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. 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.

  4. 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

  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. 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

  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. 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

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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

  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 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. 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.

  18. 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

  19. 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

  20. 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.

  1. 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)

  2. 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)

  3. 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

  4. Continuing professional development and ICT: target practice.

    Science.gov (United States)

    Eaton, K A; Reynolds, P A

    2008-07-26

    Ever-increasing needs and demands by dentists and all other members of the dental team for education and training at all levels - undergraduate, postgraduate and continuing - are straining the resources of existing providers of such education. At the same time, there are ever-increasing opportunities to develop online delivery and the use of a range of information and communication technology (ICT) systems and services further, in all aspects of dental education. This paper reviews recent developments that have led to an increased demand for dental postgraduate programmes and continuing professional development (CPD) courses in the United Kingdom and then discusses how ICT has and will impact on teaching practice. Examples include the use of teaching and learning resources in a virtual learning environment (VLE) and the increasing use of blended learning. The paper then explores the need for both teachers and students to adapt to the new environment to ensure they can benefit to the maximum and that teaching and learning practices are changed accordingly.

  5. 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.

  6. Development of labelled biomolecules for targeted radiotherapy

    International Nuclear Information System (INIS)

    Arteaga de Murphy, C.

    2000-01-01

    The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides, 2) optimised radiolabelling procedures and reaction parameters using Sm-153 and Re-188, 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188. 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling, b) continue with the work to prepare a kit, c) in-vivo and in-vitro studies, d) lanreotide labelling. The group formed by researchers from several Mexican Institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims (our published work listed)

  7. Development of labelled biomolecules for targeted radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Arteaga de Murphy, C [Instituto Nacional de la Nutricion Salvador Zubiran, Departmento de Medicina Nuclear, Mexico D.F. (Mexico). E-mail: cmurphy at data.net.mx

    2000-07-01

    The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides, 2) optimised radiolabelling procedures and reaction parameters using Sm-153 and Re-188, 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188. 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling, b) continue with the work to prepare a kit, c) in-vivo and in-vitro studies, d) lanreotide labelling. The group formed by researchers from several Mexican Institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims (our published work listed)

  8. 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

  9. 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)

  10. 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

  11. 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)

  12. 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

  13. 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.

  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. 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.)

  17. 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

  18. 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 ...

  19. 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.)

  20. 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.

  1. 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

  2. [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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  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. 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.

  14. 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)

  15. 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)

  16. 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.

  17. 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)

  18. 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.

  19. 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

  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. 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)

  2. 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.

  3. 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.

  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. 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. 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.

  7. 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...

  8. 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.

  9. 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

  10. 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)

  11. 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)

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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) ...

  1. 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).

  2. 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).

  3. 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.

  4. 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)

  5. 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.

  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. 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.

  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. New development is targeted at the future nuclear generating market

    Energy Technology Data Exchange (ETDEWEB)

    1974-01-01

    The results are given of a survey of the reserves, exploitation and processing of uranium ore in the USA, Australia, Canada, France (including Gabon and Niger), and South Africa indicating estimated development up to 1990 and the estimated impact of the development of mining on the world natural uranium and enriched fuel market.

  10. The Cellular Targets of Estrogen in Mammary Ductal Development

    National Research Council Canada - National Science Library

    Kushner, Peter

    2002-01-01

    ...) or with alternative response elements, especially AP-i and CRE elements, mediate proliferation. We have been successful in developing transgenic mice with expression of wild type and AP-1/CRE superactive human ER alpha (K206A...

  11. Development of target capsules for muon catalyzed fusion experiments

    International Nuclear Information System (INIS)

    Watts, K.D.; Jones, S.E.; Caffrey, A.J.

    1983-01-01

    A series of Muon Catalyzed Fusion experiments has been conducted at the Los Alamos Meson Physics Facility to determine how many fusion reactions one muon would catalyze under various temperature, pressure, contamination, and tritium concentration conditions. Target capsules to contain deuterium and tritium at elevated temperatures and pressures were engineered for a maximum temperature of 540 K (512 0 F) and a maximum pressure of 103 MPa (15,000 psig). Experimental data collected with these capsules indicated that the number of fusion reactions per muon continued to increase with temperature up to the 540-K design limit. Theory had indicated that the reaction rate should peak at approximately 540 K, but this was not confirmed during the experiments. A second generation of capsules which have a maximum design temperature of 800 K (980 0 F) and a maximum design pressure of 103 MPa (15,000 psig) has now been engineered. These new capsules will be used to further study the muon catalysis rate versus deuterium-tritium mixture temperature

  12. Developing a crevice chemistry control target from uncertain data

    International Nuclear Information System (INIS)

    Millett, P.J.

    1996-01-01

    It has been generally accepted that the corrosion of steam generator tubing could be reduced if the local pH in regions where impurities concentrate could be controlled. The practice of molar ratio control is based on this assumption. Direct measurement of the crevice chemistry is not possible at this time. Deterministic models based on bulk water conditions are quite uncertain, due to both the variability of crevices in the steam generator and the level of impurities in the bulk water which are often below or at the level of detection. The current methodology for assessing the crevice chemistry is to monitor the hideout return chemistry when the plant shuts down. This approach also has its shortcomings, but may provide sufficient data to evaluate whether the crevice pH is in a desirable range. In this paper, an approach for establishing a target crevice chemistry based on the plant data which is believed to be the most certain or reliable is presented

  13. A drug target that stimulates development of healthy stem cells

    Science.gov (United States)

    Scientists have overcome a major impediment to the development of effective stem cell therapies by studying mice that lack CD47, a protein found on the surface of both healthy and cancer cells. They discovered that cells obtained from the lungs of CD47-de

  14. 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

  15. Molecular target in oncology. Opportunity for radiopharmaceuticals development

    International Nuclear Information System (INIS)

    Navarro Marques, Fabio Luiz

    2016-01-01

    Cancer is a cellular multifactorial disease, regulated by changes in phenotype characteristics, such as adhesion, invasion, migration, and tumorigenesis; genotypic status of commonly altered genes (KRAS and p53); microenvironmental conditions, such pH, oxygen and nutrient supply. All these features provide opportunities for radiopharmaceuticals development, both for diagnostic and therapy. For both applications, radiopharmaceuticals molecules can be divided in small synthetic molecules, small peptides (natural or modified), large molecules such as antibody or nanoparticles. The characteristics of those molecules and use will guide the choice of the radionuclide to be used for labeling it. In the presentation, data from literature and research ongoing in the Faculty of Medicine of the University of São Paulo/Brazil will be used for demonstrate the potential for radiopharmaceuticals development. (author)

  16. Trees, poverty and targets: Forests and the Millennium Development Goals

    Energy Technology Data Exchange (ETDEWEB)

    Myers, James

    2007-04-15

    Where are the forests in the MDGs? When players in the forestry world get together they are good at setting goals. They are a good match for the political leaders that gave us the Millennium Development Goals (MDGs). Since the 1980s there has been a proliferation of international dialogues dealing with forests and, a bit like the football World Cup, every four years or so they come up with a feast of goals. If forestry goals were all we needed to make progress, then sustainable and pro-poor forestry would have long since become a worldwide reality. Of course, implementation still lags well behind aspiration, but at least there is now a considerable body of international knowledge and agreement on how forests can contribute to development.

  17. Targeted On-Demand Team Performance App Development

    Science.gov (United States)

    2016-10-01

    Data collection ongoing, to be completed Q2 2017. 30Sept2015 - 29Sept2016 Email: pandreatta@ist.ucf.edu 15. SUBJECT TERMS Team Characteristics ...The resulting solutions will be adaptable for applicability to all types of military and civilian healthcare teams .  KEYWORDS: Team Characteristics ...27. Carron, A. V., Widmeyer, N. W., & Brawey, L. R. (1985). The development of an instrument to assess cohesion in sports teams : The group

  18. Targeting development of incretin-producing cells increases insulin secretion

    DEFF Research Database (Denmark)

    Petersen, Natalia; Reimann, Frank; van Es, Johan H

    2015-01-01

    the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture...... of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control....

  19. Development of radioactively labelled cancer seeking biomolecules for targeted therapy

    International Nuclear Information System (INIS)

    Pillai, M.R.A.

    2000-01-01

    The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

  20. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  1. Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy

    International Nuclear Information System (INIS)

    Varvarigou, A.D.; Archimandritis, S.C.

    2000-01-01

    Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

  2. Gene therapy of cancer and development of therapeutic target gene

    International Nuclear Information System (INIS)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  3. Pengendalian Malaria dalam Upaya Percepatan Pencapaian Target Millennium Development Goals

    Directory of Open Access Journals (Sweden)

    Tri Rini Puji Lestari

    2012-08-01

    health official Malaria Center, and community leaders who observe malaria. Retrieval of data time is 10 – 16 April 2011 by in-depth interviews. It was found that malaria control programs have been implemented by the Departement of Health North Maluku Province, but have not been able to effectively reduce malaria morbidity. This is because malaria control is performed is not comprehensive. Handling is more directed to break the chain transmission to human, their habitats have not been touched up. Key words: Control of malaria, millennium development goals, malaria morbidity

  4. Psoriasis pathogenesis and the development of novel targeted immune therapies.

    Science.gov (United States)

    Hawkes, Jason E; Chan, Tom C; Krueger, James G

    2017-09-01

    Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  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. 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.

