the reactions induced by a 1 GeV proton beam of the PNPI synchrocyclotron have been measured. For the purpose to elaborate the most efficient and fast uranium carbide target prototype three kinds of the target materials were studied: a) a high density UC target material having ceramic-like structure with the density of 11 g/cm3 and the grain dimensions of about 200 microns; b) a high density UC target material with the density of 12 g/cm3 and the grain dimensions of about 20 microns prepared by the method of the powder metallurgy; c) a low density UCx target material with the density 3g/cm3 and the grain dimensions of about 20 microns prepared by the ISOLDE method. The comp...

  10. Gas target neutron generator studies

    International Nuclear Information System (INIS)

    Chatoorgoon, V.

    1978-01-01

    The need for an intense neutron source for the study of radiation damage on materials has resulted in the proposal of various solid, liquid, and gas targets. Among the gas targets proposed have been the transonic gas target, two types of hypersonic gas target, and the subsonic gas target (SGT). It has been suggested that heat deposition in a subsonic channel might create a gas density step which would constitute an attractive gas target type. The first part of the present study examines this aspect of the SGT and shows that gas density gradients are indeed formed by heat deposition in subsonic flow. The variation of beam voltage, gas density, gas pressure, and gas temperature within the channel have been calculated as functions of the system parameters: beam voltage, beam current, channel diameter, stagnation tank temperature and pressure. The analysis is applicable to any beam particle and target gas. For the case of T + on D 2 , which is relevant to the fusion application, the 14 MeV neutron profiles are presented as a function of system parameters. It is found that the SGT is compatible with concentrated intense source operation. The possibility of instability was investigated in detail using a non-linear analysis which made it possible to follow the complete time development of the SGT. It was found that the SGT is stable against all small perturbations and certain types of large perturbations. It appears that the SGT is the most advantageous type of gas target, operating at a lower mass flow and less severe stagnation tank conditions than the other types. The second part of the thesis examines a problem associated with the straight hypersonic target, the deuterium spill into the tritium port. The regime of practical operation for this target is established. (auth)

  11. Drug-Target Kinetics in Drug Discovery.

    Science.gov (United States)

    Tonge, Peter J

    2018-01-17

    The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

  12. Muon-catalyzed fusion experiment target and detector system. Preliminary design report

    International Nuclear Information System (INIS)

    Jones, S.E.; Watts, K.D.; Caffrey, A.J.; Walter, J.B.

    1982-03-01

    We present detailed plans for the target and particle detector systems for the muon-catalyzed fusion experiment. Requirements imposed on the target vessel by experimental conditions and safety considerations are delineated. Preliminary designs for the target vessel capsule and secondary containment vessel have been developed which meet these requirements. In addition, the particle detection system is outlined, including associated fast electronics and on-line data acquisition. Computer programs developed to study the target and detector system designs are described

  13. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Kay Andrea

    2009-10-01

    Full Text Available Abstract The mammalian target of rapamycin (mTOR is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA and the European Medicines Agency (EMEA for the treatment of advanced renal cell carcinoma (RCC. Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

  14. 100-N Area Decision Unit Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    Ovink, R.

    2012-09-18

    This report documents the process used to identify source area target analytes in support of the 100-N Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

  15. MicroRNA-targeted therapeutics for lung cancer treatment.

    Science.gov (United States)

    Xue, Jing; Yang, Jiali; Luo, Meihui; Cho, William C; Liu, Xiaoming

    2017-02-01

    Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists. Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease. Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.

  16. Autonomous Vehicles Navigation with Visual Target Tracking: Technical Approaches

    Directory of Open Access Journals (Sweden)

    Zhen Jia

    2008-12-01

    Full Text Available This paper surveys the developments of last 10 years in the area of vision based target tracking for autonomous vehicles navigation. First, the motivations and applications of using vision based target tracking for autonomous vehicles navigation are presented in the introduction section. It can be concluded that it is very necessary to develop robust visual target tracking based navigation algorithms for the broad applications of autonomous vehicles. Then this paper reviews the recent techniques in three different categories: vision based target tracking for the applications of land, underwater and aerial vehicles navigation. Next, the increasing trends of using data fusion for visual target tracking based autonomous vehicles navigation are discussed. Through data fusion the tracking performance is improved and becomes more robust. Based on the review, the remaining research challenges are summarized and future research directions are investigated.

  17. Angiogenesis and vascular targeting: Relevance for hyperthermia

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2008-01-01

    The creation of a functional blood supply from the normal tissue vasculature via the process of angiogenesis is critical for the continued growth and development of solid tumours. This importance has led to the concept of targeting the tumour vasculature as a therapeutic strategy, and two major...... types of vascular targeting agents (VTAs) have developed; those that inhibit the angiogenic process-angiogenesis inhibiting agents (AIAs)-and those that specifically damage the already established neovasculature-vascular disrupting agents (VDAs). The tumour vasculature also plays a critical role...