  7. Development of labelled biomolecules for targeted radiotherapy. Mexico

    International Nuclear Information System (INIS)

    Arteaga de Murphy, Consuelo

    2000-01-01

    The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides; 2) optimise radiolabelling procedures and reaction parameters using Sm-153 and Re-188; 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188; 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling; b) continue with the work to prepare a kit; c) in-vivo and in-vitro studies; d) Lanreotide labelling. The group formed by researchers from several Mexican institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims

  8. Development of the systems for uniform target irradiation

    International Nuclear Information System (INIS)

    Voronin, A.Yu.; Garanin, S.G.; Derkach, V.N.; Zhidkov, N.V.; Kravchenko, A.G.; Petrazhitskaya, N.A.; Starodubtsev, K.V.; Sukharev, S.A.; Shnyagin, R.A.

    2010-01-01

    Complete text of publication follows. The new devices have been developed for laser beams homogenizing in the focal spot - multi-component lens raster and raster with the edges smoothing phase mask. The envelope non-uniformity of -4 radians. Investigation into the temporary-spatial smoothing with the use of low-density foams with the density less than the critical one is still in progress. Experiments on the foams with the density of 1-2.3 mg/cm 3 , thickness of 100-200 μm, and the cells' sizes up to the tens of micrometers were carried out with the radiation wavelength of 0.657 μm. The RMS non-uniformity < 5% has been found for the beam passed through the foam. The non-uniformity is evenly distributed over the spatial frequency spectrum. The induced divergence of radiation is measured to be 0.35 radian. The frequency of the rearranged speckled field of about 2 THz was obtained. The beam smoothing was recorded from the start of pulse of radiation, had the duration up to 1 ns, and the width of the radiation spectrum was about 30 A. The work was performed in part under the sponsorship of the RFFI (grants No. 09-02-12157-ofi-m and No. 09-02-97095-r-povolzh'ye-a) and grant of the President of the RF to leading scientific schools No. 65192.2010.2.

  9. Development of production of {sup 99}Mo from LEU target

    Energy Technology Data Exchange (ETDEWEB)

    Adang, H G; Mutalib, A; Lubis, H [Radioisotope Production Centre, National Atomic Energy Agency, Kawasan Puspiptek, Serpong (Indonesia); and others

    1998-10-01

    {sup 99}TC, the most popular radioisotope in nuclear medicine, is daughter of {sup 99}Mo. {sup 99}Mo is produced in research reactor by irradiating of high enriched uranium (HEU). However, in recent year, strict regulation that has been implemented by USA DOE and NPT has led to the difficulty in getting HEU. Therefore, BATAN has tried to develop the production of {sup 99}Mo by using low enriched uranium (LEU). The research involves the use of LEU in the production of {sup 99}Mo. This research was started in 1994 by joint-research between BATAN and Argonne National Laboratory USA. This program is divided into three research groups. The first group emphasizes its research on fabrication of LEU foil that is going to be irradiated. The second group studies the irradiation`s aspects and physical characteristic of irradiated LEU foils. The third group studies the radiochemical separation process of fission product {sup 99}Mo from solution of irradiated LEU foils. There are five steps that are carried out in studying of radiochemical separation of {sup 99}Mo from irradiated LEU. First is designing a dissolver that is going to be used in dissolving of LEU foil and testing its reliability. Second is dissolving LEU in the new design dissolver. Third is evaluation the modified of Cintichem`s radiochemical separation process of {sup 99}Mo from LEU. Forth is modifying the Cintichem`s radiochemical separation process of {sup 99}Mo from the solution of irradiated LEU. And fifth is using the modified of Cintichem`s radiochemical separation process for separation {sup 99}Mo from solution of irradiated LEU. The first through the forth steps of experiments were already carried out and will be reported in this workshop, whereas the fifth step of experiment is going to be conducted in February 1998. (author)

  10. Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Jeong Sun [Division of Undeclared Majors, Chosun University, Gwangju 501-759 (Korea, Republic of); Yoon, Doo-Soo; Sohn, Jun Youn [Department of Bioenvironmental & Chemical Engineering, Chosun College of Science & Technology, Gwangju 501-744 (Korea, Republic of); Park, Jeong-Sook, E-mail: eicosa@cnu.ac.kr [College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134 (Korea, Republic of); Choi, Jin-Seok, E-mail: c34281@gmail.com [College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134 (Korea, Republic of)

    2017-03-01

    To overcome the toxicity of excipient or blank nanoparticles for drug delivery nano-system, the surface modified paclitaxel nanocrystals (PTX-NC) have been developed. PTX-NCs were prepared by nano-precipitation method. The surface of PTX-NCs were modified by grafting with apo-transferrin (Tf) or hyaluronic acid (HA). The physical properties of PTX-NCs were evaluated by field emission scanning electron microscope (FE-SEM), zeta-sizer, zeta-potential, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectrometry. In vitro drug release study was performed in phosphate buffered saline (PBS) with or without 0.5% (w/v) Tween 80 for 24 h. Cellular uptake was studied at time intervals of 0.5, 1, and 2 h in MCF-7 cells, and cell growth inhibition study was performed for 24 h using MCF-7 cells (cancer cells), and HaCaT cells (normal cells). Three different types of PTX-NCs with a mean size of 236.0 ± 100.6 nm (PTX-NC), 302.0 ± 152.0 nm (Tf-PTX-NC) and 339 ± 180.6 nm (HA-PTX-NC) were successfully prepared. The drug release profiles showed 29.1%/6.9% (PTX (pure)), 40.7%/23.9% (PTX-NC), 50.5%/25.1% (Tf-PTX-NC) and 46.8/24.8% (HA-PTX-NC) in PBS with/without 0.5% (w/v) Tween 80 for 24 h, respectively. As per the results, the drug release of PTX-NCs showed the faster release as compared to that of PTX (pure). Surface modified PTX-NCs exhibited higher values for cell permeability than unmodified PTX-NC in the cellular uptake study. Surface modified PTX-NCs inhibited the cell growth approximately to 60% in MCF-7 cells, however effect of surface modified PTX-NCs on normal cell line was lower than the PTX-NC and PTX (pure). In conclusion, biological macromolecules (Tf or HA) surface modified PTX-NC enhanced the cellular uptake and the cell growth inhibition. - Highlights: • Surface modified PTX-NCs with HA and Tf are successfully prepared by adsorption method. • Enhanced cellular uptake of modified PTX-NCs compared to unmodified PTX-NC • Improved

  11. 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.

  12. 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.

  13. 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.)

  14. 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)

  15. 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.

  16. 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.

  17. 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...

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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...

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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)

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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)

  15. 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.

  16. 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.

  17. 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.

  18. 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…

  19. 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)

  20. 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

  1. 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

  2. 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.)

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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...

  12. 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.

  13. 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)

  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. 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

  16. 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...

  17. 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.

  18. 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

  19. 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.

  20. 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 ...

  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. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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...

  13. 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)

  14. 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.

  15. 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.

  16. 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

  17. 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)

  18. 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.

  19. 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...

  20. 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).

  1. 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

  2. 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.

  3. 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.)

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  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. 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

  12. 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.

  13. 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...

  14. 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.

  15. 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.)

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  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. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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)

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development.

    Science.gov (United States)

    Moraes, Gleiciane Leal; Gomes, Guelber Cardoso; Monteiro de Sousa, Paulo Robson; Alves, Cláudio Nahum; Govender, Thavendran; Kruger, Hendrik G; Maguire, Glenn E M; Lamichhane, Gyanu; Lameira, Jerônimo

    2015-03-01

    Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB. Copyright © 2015. Published by Elsevier Ltd.

  13. 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.

  14. [Development of a hydrogen and deuterium polarized gas target for application in storage rings]: Progress report

    International Nuclear Information System (INIS)

    Haeberli, W.

    1989-01-01

    This paper briefly discusses the following topics: the Wisconsin test facility for storage cells; results of target tests; the new UHV target test system; funding request for a new atomic beam system; and planning of storage ring experiments

  15. Development and performance evaluation of a dynamic phantom for biological dosimetry of moving targets

    Science.gov (United States)

    Gemmel, A.; Bert, C.; Saito, N.; von Neubeck, C.; Iancu, G.; K-Weyrather, W.; Durante, M.; Rietzel, E.

    2010-06-01

    A dynamic phantom has been developed to allow for measurement of 3D cell survival distributions and the corresponding distributions of the RBE-weighted dose (RBED) in the presence of motion. The phantom consists of two 96-microwell plates holding Chinese hamster ovary cells inside a container filled with culture medium and is placed on a movable stage. Basic biological properties of the phantom were investigated without irradiation and after irradiation with a carbon ion beam, using both a stationary (reference) exposure and exposure during motion of the phantom perpendicular to the beam with beam tracking. There was no statistically significant difference between plating efficiency measured in the microwells with and without motion (0.75) and values reported in the literature. Mean differences between measured and calculated cell survival for these two irradiation modes were within ±5% of the target dose of 6 Gy (RBE).

  16. 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

  17. Development and performance evaluation of a dynamic phantom for biological dosimetry of moving targets

    Energy Technology Data Exchange (ETDEWEB)

    Gemmel, A; Bert, C; Saito, N; Von Neubeck, C; Iancu, G; K-Weyrather, W; Durante, M; Rietzel, E, E-mail: alexander.ag.gemmel@siemens.co [GSI Helmholtzzentrum fuer Schwerionenforschung, Planckstr 1, 64291 Darmstadt (Germany)

    2010-06-07

    A dynamic phantom has been developed to allow for measurement of 3D cell survival distributions and the corresponding distributions of the RBE-weighted dose (RBED) in the presence of motion. The phantom consists of two 96-microwell plates holding Chinese hamster ovary cells inside a container filled with culture medium and is placed on a movable stage. Basic biological properties of the phantom were investigated without irradiation and after irradiation with a carbon ion beam, using both a stationary (reference) exposure and exposure during motion of the phantom perpendicular to the beam with beam tracking. There was no statistically significant difference between plating efficiency measured in the microwells with and without motion (0.75) and values reported in the literature. Mean differences between measured and calculated cell survival for these two irradiation modes were within {+-}5% of the target dose of 6 Gy (RBE).

  18. 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.

  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. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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)

  6. Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

    Science.gov (United States)

    Dumeige, Laurence; Storey, Caroline; Decourtye, Lyvianne; Nehlich, Melanie; Lhadj, Christophe; Viengchareun, Say; Kappeler, Laurent; Lombès, Marc; Martinerie, Laetitia

    2017-01-01

    Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology. PMID:28230786

  7. Development of Detector Systems for Internal and Fixed Target Heavy Ion Physics Experiments

    International Nuclear Information System (INIS)

    Golubev, Pavel

    2003-04-01

    This thesis deals with intermediate energy heavy ion reactions with the particular aim to study the nuclear matter equation of state which defines the relation between statistical parameters of a fermionic system. The development of equipment for two experiments, CA47 at The Svedberg Laboratory in Uppsala, Sweden and R16 at Kernfysisch Versneller Inst. (KVI), Groningen, The Netherlands, are described. CA47 contains the CHICSi detector, a modular, ultra-high vacuum (UHV) compatible, multi-detector system, covering a solid angle of 3pi sr around the collision point. Together with two auxiliary detector systems CHICSi is placed at the cluster-jet target chamber of the CELSIUS storage ring. This thesis gives a technical overview of the detector and the development carried out in order to achieve the desired detection performance. Some laboratory and in-beam tests are described and the analysis of the first experimental results is discussed. The nuclear intensity interferometry experiment (R16) was performed in a dedicated beam-line of the AGOR superconducting cyclotron. Small-angle two-particle correlations were measured for the E/A = 61 MeV 36 Ar + 27 Al, 112 Sn, 124 Sn reactions, together with singles spectra. The experimental energy distributions of neutrons and light charged particles for the 36 Ar + 27 Al reaction have been analyzed with a Maxwellian multi-source prescription. These results, together with correlation function data, are used to extract information on the size of the emitting sources and their time evolution

  8. 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.

  9. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.

    Science.gov (United States)

    Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide; Sonenberg, Nahum

    2015-01-15

    Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents. ©2014 American Association for Cancer Research.

  10. 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.

  11. Reduced Treatment-Emergent Sexual Dysfunction as a Potential Target in the Development of New Antidepressants

    Directory of Open Access Journals (Sweden)

    David S. Baldwin

    2013-01-01

    Full Text Available Pleasurable sexual activity is an essential component of many human relationships, providing a sense of physical, psychological, and social well-being. Epidemiological and clinical studies show that depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction, both in untreated and treated patients. The findings of randomized placebo-controlled trials demonstrate that most of the currently available antidepressant drugs are associated with the development or worsening of sexual dysfunction, in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts but can endure over long periods and may reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk and type of dysfunction vary with differing compounds and should be considered when making decisions about the relative merits and drawbacks of differing antidepressants. A range of interventions can be considered when managing patients with sexual dysfunction associated with antidepressants, including the prescription of phosphodiesterase-5 inhibitors, but none of these approaches can be considered “ideal.” As treatment-emergent sexual dysfunction is less frequent with certain drugs, presumably related to differences in their pharmacological properties, and because current management approaches are less than ideal, a reduced burden of treatment-emergent sexual dysfunction represents a tolerability target in the development of novel antidepressants.

  12. Development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors

    Directory of Open Access Journals (Sweden)

    Daniel C Farley

    Full Text Available It is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (RCL in lentiviral vector products prior to use in clinical trials. Immune Design previously described an HIV-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (VP02. VP02 is enveloped with E1001, a modified Sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN expressed on dendritic cells in vivo. Vector enveloped with E1001 does not transduce T-cell lines used in standard HIV-1-based RCL assays, making current RCL testing formats unsuitable for testing VP02. We therefore developed a novel assay to test for RCL in clinical lots of VP02. This assay, which utilizes a murine leukemia positive control virus and a 293F cell line expressing the E1001 receptor DC-SIGN, meets a series of evaluation criteria defined in collaboration with US regulatory authorities and demonstrates the ability of the assay format to amplify and detect a hypothetical RCL derived from VP02 vector components. This assay was qualified and used to test six independent GMP production lots of VP02, in which no RCL was detected. We propose that the evaluation criteria used to rationally design this novel method should be considered when developing an RCL assay for any lentiviral vector.

  13. Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Tetsuro Tago

    2018-01-01

    Full Text Available Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs, which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET. We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.

  14. 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.

  15. A review of global progress toward the Millennium Development Goal 1 Hunger Target.

    Science.gov (United States)

    Fanzo, Jessica C; Pronyk, Paul M

    2011-06-01

    The hunger component of the first Millennium Development Goal (MDG) aims to reduce the proportion of people who suffer from hunger by half between 1990 and 2015. In low- and middle-income countries, progress has been mixed, with approximately 925 million people hungry and 125 million and 195 million children underweight and stunted, respectively. To assess global progress on the hunger component of MDG1 and evaluate the success of interventions and country programs in reducing undernutrition. We review global progress on the hunger component of MDG1, examining experience from 40 community-based programs as well as national efforts to move interventions to scale drawn from the published and gray literature, alongside personal interviews with representatives of governments and development agencies. Based on this review, most strategies being implemented and scaled are focusing on treatment of malnutrition and rooted within the health sector. While critical, these programs generally address disease-related effects and emphasize the immediate determinants of undernutrition. Other major strategies to tackle undernutrition rely on the production of staple grains within the agriculture sector. These programs address hunger, as opposed to improving the quality of diets within communities. Strategies that adopt multisectoral programming as crucial to address longer-term determinants of undernutrition, such as poverty, gender equality, and functioning food and health systems, remain underdeveloped and under-researched. This review suggests that accelerating progress toward the MDG1 targets is less about the development of novel innovations and new technologies and more about putting what is already known into practice. Success will hinge on linking clear policies with effective delivery systems in working towards an evidence-based and contextually relevant multisectoral package of interventions that can rapidly be taken to scale.

  16. Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development.

    Science.gov (United States)

    Lu, Tianjing; Lin, Wen-Jye; Izumi, Kouji; Wang, Xiaohai; Xu, Defeng; Fang, Lei-Ya; Li, Lei; Jiang, Qi; Jin, Jie; Chang, Chawnshang

    2012-10-01

    Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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…

  4. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    Science.gov (United States)

    Hutton, Guy; Chase, Claire

    2016-01-01

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID:27240389

  5. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene.

    Science.gov (United States)

    Hutton, Guy; Chase, Claire

    2016-05-27

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  6. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    Directory of Open Access Journals (Sweden)

    Guy Hutton

    2016-05-01

    Full Text Available Safe drinking water, sanitation, and hygiene (WASH are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  7. Development of Genetic Markers in Eucalyptus Species by Target Enrichment and Exome Sequencing

    Science.gov (United States)

    Dasgupta, Modhumita Ghosh; Dharanishanthi, Veeramuthu; Agarwal, Ishangi; Krutovsky, Konstantin V.