  18. Deep-Learning-Based Drug-Target Interaction Prediction.

    Science.gov (United States)

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-04-07

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  19. Interactions between entorhinal axons and target hippocampal neurons: a role for glutamate in the development of hippocampal circuitry.

    Science.gov (United States)

    Mattson, M P; Lee, R E; Adams, M E; Guthrie, P B; Kater, S B

    1988-11-01

    A coculture system consisting of input axons from entorhinal cortex explants and target hippocampal pyramidal neurons was used to demonstrate that glutamate, released spontaneously from afferent axons, can influence both dendritic geometry of target neurons and formation of presumptive synaptic sites. Dendritic outgrowth was reduced in hippocampal neurons growing on entorhinal axons when compared with neurons growing off the axons. Presumptive presynaptic sites were observed in association with hippocampal neuron dendrites and somas. HPLC analysis showed that glutamate was released from the explants in an activity- and Ca2(+)-dependent manner. The general glutamate receptor antagonist D-glutamylglycine significantly increased dendritic outgrowth in pyramidal neurons associated with entorhinal axons and reduced presumptive presynaptic sites. Tetrodotoxin and reduction of extracellular Ca2+ also promoted dendritic outgrowth and reduced the formation of presumptive synaptic sites. The results suggest that the neurotransmitter glutamate may play important roles in the development of hippocampal circuitry.

  20. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

    Directory of Open Access Journals (Sweden)

    Karina Soares de Oliveira

    Full Text Available ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF. Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

  1. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  2. Development of low enrichment technologies for high density fuels and for isotope production targets

    International Nuclear Information System (INIS)

    Taboada, Horacio; Gonzalez, Alfredo G.

    2005-01-01

    Since more than twenty years ago, CNEA has carried out RERTR activities. Main goals are to convert the RA 6 reactor core from HEU to LEU, to get a comprehensive understanding of U-Mo/Al compounds phase formation in dispersed and monolithic fuels, to develop possible solutions to VHD dispersed and monolithic fuels technical problems, and to optimize techniques to recover U from silicide scrap samples. The future plans include: 1) Completion the RA 6 reactor conversion to LEU; 2) Qualification by irradiation of the promising solutions found for the high density fuels; 3) Irradiation of mini plates and full scale fuel assemblies at the RA 3 reactor and at higher flux and temperature reactors; 4) Optimization of LEU target and radiochemical techniques for radioisotope production. (author) [es

  3. Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells.

    Science.gov (United States)

    Childs-Disney, Jessica L; Disney, Matthew D

    2016-01-01

    RNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets.

  4. Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Sateesh Kumar Vemula

    2013-01-01

    Full Text Available The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4 showed almost complete drug release in the colon (99.86% within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period. The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The Cmax of colon targeted tablets was 11956.15 ng/mL at Tmax of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

  5. Targeting the Thioredoxin System for Cancer Therapy.

    Science.gov (United States)

    Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

    2017-09-01

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Target materials for exotic ISOL beams

    CERN Document Server

    Gottberg, A

    2016-01-01

    The demand for intensity, purity, reliability and availability of short-lived isotopes far from stability is steadily high, and considerably exceeding the supply. In many cases the ISOL (Isotope Separation On-Line) method can provide beams of high intensity and purity. Limitations in terms of accessible chemical species and minimum half-life are driven mainly by chemical reactions and physical processes inside of the thick target. A wide range of materials are in use, ranging from thin metallic foils and liquids to refractory ceramics, while poly-phasic mixed uranium carbides have become the reference target material for most ISOL facilities world-wide. Target material research and development is often complex and especially important post-irradiation analyses are hindered by the high intrinsic radiotoxicity of these materials. However, recent achievements have proven that these investigations are possible if the effort of different facilities is combined, leading to the development of new material matrices t...

  7. Antigen-targeting strategies using single-domain antibody fragments

    NARCIS (Netherlands)

    Duarte, Joao Nuno Silva

    2017-01-01

    Antibodies display high selectivity and affinity and have been the preferred platform for antigen targeting. Despite the development of antigen-delivery systems that enable T cell activation, targeting approaches that enhance antibody responses need improvement. This need specially applies to poorly

  8. Molecular nuclear imaging for targeting and trafficking

    International Nuclear Information System (INIS)