    2015-01-01

    The advent of next-generation sequencing has facilitated large-scale discovery, validation and assessment of genetic markers for high density genotyping. The present study was undertaken to identify markers in genes supposedly related to wood property traits in three Eucalyptus species. Ninety four genes involved in xylogenesis were selected for hybridization probe based nuclear genomic DNA target enrichment and exome sequencing. Genomic DNA was isolated from the leaf tissues and used for on-array probe hybridization followed by Illumina sequencing. The raw sequence reads were trimmed and high-quality reads were mapped to the E. grandis reference sequence and the presence of single nucleotide variants (SNVs) and insertions/ deletions (InDels) were identified across the three species. The average read coverage was 216X and a total of 2294 SNVs and 479 InDels were discovered in E. camaldulensis, 2383 SNVs and 518 InDels in E. tereticornis, and 1228 SNVs and 409 InDels in E. grandis. Additionally, SNV calling and InDel detection were conducted in pair-wise comparisons of E. tereticornis vs. E. grandis, E. camaldulensis vs. E. tereticornis and E. camaldulensis vs. E. grandis. This study presents an efficient and high throughput method on development of genetic markers for family– based QTL and association analysis in Eucalyptus. PMID:25602379

  8. Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size

    Science.gov (United States)

    Vermeer, W M; Steenhuis, I H M; Poelman, M P

    2014-01-01

    In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a ‘super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes. PMID:25033959

  9. Research on the development of space target detecting system and three-dimensional reconstruction technology

    Science.gov (United States)

    Li, Dong; Wei, Zhen; Song, Dawei; Sun, Wenfeng; Fan, Xiaoyan

    2016-11-01

    With the development of space technology, the number of spacecrafts and debris are increasing year by year. The demand for detecting and identification of spacecraft is growing strongly, which provides support to the cataloguing, crash warning and protection of aerospace vehicles. The majority of existing approaches for three-dimensional reconstruction is scattering centres correlation, which is based on the radar high resolution range profile (HRRP). This paper proposes a novel method to reconstruct the threedimensional scattering centre structure of target from a sequence of radar ISAR images, which mainly consists of three steps. First is the azimuth scaling of consecutive ISAR images based on fractional Fourier transform (FrFT). The later is the extraction of scattering centres and matching between adjacent ISAR images using grid method. Finally, according to the coordinate matrix of scattering centres, the three-dimensional scattering centre structure is reconstructed using improved factorization method. The three-dimensional structure is featured with stable and intuitive characteristic, which provides a new way to improve the identification probability and reduce the complexity of the model matching library. A satellite model is reconstructed using the proposed method from four consecutive ISAR images. The simulation results prove that the method has gotten a satisfied consistency and accuracy.

  10. Development of Molecularly Imprinted Polymers to Target Polyphenols Present in Plant Extracts

    Directory of Open Access Journals (Sweden)

    Catarina Gomes

    2017-11-01

    Full Text Available The development of molecularly imprinted polymers (MIPs to target polyphenols present in vegetable extracts was here addressed. Polydatin was selected as a template polyphenol due to its relatively high size and amphiphilic character. Different MIPs were synthesized to explore preferential interactions between the functional monomers and the template molecule. The effect of solvent polarity on the molecular imprinting efficiency, namely owing to hydrophobic interactions, was also assessed. Precipitation and suspension polymerization were examined as a possible way to change MIPs morphology and performance. Solid phase extraction and batch/continuous sorption processes were used to evaluate the polyphenols uptake/release in individual/competitive assays. Among the prepared MIPs, a suspension polymerization synthesized material, with 4-vinylpyridine as the functional monomer and water/methanol as solvent, showed a superior performance. The underlying cause of such a significant outcome is the likely surface imprinting process caused by the amphiphilic properties of polydatin. The uptake and subsequent selective release of polyphenols present in natural extracts was successfully demonstrated, considering a red wine solution as a case study. However, hydrophilic/hydrophobic interactions are inevitable (especially with complex natural extracts and the tuning of the polarity of the solvents is an important issue for the isolation of the different polyphenols.

  11. Development of genetic markers in Eucalyptus species by target enrichment and exome sequencing.

    Directory of Open Access Journals (Sweden)

    Modhumita Ghosh Dasgupta

    Full Text Available The advent of next-generation sequencing has facilitated large-scale discovery, validation and assessment of genetic markers for high density genotyping. The present study was undertaken to identify markers in genes supposedly related to wood property traits in three Eucalyptus species. Ninety four genes involved in xylogenesis were selected for hybridization probe based nuclear genomic DNA target enrichment and exome sequencing. Genomic DNA was isolated from the leaf tissues and used for on-array probe hybridization followed by Illumina sequencing. The raw sequence reads were trimmed and high-quality reads were mapped to the E. grandis reference sequence and the presence of single nucleotide variants (SNVs and insertions/ deletions (InDels were identified across the three species. The average read coverage was 216X and a total of 2294 SNVs and 479 InDels were discovered in E. camaldulensis, 2383 SNVs and 518 InDels in E. tereticornis, and 1228 SNVs and 409 InDels in E. grandis. Additionally, SNV calling and InDel detection were conducted in pair-wise comparisons of E. tereticornis vs. E. grandis, E. camaldulensis vs. E. tereticornis and E. camaldulensis vs. E. grandis. This study presents an efficient and high throughput method on development of genetic markers for family- based QTL and association analysis in Eucalyptus.

  12. Development of a Rickettsia bellii-Specific TaqMan Assay Targeting the Citrate Synthase Gene.

    Science.gov (United States)

    Hecht, Joy A; Allerdice, Michelle E J; Krawczak, Felipe S; Labruna, Marcelo B; Paddock, Christopher D; Karpathy, Sandor E

    2016-11-01

    Rickettsia bellii is a rickettsial species of unknown pathogenicity that infects argasid and ixodid ticks throughout the Americas. Many molecular assays used to detect spotted fever group (SFG) Rickettsia species do not detect R. bellii, so that infection with this bacterium may be concealed in tick populations when assays are used that screen specifically for SFG rickettsiae. We describe the development and validation of a R. bellii-specific, quantitative, real-time PCR TaqMan assay that targets a segment of the citrate synthase (gltA) gene. The specificity of this assay was validated against a panel of DNA samples that included 26 species of Rickettsia, Orientia, Ehrlichia, Anaplasma, and Bartonella, five samples of tick and human DNA, and DNA from 20 isolates of R. bellii, including 11 from North America and nine from South America. A R. bellii control plasmid was constructed, and serial dilutions of the plasmid were used to determine the limit of detection of the assay to be one copy per 4 µl of template DNA. This assay can be used to better determine the role of R. bellii in the epidemiology of tick-borne rickettsioses in the Western Hemisphere. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

  13. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors

    Directory of Open Access Journals (Sweden)

    Thangavel P

    2017-04-01

    Full Text Available Prakash Thangavel,1 Buddolla Viswanath,1 Sanghyo Kim1,2 1Department of Bionanotechnology, Gachon University, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 2Graduate Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea Abstract: In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on “traditional” (ie, non-nanostructured Ru-based cancer therapies is included in a precise manner. Keywords: metallodrugs, nanotechnology, cancer treatment, cell apoptosis, DNA damage, toxicity

  14. 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.

  15. 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...

  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. Development of Detector Systems for Internal and Fixed Target Heavy Ion Physics Experiments

    Energy Technology Data Exchange (ETDEWEB)

    Golubev, Pavel

    2003-04-01

    This thesis deals with intermediate energy heavy ion reactions with the particular aim to study the nuclear matter equation of state which defines the relation between statistical parameters of a fermionic system. The development of equipment for two experiments, CA47 at The Svedberg Laboratory in Uppsala, Sweden and R16 at Kernfysisch Versneller Inst. (KVI), Groningen, The Netherlands, are described. CA47 contains the CHICSi detector, a modular, ultra-high vacuum (UHV) compatible, multi-detector system, covering a solid angle of 3pi sr around the collision point. Together with two auxiliary detector systems CHICSi is placed at the cluster-jet target chamber of the CELSIUS storage ring. This thesis gives a technical overview of the detector and the development carried out in order to achieve the desired detection performance. Some laboratory and in-beam tests are described and the analysis of the first experimental results is discussed. The nuclear intensity interferometry experiment (R16) was performed in a dedicated beam-line of the AGOR superconducting cyclotron. Small-angle two-particle correlations were measured for the E/A = 61 MeV {sup 36}Ar + {sup 27}Al, {sup 112}Sn, {sup 124}Sn reactions, together with singles spectra. The experimental energy distributions of neutrons and light charged particles for the {sup 36}Ar + {sup 27}Al reaction have been analyzed with a Maxwellian multi-source prescription. These results, together with correlation function data, are used to extract information on the size of the emitting sources and their time evolution.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. Development and evaluation of a targeted orchard sprayer using machine vision technology

    Directory of Open Access Journals (Sweden)

    H Asaei

    2016-09-01

    Full Text Available Introduction In conventional methods of spraying in orchards, the amount of pesticide sprayed, is not targeted. The pesticide consumption data indicates that the application rate of pesticide in greenhouses and orchards is more than required. Less than 30% of pesticide sprayed actually reaches nursery canopies while the rest are lost and wasted. Nowadays, variable rate spray applicators using intelligent control systems can greatly reduce pesticide use and off-target contamination of environment in nurseries and orchards. In this research a prototype orchard sprayer based on machine vision technology was developed and evaluated. This sprayer performs real-time spraying based on the tree canopy structure and its greenness extent which improves the efficiency of spraying operation in orchards. Materials and Methods The equipment used in this study comprised of three main parts generally: 1- Mechanical Equipment 2- Data collection and image processing system 3- Electronic control system Two booms were designed to support the spray nozzles and to provide flexibility in directing the spray nozzles to the target. The boom comprised two parts, the vertical part and inclined part. The vertical part of the boom was used to spray one side of the trees during forward movement of the tractor and inclined part of the boom was designed to spray the upper half of the tree canopy. Three nozzles were considered on each boom. On the vertical part of the boom, two nozzles were placed, whereas one other nozzle was mounted on the inclined part of the boom. To achieve different tree heights, the vertical part of the boom was able to slide up and down. Labview (version 2011 was used for real time image processing. Images were captured through RGB cameras mounted on a horizontal bar attached on top of the tractor to take images separately for each side of the sprayer. Images were captured from the top of the canopies looking downward. The triggering signal for

  4. 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.

  5. 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.

  6. 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.)

  7. 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.

  8. Developing a Novel Therapeutic Strategy Targeting Kallikrein-4 to Inhibit Prostate Cancer Growth and Metastasis

    Science.gov (United States)

    2015-08-01

    Medical Center, USA) were maintained in RPMI media containing 5% fetal bovine serum (Gibco, Life Technologies). All cell lines were incubated at 37°C in... acidosis upon degradation.35–38 Thus, a theranostic device that enters a tumour cell via receptor mediated endo- cytosis can undergo rapid degradation of...Technologies, Mulgrave, Vic, Aust) containing 10% fetal bovine serum (FBS; Moregate, Brisbane, Aust). The targeted and non- targeted polymers were made to 5

  9. DEVELOPMENT OF THE METHOD OF DETERMINING THE TARGET FUNCTION OF OPTIMIZATION OF POWER PLANT

    Directory of Open Access Journals (Sweden)

    O. Maksymovа

    2017-08-01

    Full Text Available It has been proposed the application of an optimization criterion based on properties of target functions, taken from the elements of technical, economic and thermodynamic analyses. Marginal costs indicators of energy for different energy products have also been identified. Target function of the power plant optimization was proposed, that considers energy expenditure in the presented plant and in plants closing the energy sources generation and consumption balance.

  10. Application of the pyrochemical DOS, developed by the CEA, within reprocessing of CERCER transmutation fuel targets

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, E.; Ducasse, T.; Bertrand, M. [CEA, Centre de Marcoule, Nuclear Energy Division, Radiochemistry and Processes Department, SMCS, LDPS, F-30207 Bagnols-sur-Ceze (France); Miguirditchian, M. [CEA, Centre de Marcoule, Nuclear Energy Division, Radiochemistry and Processes Department, SMCS, LCPE, F-30207 Bagnols-sur-Ceze (France)

    2016-07-01

    Pyrochemical technology using high-temperature molten salts and molten metal media presents a potential interest for an overall separation and transmutation strategy for long-lived radionuclides. Within the frame of the two French acts on radioactive waste management, a pyrochemical research/development program was launched at the CEA Marcoule in the late 90's. The second step is the actinides back-extraction, which consists in a liquid/liquid oxidative stripping of the An from aluminium matrix into molten chloride media. The DOS process has been successfully demonstrated for treatment of oxide type fuels within the last years: the core of the process has been already assessed and the studies have shown high selectivity and a quantitative recovery of actinides. Within the framework of the SACSESS European research program, the pyrochemical activities focused on applications of the DOS process to reprocess CERCER transmutation targets. These particular types of fuels consist of a mixture of minor actinides (MA) oxides diluted in an inert (oxide MgO) matrices. The behaviour of matrices material was first investigated regarding the solubility in the fluoride salt, starting from both oxide powders or sintered pellets. The saturation of Mg in the salt could be estimated at ∼ 3 wt%. Regarding the reductive extraction, as expected no Mg was reduced by the metallic phase. The present work also highlights that Mg has low impact on the extraction efficiency of U as long as the salt is not saturated. Once the saturation occurs, the efficiency starts to decrease. So we recommend recycling the salt when Mg saturation is reached.

  11. Development and evaluation of intestinal targeted mucoadhesive microspheres of Bacillus coagulans.

    Science.gov (United States)

    Alli, Sk Md Athar; Ali, Sk Md Ajhar; Samanta, Amalesh

    2011-11-01

    Intestinal targeted mucoadhesive microsphere of probiotics may provide numerous associated health benefits. To develop mucoadhesive microspheres that will deliver viable probiotic cells into gut protectively against harsh environmental conditions of stomach for extended period. Core mucoadhesive microspheres of Bacillus coagulans were prepared using hypromellose, following coacervation and phase separation technique and were then coated with hypromellose phthalate to achieve their site-specific release. Microspheres were evaluated for percent yield, entrapment efficiency, surface morphology, particle size and size distribution, flow property, swelling property, mucoadhesion property by the in vitro wash-off and the ex vivo mucoadhesive strength tests, in vitro release profile and release kinetic, in vivo probiotic activity, and stability. The values for kinetic constant and regression coefficient of model-dependent approaches and the difference factor, the similarity factor, and the Rescigno index of model-independent approaches were determined for accessing and comparing in vitro performance. Microsphere formulation batches have percent yield value between 56.26% and 69.13% and entrapment efficiency value between 66.95% and 77.89%. Microspheres were coarser with spherical shape having mean particle size from 28.03 to 48.31 μm. In vitro B. coagulans release profile follows zero-order kinetics and depends on the grade of hypromellose and the B. coagulans-to-hypromellose ratio. Experimental microspheres rendered adequate stability to B. coagulans at room temperature. Microspheres had delivered B. coagulans in simulated intestinal condition following zero-order kinetics, protectively in simulated gastric condition, exhibiting appreciable mucoadhesion in intestinal condition, which could be useful to achieve site-specific delivery for extended period.

  12. (Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

    Science.gov (United States)

    Kanda, Atsuhiro; Ishida, Susumu

    2018-03-25

    The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis. © 2018 The Authors

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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 ).

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. Development of a Combination Therapy for Prostate Cancer by Targeting Stat3 and HIF-1alpha

    Science.gov (United States)

    2013-07-01

    inflammation-induced cancer, making it an attractive target (25-27). A3. Innovation 1. TEL03 is a novel anti-cancer agent from Chinese herbal medicine ...agents from Chinese herbal medicine (CHM) that targets HIF-1α /2α for prostate cancer therapy. Hypoxia orchestrated by HIF-1αis crucial for tumor...Stat3 for treatment of prostate and other cancers. TEL03, which is a novel anti-cancer agent derived from Chinese herbal medicine (CHM: Hypocrella

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. Development of a Software for Quantitative Evaluation Radiotherapy Target and Organ-at-Risk Segmentation Comparison

    NARCIS (Netherlands)

    Kalpathy-Cramer, Jayashree; Awan, Musaddiq; Bedrick, Steven; Rasch, Coen R. N.; Rosenthal, David I.; Fuller, Clifton D.

    2014-01-01

    Modern radiotherapy requires accurate region of interest (ROI) inputs for plan optimization and delivery. Target delineation, however, remains operator-dependent and potentially serves as a major source of treatment delivery error. In order to optimize this critical, yet observer-driven process, a

  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. 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.

  16. 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

  17. Target irradiation facility and targetry development at 160 MeV proton beam of Moscow linac

    CERN Document Server

    Zhuikov, B L; Konyakhin, N A; Vincent, J

    1999-01-01

    A facility has been built and successfully operated with the 160 MeV proton beam of Moscow Meson factory LINAC, Institute for Nuclear Research (INR) of Russian Academy of Science, Troitsk. The facility was created for various isotope production goals as well as for fundamental nuclear investigations at high intensity beam (100 mu A and more). An important part of the facility targetry system is a high-intensity beam monitoring collimator device. Measurements of the temperature distribution between collimator sectors, cooling water flow and temperature, and the beam current, provide an opportunity to compute beam losses and beam position. The target holder design allows easy insertion by manipulator and simultaneous bombardment of several different targets of various types and forms, and variation of proton energy on each target over a wide range below 160 MeV. The main target utilized for commercial sup 8 sup 2 Sr isotope production is metallic rubidium in a stainless-steel container. A regular wet chemistry ...

  18. 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)

  19. The Uses and Future Prospects of Metabolomics and Targeted Metabolite Profiling in Cell Factory Development

    DEFF Research Database (Denmark)

    Harrison, Scott James; Herrgard, Markus

    2013-01-01

    , these broader measurements of the cellular metabolic state are now becoming part of the toolbox used to characterize cell factories. In this review we briefly summarize the benefits and challenges of global metabolomics and targeted metabolite profiling methods and discuss the application of these methods...

  20. Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators

    NARCIS (Netherlands)

    Rwigema, Jean-Claude M.; Beck, Barbara; Wang, Wei; Doemling, Alexander; Epperly, Michael W.; Shields, Donna; Goff, Julie P.; Franicola, Darcy; Dixon, Tracy; Frantz, Marie-Céline; Wipf, Peter; Tyurina, Yulia; Kagan, Valerian E.; Wang, Hong; Greenberger, Joel S.

    2011-01-01

    Purpose: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules. Methods and Materials: We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere

  1. Design and development of a magnetic device for mesenchymal stem cell retaining in deep targets

    Science.gov (United States)

    Banis, G. C.

    2017-12-01

    This paper focuses on the retaining of mesenchymal stem cells in blood flow conditions using the appropriate magnetic field. Mesenchymal stem cells can be tagged with magnetic nanoparticles and thus, they can be manipulated from distance, through the application of an external magnetic field. In this paper the case of kidney as target of the therapy is being studied.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. A QFD-Based Mathematical Model for New Product Development Considering the Target Market Segment

    OpenAIRE

    Chen, Liang-Hsuan; Chen, Cheng-Nien

    2014-01-01

    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 consider...