    Bom, Hee Seung; Min, Jung Jun; Jeong, Hwan-Jeong

    2006-01-01

    Noninvasive molecular targeting in living subjects is highly demanded for better understanding of such diverse topics as the efficient delivery of drugs, genes, or radionuclides for the diagnosis or treatment of diseases. Progress in molecular biology, genetic engineering and polymer chemistry provides various tools to target molecules and cells in vivo. We used chitosan as a polymer, and 99m Tc as a radionuclide. We developed 99m Tc-galactosylated chitosan to target asialoglycoprotein receptors for nuclear imaging. We also developed 99m Tc-HYNIC-chitosan-transferrin to target inflammatory cells, which was more effective than 67 Ga-citrate for imaging inflammatory lesions. For an effective delivery of molecules, a longer circulation time is needed. We found that around 10% PEGylation was most effective to prolong the circulation time of liposomes for nuclear imaging of 99m Tc-HMPAO-labeled liposomes in rats. Using various characteristics of molecules, we can deliver drugs into targets more effectively. We found that 99m Tc-labeled biodegradable pullulan-derivatives are retained in tumor tissue in response to extracellular ion-strength. For the trafficking of various cells or bacteria in an intact animal, we used optical imaging techniques or radiolabeled cells. We monitored tumor-targeting bacteria by bioluminescent imaging techniques, dentritic cells by radiolabeling and neuronal stem cells by sodium-iodide symporter reporter gene imaging. In summary, we introduced recent achievements of molecular nuclear imaging technologies in targeting receptors for hepatocyte or inflammatory cells and in trafficking bacterial, immune and stem cells using molecular nuclear imaging techniques

  9. Target validation for FCV technology development in Japan from energy competition point of view

    International Nuclear Information System (INIS)

    ENDO Eiichi

    2006-01-01

    The objective of this work is to validate the technical targets in the governmental hydrogen energy road-map of Japan by analyzing market penetration of fuel cell vehicle(FCV)s and effects of fuel price and carbon tax on it from technology competition point of view. In this analysis, an energy system model of Japan based on MARKAL is used. The results of the analysis show that hydrogen FCVs could not have cost-competitiveness until 2030 without carbon tax, including the governmental actual plan of carbon tax. However, as the carbon tax rate increases, instead of conventional vehicles including gasoline hybrid electric vehicle, hydrogen FCVs penetrate to the market earlier and more. By assuming higher fuel price and severer carbon tax rate, market share of hydrogen FCVs approaches to the governmental goal. This suggests that cheaper vehicle cost and/or hydrogen price than those targeted in the road-map is required. At the same time, achievement of the technical targets in the road-map also allows to attain the market penetration target of hydrogen FCVs in some possible conditions. (authors)

  10. Parametric study of a target factory for laser fusion

    International Nuclear Information System (INIS)

    Sherohman, J.W.; Meier, W.R.

    1980-01-01

    An analysis of a target factory leading to the derivation of production rate equations has provided the basis for a parametric study. Rate equations describing the production of laser fusion targets have been developed for the purpose of identifying key parameters, attractive production techniques and cost scaling relationships for a commercial target factory

  11. Targeting protein-protein interactions for parasite control.

    Directory of Open Access Journals (Sweden)

    Christina M Taylor

    2011-04-01

    Full Text Available Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs offer a realm of unexplored potential drug targets and are thought to be the next-generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific orthologous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank. EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite and B. malayi (H. sapiens parasite, which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly

  12. The effects of color cues on typically developing preschoolers' speed of locating a target line drawing: implications for augmentative and alternative communication display design.

    Science.gov (United States)

    Thistle, Jennifer J; Wilkinson, Krista

    2009-08-01

    This research examined how the presence of color in relation to a target within an augmentative and alternative communication array influenced the speed with which typically developing preschoolers located a target line drawing. Fifteen children over the age of 4 years (from 4;2 [years;months] to 5;4) and 15 children under the age of 4 years (2;10-3;11) participated. Participants were asked to find a target line drawing of foods (e.g., banana and tomato) among an array of 12. The reaction time of locating the target was measured across 4 conditions in which the foreground color and the background color of the line drawing were manipulated. For all participants, line drawings featuring foreground color provided greater advantages in the speed of locating the target compared with drawings featuring only background color. Younger participants demonstrated faster reaction times when color was limited to the foreground. Clinicians should consider incorporating color in the foreground of the line drawing when constructing visual displays. Targets that contain only background color but no foreground color appear to have a negative effect on the speed with which younger children can locate a target. Further research is needed to determine the effects in children with disabilities.

  13. Metallic beryllium-7 target of small diameter

    CERN Document Server

    Zyuzin, A Yu; Vincent, J S; Buckley, K R; Bateman, N P; Snover, K A; Csandjan, J M; Steiger, T D; Adelberger, E G; Swanson, H E

    1999-01-01

    The stellar sup 7 Be(p, gamma) sup 8 B reaction rate has the largest uncertainty among all nuclear reaction rates in the standard solar model. However, the solar neutrino flux predicted for the majority of proposed and existing solar neutrino detectors is directly dependent on the rate of sup 7 Be(p, gamma) sup 8 B reaction. The existing solar neutrino detectors measure rate of sup 8 B decay neutrinos that is too low. This constitutes largely the solar neutrino problem. Existing measurements of the sup 7 Be(p, gamma) sup 8 B reaction rate disagree with one another, indicating the need for more precise experiments. To provide the required targets a new procedure for sup 7 Be production, separation and target manufacturing has been developed. First, a lithium target has been designed for sup 7 Be production at TRIUMF's 13 MeV cyclotron. The lithium target has been extensively tested at 50 mu A proton beam current yielding 8.1 MBq/mu A h of sup 7 Be. An adsorption filtration technique has been developed for sup ...

  14. Targeted Phototherapy (newer phototherapy

    Directory of Open Access Journals (Sweden)

    Zonunsanga

    2015-04-01

    Full Text Available Conventional phototherapy uses a whole body cabinet or body part machine such as hand, foot or scalp machines. They have many disadvantages due to which new phototherapy technique was then developed to overcome this situation. This new technique is called targeted phototherapy which includes excimer laser, intense pulse light system (IPL, photodynamic therapy and ultraviolet (UV light source with a sophisticated delivery system which is easy to be operated by hands. The mechanisms of action of targeted phototherapy systems are similar to those in conventional UVB/UVA therapy. They have many advantages like less chances of side effects, avoidance of exposure of unnecessary sites, faster response, shortening of the duration of treatments. But they have disadvantages like high costs and inability to use for extensive areas. This review article discusses targeted phototherapy in considerable to the mechanism of actions and advantages and disadvantages in comparison to the conventional phototherapy.

  15. Pentanol-based target material with polarized protons

    International Nuclear Information System (INIS)

    Bunyatova, E.I.

    1992-01-01

    1-pentanol is a promising material for a target with polarized protons owing to its high resistance to radiation damage. To develop the target, the solutions of 1-pentanol or 2-pentanol with complexes of pentavalent chromium ware investigated. The material based EHBA-Cr(V) solution in a glass-like matrix, consisting of 1-pentanol, 3-pentanol and 1,2-propanediol, was proposed as a target material. It was investigated by the electron paramagnetic resonance and differential scanning calorimetry methods. 24 refs.; 3 figs.; 1 tab

  16. Utilizing random Forest QSAR models with optimized parameters for target identification and its application to target-fishing server.

    Science.gov (United States)

    Lee, Kyoungyeul; Lee, Minho; Kim, Dongsup

    2017-12-28

    The identification of target molecules is important for understanding the mechanism of "target deconvolution" in phenotypic screening and "polypharmacology" of drugs. Because conventional methods of identifying targets require time and cost, in-silico target identification has been considered an alternative solution. One of the well-known in-silico methods of identifying targets involves structure activity relationships (SARs). SARs have advantages such as low computational cost and high feasibility; however, the data dependency in the SAR approach causes imbalance of active data and ambiguity of inactive data throughout targets. We developed a ligand-based virtual screening model comprising 1121 target SAR models built using a random forest algorithm. The performance of each target model was tested by employing the ROC curve and the mean score using an internal five-fold cross validation. Moreover, recall rates for top-k targets were calculated to assess the performance of target ranking. A benchmark model using an optimized sampling method and parameters was examined via external validation set. The result shows recall rates of 67.6% and 73.9% for top-11 (1% of the total targets) and top-33, respectively. We provide a website for users to search the top-k targets for query ligands available publicly at http://rfqsar.kaist.ac.kr . The target models that we built can be used for both predicting the activity of ligands toward each target and ranking candidate targets for a query ligand using a unified scoring scheme. The scores are additionally fitted to the probability so that users can estimate how likely a ligand-target interaction is active. The user interface of our web site is user friendly and intuitive, offering useful information and cross references.

  17. Targeting MDM2 by the small molecule RITA: towards the development of new multi-target drugs against cancer

    Directory of Open Access Journals (Sweden)

    Espinoza-Fonseca L Michel

    2005-09-01

    Full Text Available Abstract Background The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Among these compounds, RITA (reactivation of p53 and induction of tumor cell apoptosis has been shown to be effective in the selective induction of apoptosis, and this effect is due to its binding to the p53 tumor suppressor. Since biological systems are highly dynamic and MDM2 may bind to different regions of p53, new alternatives should be explored. On this basis, the computational "blind docking" approach was employed in this study to see whether RITA would bind to MDM2. Results It was observed that RITA binds to the MDM2 p53 transactivation domain-binding cleft. Thus, RITA can be used as a lead compound for designing improved "multi-target" drugs. This novel strategy could provide enormous benefits to enable effective anti-cancer strategies. Conclusion This study has demonstrated that a single molecule can target at least two different proteins related to the same disease.

  18. Endothelial Cell-Targeted Adenoviral Vector for Suppressing Breast Malignancies

    National Research Council Canada - National Science Library

    Huang, Shuang

    2004-01-01

    .... Our proposal is designed to develop an endothelial cell-targeted adenoviral vector and to use the targeted vector to express high levels of anticancer therapeutic genes in the sites of angiogenenic...