  8. Transmutation technology development; thermal hydraulic power analysis and structure analysis of the HYPER target beam window

    Energy Technology Data Exchange (ETDEWEB)

    Choi, J. H.; Ju, E. S.; Song, M. K.; Jeon, Y. Z. [Gyeongsang National University, Jinju (Korea)

    2002-03-01

    A thermal hydraulic power analysis, a structure analysis and optimization computation for some design factor for the design of spallation target suitable for HYPER with 1000 MW thermal power in this study was performed. Heat generation formula was used which was evaluated recently based on the LAHET code, mainly to find the maximum beam current under given computation conditions. Thermal hydraulic power of HYPER target system was calculated using FLUENT code, structure conducted by inputting the data into ANSYS. On the temp of beam windows and the pressure distribution calculated using FLUENT. Data transformation program was composed apply the data calculated using FLUENT being commercial CFD code and ANSYS being FEM code for CFX structure analysis. A basic study was conducted on various singular target to obtain fundamental data on the shape for optimum target design. A thermal hydraulic power analysis and structure analysis were conducted on the shapes of parabolic, uniform, scanning beams to choose the optimum shape of beam current analysis was done according to some turbulent model to simulate the real flow. To evaluate the reliability of numerical analysis result, benchmarking of FLUENT code reformed at SNU and Korea Advanced Institute of Science and Technology and it was compared to CFX in the possession of Korea Atomic Energy Research Institute and evaluated. Reliable deviation was observed in the results calculated using FLUENT code, but temperature deviation of about 200 .deg. C was observed in the result from CFX analysis at optimum design condition. Several benchmarking were performed on the basis of numerical analysis concerning conventional HYPER. It was possible to allow a beam arrests of 17.3 mA in the case of the {phi} 350 mm parabolic beam suggested to the optimum in nuclear transmutation when stress equivalent to VON-MISES was calculated to be 140 MPa. 29 refs., 109 figs. (Author)

  9. 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.

  10. Developing Demand-Response Based Solutions for Hawaii’s 100% Renewable Energy Target

    OpenAIRE

    Kansal, Rachit

    2017-01-01

    The State of Hawaii has set a target to achieve a 100% Renewables by 2045. Due to the State’s high electricity prices and dependence on imported oil, renewables are seen as an environmental and economic solution to the problem. While the state has seen substantial renewables growth in the last few years, a truly transformative system is needed to push for a fully renewable future. This system would be likely to include Demand Response (DR) capability, Distributed Energy Reso...

  11. [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".

  12. Development And Characterization Of A Liner-On-Target Injector For Staged Z-Pinch Experiments

    Science.gov (United States)

    Valenzuela, J. C.; Conti, F.; Krasheninnikov, I.; Narkis, J.; Beg, F.; Wessel, F. J.; Rahman, H. U.

    2016-10-01

    We present the design and optimization of a liner-on-target injector for Staged Z-pinch experiments. The injector is composed of an annular high atomic number (e.g. Ar, Kr) gas-puff and an on-axis plasma gun that delivers the ionized deuterium target. The liner nozzle injector has been carefully studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated 1 cm radius gas profile that satisfies the theoretical requirement for best performance on the 1 MA Zebra current driver. The CFD simulations produce density profiles as a function of the nozzle shape and gas. These profiles are initialized in the MHD MACH2 code to find the optimal liner density for a stable, uniform implosion. We use a simple Snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector. We have performed line-integrated density measurements using a CW He-Ne laser to characterize the liner gas and the plasma gun density as a function of time. The measurements are compared with models and calculations and benchmarked accordingly. Advanced Research Projects Agency - Energy, DE-AR0000569.

  13. Development and characterization of plasma targets for controlled injection of electrons into laser-driven wakefields

    Science.gov (United States)

    Kleinwaechter, Tobias; Goldberg, Lars; Palmer, Charlotte; Schaper, Lucas; Schwinkendorf, Jan-Patrick; Osterhoff, Jens

    2012-10-01

    Laser-driven wakefield acceleration within capillary discharge waveguides has been used to generate high-quality electron bunches with GeV-scale energies. However, owing to fluctuations in laser and plasma conditions in combination with a difficult to control self-injection mechanism in the non-linear wakefield regime these bunches are often not reproducible and can feature large energy spreads. Specialized plasma targets with tailored density profiles offer the possibility to overcome these issues by controlling the injection and acceleration processes. This requires precise manipulation of the longitudinal density profile. Therefore our target concept is based on a capillary structure with multiple gas in- and outlets. Potential target designs are simulated using the fluid code OpenFOAM and those meeting the specified criteria are fabricated using femtosecond-laser machining of structures into sapphire plates. Density profiles are measured over a range of inlet pressures utilizing gas-density profilometry via Raman scattering and pressure calibration with longitudinal interferometry. In combination these allow absolute density mapping. Here we report the preliminary results.

  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. 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...

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. Development and analysis of diffusion bonding techniques for LBE-cooled spallation targets

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, A.T., E-mail: atnelson@lanl.gov [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Hosemann, P. [University of California - Berkeley, Berkeley, CA 94720 (United States); Maloy, S.A. [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States)

    2012-12-15

    Spallation sources incorporating solid targets may be driven to utilize liquid metal coolants by neutronics or temperature concerns. If tungsten is chosen as the target material, it will require cladding given its poor performance under irradiation. One option to meet this need are ferritic/martensitic stainless steel alloys. This study investigates possible diffusion bonding techniques suitable to clad tungsten targets with HT9, a high chromium stainless steel familiar to the nuclear industry. A test bonding matrix was performed to identify bonding conditions and process parameters suitable for the three material systems of interest (HT9/Ta, HT9/W, and HT9/HT9). Temperatures of 900 and 1060 Degree-Sign C were investigated along with bonding pressures of 7 and 70 MPa. A nominal soak time of 3 h was used for all tests. Three interlayers were investigated: pure nickel, Ni-6P, and vanadium. Finally, different surface preparation techniques for the tungsten were explored in order to gage their effect on the bond quality. Following joining, the bonds were characterized using an array of microscopy and micromechanical techniques to determine the resulting interface character. The nickel and NiP coatings were found to stabilize austenite at the HT9 surface during bonding, while the vanadium remained generally inert given good solubility in each of the three systems. Intermetallic formation is also a significant concern at elevated bonding temperatures as FeTa, FeW, NiTa, and NiW each rapidly form during interdiffusion. Multiple failures were observed through crack propagation parallel to the interface along the intermetallic phases. Differing contraction rates among the base materials also resulted in brittle fracture within the tungsten during cooling from bonding temperatures. Bonding performed at 900 Degree-Sign C under 70 MPa for 3 h with the inclusion of a vanadium interlayer was found to be superior of the conditions explored in this work.

  1. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics.

    Science.gov (United States)

    Sarkar, Fazlul H; Li, Yiwei

    2009-11-01

    Cancer cells exhibit deregulation in multiple cellular signaling pathways. Therefore, treatments using specific agents that target only one pathway usually fail in cancer therapy. The combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity. Emerging evidence has shown that some "natural products" such as isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin among many others, have growth inhibitory and apoptosis inducing effects on human and animal cancer cells mediated by targeting multiple cellular signaling pathways in vitro without causing unwanted toxicity in normal cells. Therefore, these non-toxic "natural products" from natural resources could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher efficacy. In fact, recently increasing evidence from pre-clinical in vivo studies and clinical trials have shown some success in support of the use of rational design of multi-targeted therapies for the treatment of cancers using conventional chemotherapeutic agents in combination with "natural products". These studies have provided promising results and further opened-up newer avenues for cancer therapy. In this review article, we have succinctly summarized the known effects of "natural products" especially by focusing on isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin, and provided a comprehensive view on the molecular mechanisms underlying the principle of cancer therapy using combination of "natural products" with conventional therapeutics.

  2. One of the polarized targets that was developed for the S134 experiment

    CERN Multimedia

    1974-01-01

    The target is polarized dynamically as usual in a 25 kg homogeneous magnetic field. It is then cooled to some 50 millidegrees and moved into the large gap of the ETH spectrometer magnet, where the field is 10 kg, with a poorer homogeneity. It stands in front of the beam, in the centre of the detection system, for studying all the spin parameters in the reaction pi-p - K0LAMBDA0 at 5 GeV/c, with an available solid angle of nearly 4 p.

  3. Mental health and development: targeting people with mental health conditions as a vulnerable group

    National Research Council Canada - National Science Library

    Drew, Natalie; Faydi, Edwige; Freeman, Melvyn; Funk, Michelle; Kettaneh, Audrey; Van Ommeren, Mark

    2010-01-01

    .... It argues that mental health should be included in sectoral and broader development strategies and plans, and that development stakeholders have important roles to play in ensuring that people...

  4. 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.

  5. Prosperous pacifists: The effects of development on initiators and targets of territorial conflict

    OpenAIRE

    Erik Gartzke; Dominic Rohner

    2010-01-01

    Scholars have suggested several ways in which economic development could affect interstate conflict. Supply side arguments view modern economies as more difficult to subdue or exploit through force (i.e., development creates states that are 'bitter pills'). The demand side perspective argues in contrast that development lessens the appeal of conquest among potential aggressors (i.e., development creates 'prosperous pacifists'). We offer a formal model that isolates contrasting consequences of...

  6. 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.