  19. Liquid-4He target with a small refrigerator

    International Nuclear Information System (INIS)

    Kato, S.; Kitami, T.; Maruyama, K.; Murata, Y.; Endo, S.; Niki, K.; Morita, T.

    1989-10-01

    A liquid- 4 He target system with a small refrigerator has been developed for the first time to study γ 4 He reactions at intermediate energies. The density of the target is controlled within an accuracy of 3 %. The target system has been operated successfully for more than 1,000 hours of the experiment using the π-sr TAGX spectrometer at the 1.3-GeV Tokyo electron synchrotron. (author)

  20. A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against Leishmania major.

    Science.gov (United States)

    Catharina, Larissa; Lima, Carlyle Ribeiro; Franca, Alexander; Guimarães, Ana Carolina Ramos; Alves-Ferreira, Marcelo; Tuffery, Pierre; Derreumaux, Philippe; Carels, Nicolas

    2017-01-01

    We present an approach for detecting enzymes that are specific of Leishmania major compared with Homo sapiens and provide targets that may assist research in drug development. This approach is based on traditional techniques of sequence homology comparison by similarity search and Markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. From 67 enzymes represented by 42 enzymatic activities classified by AnEnPi (Analogous Enzymes Pipeline) as specific for L major compared with H sapiens , only 40 (23 Enzyme Commission [EC] numbers) could actually be considered as strictly specific of L major and 27 enzymes (19 EC numbers) were disregarded for having ambiguous homologies or analogies with H sapiens . Among the 40 strictly specific enzymes, we identified sterol 24-C-methyltransferase, pyruvate phosphate dikinase, trypanothione synthetase, and RNA-editing ligase as 4 essential enzymes for L major that may serve as targets for drug development.

  1. Model Penentuan Nilai Target Functional Requirement Berbasis Utilitas

    Directory of Open Access Journals (Sweden)

    Cucuk Nur Rosyidi

    2012-01-01

    Full Text Available In a product design and development process, a designer faces a problem to decide functional requirement (FR target values. That decision is made under a risk since it is conducted in the early design phase using incomplete information. Utility function can be used to reflect the decision maker attitude towards the risk in making such decision. In this research, we develop a utility-based model to determine FR target values using quadratic utility function and information from Quality Function Deployment (QFD. A pencil design is used as a numerical example using quadratic utility function for each FR. The model can be applied for balancing customer and designer interest in determining FR target values.

  2. Nuclear physics with internal targets in electron storage rings

    International Nuclear Information System (INIS)

    Holt, R.J.

    1986-01-01

    Two key experiments in nuclear physics will be discussed in order to illustrate the advantages of the internal target method and demonstrate the power of polarization techniques in electron scattering studies. The progress of internal target experiments will be discussed and the technology of internal polarized target development will be reviewed. 43 refs., 11 figs

  3. Trajectory Control of Rendezvous with Maneuver Target Spacecraft

    Science.gov (United States)

    Zhou, Zhinqiang

    2012-01-01

    In this paper, a nonlinear trajectory control algorithm of rendezvous with maneuvering target spacecraft is presented. The disturbance forces on the chaser and target spacecraft and the thrust forces on the chaser spacecraft are considered in the analysis. The control algorithm developed in this paper uses the relative distance and relative velocity between the target and chaser spacecraft as the inputs. A general formula of reference relative trajectory of the chaser spacecraft to the target spacecraft is developed and applied to four different proximity maneuvers, which are in-track circling, cross-track circling, in-track spiral rendezvous and cross-track spiral rendezvous. The closed-loop differential equations of the proximity relative motion with the control algorithm are derived. It is proven in the paper that the tracking errors between the commanded relative trajectory and the actual relative trajectory are bounded within a constant region determined by the control gains. The prediction of the tracking errors is obtained. Design examples are provided to show the implementation of the control algorithm. The simulation results show that the actual relative trajectory tracks the commanded relative trajectory tightly. The predicted tracking errors match those calculated in the simulation results. The control algorithm developed in this paper can also be applied to interception of maneuver target spacecraft and relative trajectory control of spacecraft formation flying.

  4. Development and testing of a deuterium gas target assembly for neutron production via the H-2(d,n)He-3 reaction at a low-energy accelerator facility

    International Nuclear Information System (INIS)

    Feautrier, D.; Smith, D.L.