  7. A Synthetic Biology Project - Developing a single-molecule device for screening drug-target interactions.

    Science.gov (United States)

    Firman, Keith; Evans, Luke; Youell, James

    2012-07-16

    This review describes a European-funded project in the area of Synthetic Biology. The project seeks to demonstrate the application of engineering techniques and methodologies to the design and construction of a biosensor for detecting drug-target interactions at the single-molecule level. Production of the proteins required for the system followed the principle of previously described "bioparts" concepts (a system where a database of biological parts - promoters, genes, terminators, linking tags and cleavage sequences - is used to construct novel gene assemblies) and cassette-type assembly of gene expression systems (the concept of linking different "bioparts" to produce functional "cassettes"), but problems were quickly identified with these approaches. DNA substrates for the device were also constructed using a cassette-system. Finally, micro-engineering was used to build a magnetoresistive Magnetic Tweezer device for detection of single molecule DNA modifying enzymes (motors), while the possibility of constructing a Hall Effect version of this device was explored. The device is currently being used to study helicases from Plasmodium as potential targets for anti-malarial drugs, but we also suggest other potential uses for the device. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  8. CPTAC Collaborates with Molecular & Cellular Proteomics to Address Reproducibility in Targeted Assay Development | Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The journal Molecular & Cellular Proteomics (MCP), in collaboration with the Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI), part of the National Institutes of Health, announce new guidelines and requirements for papers describing the development and application of targeted mass spectrometry measurements of peptides, modified peptides and proteins (Mol Cell Proteomics 2017; PMID: 28183812).  NCI’s participation is part of NIH’s overall effort to address the r

  9. 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.

  10. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

    Directory of Open Access Journals (Sweden)

    Huixiang Xiao

    2017-01-01

    Full Text Available Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae. Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s.

  11. Progress in the Design of the Stabilized Liner Compressor for MTF/MIF Plasma Target Development

    Science.gov (United States)

    Frese, Sherry; Frese, Michael; Turchi, Peter; Gale, Don

    2016-10-01

    The Stabilized Liner Compressor (SLC) seeks to extend concepts for repetitive, rotationally stabilized, liquid-metal liners driven by free-pistons to much higher drive pressures (25 vs 5 kpsi) and faster implosion speeds (2000 vs 100 m/s) than previously demonstrated. Such extension is needed to enable experiments with magnetized-plasma targets presently offering sizes and lifetimes of 10's cm diam and 10's microsec. SLC represents the confluence of several difficult technologies, including pulsed high pressures, high-speed rotating machinery and alkali-metal (Na, NaK) handling. Solution of the two-dimensional, unsteady, compressible flow of a rotating liquid-metal liner requires advanced numerical techniques. We report the use of the 2-1/2 dimensional MHD code MACH2 to explore flow options, including magnetic flux compression, and to provide pulsed pressure distributions for mechanical design. Supported by ARPA-E ALPHA Program.

  12. 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.

  13. 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

  14. 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

  15. On the importance of targeting parasite stem cells in anti-echinococcosis drug development

    Directory of Open Access Journals (Sweden)

    Brehm Klaus

    2014-01-01

    Full Text Available The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite’s stem cell population.

  16. 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.

  17. Fish early life stage: Developing AOPs to support targeted reduction and replacement

    Science.gov (United States)

    There is an interest in developing alternatives to the fish early-life stage (FELS) test (OECD test guideline 210), for predicting adverse chronic toxicity outcomes (e.g., impacts on growth and survival). Development and characterization of adverse outcome pathways (AOPs) related...

  18. Development of a real time multiple target, multi camera tracker for civil security applications

    Science.gov (United States)

    Åkerlund, Hans

    2009-09-01

    A surveillance system has been developed that can use multiple TV-cameras to detect and track personnel and objects in real time in public areas. The document describes the development and the system setup. The system is called NIVS Networked Intelligent Video Surveillance. Persons in the images are tracked and displayed on a 3D map of the surveyed area.

  19. Development of lightweight mortars targeted on the high strength, low density and low permeability

    NARCIS (Netherlands)

    Spiesz, P.R.; Yu, Q.; Brouwers, H.J.H.; Uzoegbo, H.C.; Schmidt, W.

    2013-01-01

    This article presents a mix design methodology for the development of cement-based lightweight mortars. Expanded-glass lightweight aggregates were used in this study as the lightweight material. The mix design was developed applying the packing theory using the modified Andreasen and Andersen model

  20. Firm Foundations: The Effectiveness of an Educational Psychologist Developed Intervention Targeting Early Numeracy Skills

    Science.gov (United States)

    Somerville, Ros; Ayre, Kate; Tunbridge, Daniel; Cole, Katy; Stollery, Richard; Sanders, Mary

    2015-01-01

    This study evaluates the efficacy of a mathematics intervention devised by Essex Educational Psychology Service (EPS), UK. The intervention was designed to develop understanding and skills across four key domains within arithmetical development, by applying the principles of errorless learning, distributed practice and teaching to mastery. A…

  1. Development and application of deep convolutional neural network in target detection

    Science.gov (United States)

    Jiang, Xiaowei; Wang, Chunping; Fu, Qiang

    2018-04-01

    With the development of big data and algorithms, deep convolution neural networks with more hidden layers have more powerful feature learning and feature expression ability than traditional machine learning methods, making artificial intelligence surpass human level in many fields. This paper first reviews the development and application of deep convolutional neural networks in the field of object detection in recent years, then briefly summarizes and ponders some existing problems in the current research, and the future development of deep convolutional neural network is prospected.

  2. Two Strategies for the Development of Mitochondrion-Targeted Small Molecule Radiation Damage Mitigators

    International Nuclear Information System (INIS)

    Rwigema, Jean-Claude M.; Beck, Barbara; Wang Wei; Doemling, Alexander; Epperly, Michael W.; Shields, Donna; Goff, Julie P.; Franicola, Darcy; Dixon, Tracy; Frantz, Marie-Celine; Wipf, Peter; Tyurina, Yulia; Kagan, Valerian E.; Wang, Hong

    2011-01-01

    Purpose: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules. Methods and Materials: We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/mdm4 protein complex inhibitor BEB55 to mitigate radiation effects by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3 and the human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell lines. The p53-dependent mechanism of action was tested with p53 +/+ and p53 -/- murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected i.p. with JP4-039, MCF201-89, or BEB55 individually or in combination, after receiving 9.5 Gy total body irradiation (TBI). Results: Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all three compounds increased the survival of 32D cl 3 (p = 0.0021, p = 0.0011, p = 0.0038, and p = 0.0073, respectively) and IB3 cells (p = 0.0193, p = 0.0452, p = 0.0017, and p = 0.0019, respectively) significantly relative to that of control irradiated cells. KM101 cells were protected by individual drugs (p = 0.0007, p = 0.0235, p = 0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53 +/+ (p = 0.0396 and p = 0.0071, respectively) and p53 -/- cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53 -/- cells. Drugs administered individually or as a mixtures of all three after TBI significantly increased mouse survival (p = 0.0234, 0.0009, 0.0052, and 0.0167, respectively). Conclusion: Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Executable Model Development from Architectural Description with Application to the Time Sensitive Target Problem

    National Research Council Canada - National Science Library

    Diaz-Rodriguez, Luis M

    2005-01-01

    As the Department of Defense (DoD) moves to a capabilities-based approach for requirements definition and systems development, it has become necessary to conceptualize and evaluate our needs at the System of Systems (SoS) level...

  10. 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

  11. 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

  12. Vasopressin as a target for antidepressant development: an assessment of the available evidence.

    LENUS (Irish Health Repository)

    Scott, Lucinda V

    2012-02-03

    Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.

  13. Development of Reagents for Application of At-211 to Targeted Radionuclide Therapy of Cancer

    International Nuclear Information System (INIS)

    Wilbur, D. Scott

    2011-01-01

    This grant covered only a period of 4 months as the major portion of the award was returned to DOE due to an award of funding from NIH that covered the same research objectives. A letter regarding the termination of the research is attached as the last page of the Final Report. The research conducted was limited due to the short period of this grant, but the results obtained in that period are outlined in the Final Report. The studies addressed in the research effort were directed at a problem that is of critical importance to the in vivo application of the alpha-particle emitting radionuclide At-211. That problem, low in vivo stability of many astatinated molecules, severely limits the use of At-211 in therapeutic applications. The advances sought in the studies were expected to expand the types of biomolecules that can be used as carriers of At-211, and provide improved in vivo targeting of the radiation dose compared with the dose delivered to normal tissue.

  14. Developing and evaluating a target-background similarity metric for camouflage detection.

    Directory of Open Access Journals (Sweden)

    Chiuhsiang Joe Lin

    Full Text Available BACKGROUND: Measurement of camouflage performance is of fundamental importance for military stealth applications. The goal of camouflage assessment algorithms is to automatically assess the effect of camouflage in agreement with human detection responses. In a previous study, we found that the Universal Image Quality Index (UIQI correlated well with the psychophysical measures, and it could be a potentially camouflage assessment tool. METHODOLOGY: In this study, we want to quantify the camouflage similarity index and psychophysical results. We compare several image quality indexes for computational evaluation of camouflage effectiveness, and present the results of an extensive human visual experiment conducted to evaluate the performance of several camouflage assessment algorithms and analyze the strengths and weaknesses of these algorithms. SIGNIFICANCE: The experimental data demonstrates the effectiveness of the approach, and the correlation coefficient result of the UIQI was higher than those of other methods. This approach was highly correlated with the human target-searching results. It also showed that this method is an objective and effective camouflage performance evaluation method because it considers the human visual system and image structure, which makes it consistent with the subjective evaluation results.