    1992-03-01

    This report describes the development and testing of a deuterium gas target intended for use at a low-energy accelerator facility to produce neutrons for basic research and various nuclear applications. The principle source reaction is H-2(d,n)He-3. It produces a nearly mono-energetic group of neutrons. However, a lower-energy continuum neutron spectrum is produced by the H-2(d;n,p)H-2 reaction and also by deuterons which strike various components in the target assembly. The present target is designed to achieve the following objectives: (1) minimize unwanted background neutron production from the target assembly, (2) provide a relatively low level of residual long-term activity within the target components, (3) have the capacity to dissipate up to 150 watts of beam power with good target longevity, and (4) possess a relatively modest target mass in order to minimize neutron scattering from the target components. The basic physical principles that have to be considered in designing an accelerator target are discussed and the major engineering features of this particular target design are outlined. The results of initial performance tests on this target are documented and some conclusions concerning the viability of the target design are presented

  5. Preliminary investigation of solid target geometry

    Energy Technology Data Exchange (ETDEWEB)

    Haga, Katsuhiro; Kaminaga, Masanori; Hino, Ryutaro; Takada, Hiroshi [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Shafiqul, I.M.; Tsuji, Nobumasa; Okamoto, Hutoshi; Kumasaka, Katsuyuki; Hayashi, Katsumi

    1997-11-01

    In this report, we introduce the developing plan for a solid metal target structure. Supposing tantalum as the target material, the temperature distribution and the maximum thermal stress in a tantalum plate of a solid metal target was evaluated under a water cooling condition, using the heat generation rate calculated with the JAERI`s neutron transport code. The calculation results showed that the water velocity was higher than 10 m/s in order to cool the 3mm-thick target plate down to 200degC when the target surface was smooth and heat transfer rate was calculated with the Dittus-Boelter equation. In this case, the maximum thermal stress is 50 MPa at the target plate surface. The coolant water flow distribution in a target vessel was also evaluated for ISIS-type flow channels and the parallel flow channels. In the ISIS-type flow channels, at least 25mm height of the coolant plenum is needed for a uniform flow distribution. The maximum flow velocity difference between the flow gaps in the parallel flow channels was 30%. A heat transfer augmentation experiment was conducted using ribbed-surface flow channel. The heat transfer rate was confirmed to increase up to twice the value of that for a smooth surface. (author)

  6. Laval nozzles for cluster-jet targets

    Energy Technology Data Exchange (ETDEWEB)

    Grieser, Silke; Bonaventura, Daniel; Hergemoeller, Ann-Katrin; Hetz, Benjamin; Koehler, Esperanza; Lessmann, Lukas; Khoukaz, Alfons [Institut fuer Kernphysik, Westfaelische Wilhelms-Universitaet Muenster, 48149 Muenster (Germany)

    2016-07-01

    Cluster-jet targets are highly suited for storage ring experiments due to the fact that they provide high and constant beam densities. Therefore, a cluster-jet target is planned to be the first internal target for the PANDA experiment at FAIR. A cluster source generates a continuous flow of cryogenic solid clusters by the expansion of pre-cooled gases within fine Laval nozzles. For the production of clusters the geometry of the nozzle is crucial. The production of such nozzles with their complex inner geometry represents a major technical challenge. The possibility to produce new fine Laval nozzles ensures the operation of cluster-jet targets, e.g. for the PANDA experiment, and opens the way for future investigations on the cluster production process to match the required targets performance. Optimizations on the recently developed production process and the fabrication of new glass nozzles were done. Initial measurements of these nozzles at the PANDA cluster-jet target prototype and the investigation of the cluster beam origin within the nozzle will be presented and discussed. For the future more Laval nozzles with different geometries will be produced and additional measurements with these new nozzles at the PANDA cluster-jet target prototype towards higher performance will be realized.

  7. Non-targeted effects of ionising radiation

    International Nuclear Information System (INIS)

    Belyakov, O.V.

    2008-01-01

    The universality of the target theory of radiation-induced effects is challenged by observations on non-targeted effects such as bystander effects and genomic instability. Essential features of non-targeted effects are that they do not require direct nuclear exposure by radiation and they are particularly significant at low doses. This new evidence suggests a need for a new paradigm in radiation biology. The new paradigm would cover both the classical (targeted) and the non-targeted effects. New aspects include the role of cellular communication and tissue-level responses. A better understanding of non-targeted effects may have important consequences for health risk assessment and, consequently, on radiation protection. Non-targeted effects may contribute to the estimation of cancer risk from occupational, medical and environmental exposures. In particular, they may have implications for the applicability of the Linear-No-Threshold (LNT) model in extrapolating radiation risk data into the low-dose region. This also means that the adequacy of the concept of dose to estimate risk is challenged by these findings. Moreover, these effects may provide new mechanistic explanations for the development of non-cancer diseases. Further research is required to determine if these effects, typically measured in cell cultures, are applicable in tissue level, whole animals, and ultimately in humans. (orig.)

  8. Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

    Science.gov (United States)

    Bontha, Vijaya Kumar

    2013-01-01

    The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C max of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen. PMID:24260738

  9. Transient fuel and target performance testing for the HWR-NPR

    International Nuclear Information System (INIS)

    Jicha, J.J. Jr.

    1990-01-01

    This paper describes a five year program of fuel target transient performance testing and model development required for the safety assessment of the HWR new production reactor. Technical issues are described, focusing on fuel and target behavior during extremely low probability transients which can lead to fuel melting. Early work on these issues is reviewed. The program to meet remaining needs is described. Three major transient-testing activities are included: in-cell experiments on small samples of irradiated fuel and target, small-scale phenomenological experiments in the ACRR reactor, and limited-integral experiments in the TREAT reactor. A coordinated development of detailed fuel and target behavior models is also described

  10. New developments in demographic targeting--the implications of 1991.

    Science.gov (United States)

    Humby, C R

    1989-01-01

    This paper examines benefits that systems such as ACORN, a demographic marketing system that classifies neighborhoods, offer today and monitors some of the trends. It then considers the impact of the 1992 UK census and gives a view of what marketeers can expect in the next 5 years. Neighborhood classifications represent a summary of the consumption patterns of a set of neighbors. If we could reach individuals based on the current life stage the gains to be had would be as great again as that offered by the neighborhood classifications themselves. The greatest weakness of all the neighborhood-based systems is their inability to target at life stage or age.

  11. Hybridization Kinetics Explains CRISPR-Cas Off-Targeting Rules

    NARCIS (Netherlands)

    Klein, M.; Eslami Mosallam, B.; Gonzalez Arroyo, Dylan; Depken, S.M.

    2018-01-01

    Due to their specificity, efficiency, and ease of programming, CRISPR-associated nucleases are popular tools for genome editing. On the genomic scale, these nucleases still show considerable off-target activity though, posing a serious obstacle to the development of therapies. Off targeting is often

  12. Nanomedicine: Drug Delivery Systems and Nanoparticle Targeting

    International Nuclear Information System (INIS)

    Youn, Hye Won; Kang, Keon Wook; Chung, Jun Key; Lee, Dong Soo

    2008-01-01

    Applications of nanotechnology in the medical field have provided the fundamentals of tremendous improvement in precise diagnosis and customized therapy. Recent advances in nanomedicine have led to establish a new concept of theragnosis, which utilizes nanomedicines as a therapeutic and diagnostic tool at the same time. The development of high affinity nanoparticles with large surface area and functional groups multiplies diagnostic and therapeutic capacities. Considering the specific conditions related to the disease of individual patient, customized therapy requires the identification of disease target at the cellular and molecular level for reducing side effects and enhancing therapeutic efficiency. Well-designed nanoparticles can minimize unnecessary exposure of cytotoxic drugs and maximize targeted localization of administrated drugs. This review will focus on major pharmaceutical nanomaterials and nanoparticles as key components of designing and surface engineering for targeted theragnostic drug development

  13. RNA as a small molecule druggable target.

    Science.gov (United States)

    Rizvi, Noreen F; Smith, Graham F

    2017-12-01

    Small molecule drugs have readily been developed against many proteins in the human proteome, but RNA has remained an elusive target for drug discovery. Increasingly, we see that RNA, and to a lesser extent DNA elements, show a persistent tertiary structure responsible for many diverse and complex cellular functions. In this digest, we have summarized recent advances in screening approaches for RNA targets and outlined the discovery of novel, drug-like small molecules against RNA targets from various classes and therapeutic areas. The link of structure, function, and small-molecule Druggability validates now for the first time that RNA can be the targets of therapeutic agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Development of [103Pd]-2-acetylpyridine 4N-methyl thiosemicarbazone complex for targeted therapy

    International Nuclear Information System (INIS)

    Jalilian, A.R.; Sadeghi, M.; Yari-Kamrani, Y.; Ensaf, M.R.

    2006-01-01

    Due to interesting biological properties of palladium-thiosemicarbazono complexes, production of a 103 Pd-labeled anti-cancer complex, i.e., [ 103 Pd]-2-acetylpyridine 4 N-methylthiosemicarbazone ([ 103 Pd]-APMTS) was developed. Palladium-103 (T 1/2 = 16.96 d) produced via the 103 Rh(p,n) 103 Pd nuclear reaction using natural rhodium target, was separated from the irradiated target material. Proton energy was 18 MeV with 200 μA irradiation for 15 hours (final activity 700 mCi of 103 Pd 2+ , RCY>95%, radionuclidic purity>99%). The final activity was eluted in form of Pd(NH 3 ) 2 Cl 2 in order to react with 2-acetylpyridine- 4 N-methylthiosemicarbazone to yield [ 103 Pd]-APMTS. Chemical purity of the final product was confirmed to be within the accepted limits by polarography. [ 103 Pd]-APMTS was prepared with a radiochemical yield of more than 80% at room temperature after 3 hours. The labeling reaction was optimized for time, temperature and radioactivity and ligand ratio. A mixture of APMTS and Pd activity in ethanol was heated at 90 deg C for 3 hours followed by reverse phase SPE purification using C 18 plus Sep-Pak. Radiochemical purity of more than 99% using RTLC and specific activity of about 12500 Ci/mol was obtained. The stability of the tracer was checked in the final product and the presence of human serum at 37 deg C up to 3 hours. The partition coefficient of the final complex was determined by octanol:saline buffer distribution. (author)

  15. Radiation responses of stem cells: targeted and non-targeted effects

    International Nuclear Information System (INIS)

    Kavanagh, J.N.; Waring, E.J.; Prise, K.M.

    2015-01-01

    Stem cells are fundamental to the development of any tissue or organism via their ability to self-renew, which is aided by their unlimited proliferative capacity and their ability to produce fully differentiated offspring, often from multiple lineages. Stems cells are long lived and have the potential to accumulate mutations, including in response to radiation exposure. It is thought that stem cells have the potential to be induced into a cancer stem cell phenotype and that these may play an important role in resistance to radiotherapy. For radiation-induced carcinogenesis, the role of targeted and non-targeted effects is unclear with tissue or origin being important. Studies of genomic instability and bystander responses have shown consistent effects in haematopoietic models. Several models of radiation have predicted that stem cells play an important role in tumour initiation and that bystander responses could play a role in proliferation and self-renewal. (authors)

  16. Radiotherapy in combination with vascular-targeted therapies

    International Nuclear Information System (INIS)

    Ciric, Eva; Sersa, Gregor

    2010-01-01

    Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised

  17. L,L-diaminopimelate aminotransferase from Chlamydomonas reinhardtii: a target for algaecide development.

    Science.gov (United States)

    Dobson, Renwick C J; Girón, Irma; Hudson, André O

    2011-01-01

    In some bacterial species and photosynthetic cohorts, including algae, the enzyme L,L-diaminopimelate aminotransferase (DapL) (E.C. 2.6.1.83) is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA) to L,L-diaminopimelate (L,L-DAP), in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL). The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and L,L-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid L-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides.

  18. L,L-diaminopimelate aminotransferase from Chlamydomonas reinhardtii: a target for algaecide development.

    Directory of Open Access Journals (Sweden)

    Renwick C J Dobson

    Full Text Available In some bacterial species and photosynthetic cohorts, including algae, the enzyme L,L-diaminopimelate aminotransferase (DapL (E.C. 2.6.1.83 is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA to L,L-diaminopimelate (L,L-DAP, in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL. The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and L,L-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid L-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides.

  19. Polarized target physics at the Bonn electron accelerators

    International Nuclear Information System (INIS)

    Meyer, W.

    1988-12-01

    At the BONN 2.5 GeV electron synchrotron experiments with polarized nucleon targets have a long tradition. Starting with measurements of the target asymmetry in single pion photoproduction off polarized protons, resp. neutrons, the experiments have been concentrated on photodisintegration measurements of polarized deuterons. Parallel to these activities a considerable progress in the field of the target technology, e.g. cryogenics and target materials, has been made, by which all the measurements have profitted enormously. Especially the development of the new target material ammonia has allowed the first use of a polarized deuteron (ND 3 ) target in an intense electron beam. The construction of a frozen spin target, which will be used in combination with a tagged polarized photon beam, makes a new generation of polarized target experiments in photon induced reactions possible. Together with electron scattering off polarized deuterons and neutrons they will be a main activity in the physics program at the new stretcher accelerator ELSA in BONN. (orig.)

  20. KISS1 can be used as a novel target for developing a DNA immunocastration vaccine in ram lambs.

    Science.gov (United States)

    Han, Yanguo; Liu, Guiqiong; Jiang, Xunping; Ijaz, Nabeel; Tesema, Birhanu; Xie, Guangyue

    2015-02-04

    KISS1 gene-encoding kisspeptins are critical for the onset of puberty and control of adult fertility. This study investigated whether KISS1 can be used as a novel target for immunocastration. Human KISS1 was fused with the HBsAg-S gene for constructing an antibiotic-free recombinant plasmid pKS-asd that coded for 31.168 kDa target fusion protein. Six male Hu sheep lambs were divided into two equal groups, treatment and control. The vaccine (1mg/ram lamb) prepared in saline solution was injected into lambs at weeks 0, 3 and 6 of the experiment, respectively. Vaccine efficacy was evaluated in terms of KISS1-specific IgG antibody response, serum testosterone levels, scrotal circumference, testicular weight, length and breadth, extent of testicular tissue damage, and sexual behaviour changes. The specific anti-KISS1 antibody titre in vaccinated animals was significantly higher than that in controls (pvaccinated animals showed lower serum testosterone level, testicular weight and length and smaller scrotal circumference than those in controls (pvaccinated animals was suppressed; sexual behaviours in vaccinated animals were significantly lower (pvaccine induced a strong antibody response and resulted in the suppression of gonadal function and sexual behaviour in animals, demonstrating that KISS1 can be used as a novel target for developing a DNA immunocastration vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.