  15. Developing and evaluating a target-background similarity metric for camouflage detection.

    Science.gov (United States)

    Lin, Chiuhsiang Joe; Chang, Chi-Chan; Liu, Bor-Shong

    2014-01-01

    Measurement of camouflage performance is of fundamental importance for military stealth applications. The goal of camouflage assessment algorithms is to automatically assess the effect of camouflage in agreement with human detection responses. In a previous study, we found that the Universal Image Quality Index (UIQI) correlated well with the psychophysical measures, and it could be a potentially camouflage assessment tool. In this study, we want to quantify the camouflage similarity index and psychophysical results. We compare several image quality indexes for computational evaluation of camouflage effectiveness, and present the results of an extensive human visual experiment conducted to evaluate the performance of several camouflage assessment algorithms and analyze the strengths and weaknesses of these algorithms. The experimental data demonstrates the effectiveness of the approach, and the correlation coefficient result of the UIQI was higher than those of other methods. This approach was highly correlated with the human target-searching results. It also showed that this method is an objective and effective camouflage performance evaluation method because it considers the human visual system and image structure, which makes it consistent with the subjective evaluation results.

  16. NF-κB-IKKβ pathway as a target for drug development: realities, challenges and perspectives.

    Science.gov (United States)

    Freitas, Rosana H C N; Fraga, Carlos A M

    2018-02-19

    Nuclear factor κB (NF-κB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-κB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF-κB-IKKβ pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells. Inhibition of the NF-κB-IKKβ cascade can be considered an attractive therapeutic method for the genesis of new prototypes to combat these chronic multifactorial diseases. This review describes some prototypes and drugs that act to inhibit the NF-κB-IKKβ pathway, highlighting the realities, challenges and perspectives for therapeutic use. Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-κB-IKKβ pathway, some other prototypes described as IKKβ inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-κB pathway modulators as IKKβ inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. 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.

  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. 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.

  20. Developing clinical practice guidelines: target audiences, identifying topics for guidelines, guideline group composition and functioning and conflicts of interest.

    Science.gov (United States)

    Eccles, Martin P; Grimshaw, Jeremy M; Shekelle, Paul; Schünemann, Holger J; Woolf, Steven

    2012-07-04

    Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this first paper we discuss: the target audience(s) for guidelines and their use of guidelines; identifying topics for guidelines; guideline group composition (including consumer involvement) and the processes by which guideline groups function and the important procedural issue of managing conflicts of interest in guideline development.

  1. 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.

  2. 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.

  3. The early origins of food preferences: targeting the critical windows of development.

    Science.gov (United States)

    Gugusheff, Jessica Rose; Ong, Zhi Yi; Muhlhausler, Beverly Sara

    2015-02-01

    The nutritional environment to which an individual is exposed during the perinatal period plays a crucial role in determining his or her future metabolic health outcomes. Studies in rodent models have demonstrated that excess maternal intake of high-fat and/or high-sugar "junk foods" during pregnancy and lactation can alter the development of the central reward pathway, particularly the opioid and dopamine systems, and program an increased preference for junk foods in the offspring. More recently, there have been attempts to define the critical windows of development during which the opioid and dopamine systems within the reward pathway are most susceptible to alteration and to determine whether it is possible to reverse these effects through nutritional interventions applied later in development. This review discusses the progress made to date in these areas, highlights the apparent importance of sex in determining these effects, and considers the potential implications of the findings from rodent models in the human context. © FASEB.

  4. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    Energy Technology Data Exchange (ETDEWEB)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N. [Stony Brook University Health Science Center, Department of Psychiatry, Stony Brook, NY (United States)

    2016-06-15

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  5. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    International Nuclear Information System (INIS)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N.

    2016-01-01

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  6. Neuronal process structure and growth proteins are targets of heavy PTM regulation during brain development

    DEFF Research Database (Denmark)

    Edwards, Alistair V G; Schwämmle, Veit; Larsen, Martin Røssel

    2014-01-01

    UNLABELLED: Brain development is a process requiring precise control of many different cell types. One method to achieve this is through specific and temporally regulated modification of proteins in order to alter structure and function. Post-translational modification (PTM) of proteins is known...... on protein-level events, this study also provides significant insight into detailed roles for individual modified proteins in the developing brain, helping to advance the understanding of the complex protein-driven processes that underlie development. Finally, the use of a novel bioinformatic analytical tool...... provides one of the most comprehensive sets of individual PTM site regulation data for mammalian brain tissue. This will provide a valuable resource for those wishing to perform comparisons or meta-analyses of large scale PTMomic data, as are becoming increasingly common. Furthermore, being focussed...

  7. 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.

  8. 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.

  9. 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.

  10. Claudin-1 is a p63 target gene with a crucial role in epithelial development.

    Directory of Open Access Journals (Sweden)

    Teresa Lopardo

    2008-07-01

    Full Text Available The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of DeltaNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (-80%. DeltaNp63alpha binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a -1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias.

  11. Development of HER2-targeted nanobodies for molecular optical imaging and therapy of breast cancer

    NARCIS (Netherlands)

    Kijanka, M.M.

    2014-01-01

    Breast cancer is a complex disease and the most prevalent cancer in women worldwide. It has been estimated that 1 in 8 women and 1 in 1,000 men will develop breast cancer. Surgical-, chemical- and radiation based therapies are available to breast cancer patients. Early detection of cancer is crucial

  12. Developing and testing ScrollQuest: A video game targeting rejection sensitivity in adolescents

    NARCIS (Netherlands)

    Tuijnman, A.; Granic, I.; Whitkin, J.; Engels, R.C.M.E.

    2017-01-01

    Depression affects a large proportion of adolescents and current interventions only have moderate effects. With the potential of video games for emotional and mental health in mind, we developed a video game for rejection sensitivity, which is a major risk factor for depression. A process of

  13. 76 FR 60503 - Guidance for Industry on Target Animal Safety and Effectiveness Protocol Development and...

    Science.gov (United States)

    2011-09-29

    ... Safety and Effectiveness Protocol Development and Submission.'' The purpose of this document is to provide sponsors guidance in preparation of study protocols for review by the Center for Veterinary Medicine, Office of New Animal Drug Evaluation. The recommendations included in this guidance are intended...

  14. DEVELOPMENT OF A HAZARDOUS WASTE INCINERATOR TARGET ANALYTE LIST OF PRODUCTS OF INCOMPLETE COMBUSTION

    Science.gov (United States)

    The report gives results of pilot-scale incineration testing to develop a comprehensive list of products of incomplete combustion (PICs) from hazardous waste combustion (HWC) systems. Project goals were to: (1) identify the total mass of organic compounds sufficiently to estimate...

  15. Conceptual Soundness, Metric Development, Benchmarking, and Targeting for PATH Subprogram Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Mosey. G.; Doris, E.; Coggeshall, C.; Antes, M.; Ruch, J.; Mortensen, J.

    2009-01-01

    The objective of this study is to evaluate the conceptual soundness of the U.S. Department of Housing and Urban Development (HUD) Partnership for Advancing Technology in Housing (PATH) program's revised goals and establish and apply a framework to identify and recommend metrics that are the most useful for measuring PATH's progress. This report provides an evaluative review of PATH's revised goals, outlines a structured method for identifying and selecting metrics, proposes metrics and benchmarks for a sampling of individual PATH programs, and discusses other metrics that potentially could be developed that may add value to the evaluation process. The framework and individual program metrics can be used for ongoing management improvement efforts and to inform broader program-level metrics for government reporting requirements.

  16. Building an adaptive brain across development: Targets for neurorehabilitation must begin in infancy

    Directory of Open Access Journals (Sweden)

    Jamie Ogline Edgin

    2015-09-01

    Full Text Available Much progress has been made toward behavioural and pharmacological intervention in intellectual disability, which was once thought too difficult to treat. Down syndrome research has shown rapid advances, and clinical trials are currently underway, with more on the horizon. Here, we review the literature on the emergent profile of cognitive development in Down syndrome, emphasizing that treatment approaches must consider how some end state impairments, such as language deficits, may develop from early alterations in neural systems beginning in infancy. Specifically, we highlight evidence suggesting that there are pre- and early postnatal alterations in brain structure and function in Down syndrome, resulting in disturbed network function across development. We stress that these early alterations are likely amplified by Alzheimer’s disease progression and poor sleep. Focusing on three network hubs (prefrontal cortex, hippocampus, and cerebellum, we discuss how these regions may relate to evolving deficits in cognitive function in individuals with Down syndrome, and to their language profile in particular.

  17. Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

    Directory of Open Access Journals (Sweden)

    Wen Shan Yew

    2013-08-01

    Full Text Available Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  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. 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.

  4. Development of radioactively labelled cancer seeking biomolecules for targeted therapy. India

    International Nuclear Information System (INIS)

    Pillai, M.R.A.

    2000-01-01

    The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from Lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

  5. Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy. Greece

    International Nuclear Information System (INIS)

    Varvarigou, Alexandra D.; Archimandritis, Spyridon C.

    2000-01-01

    Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

  6. Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs.

    Science.gov (United States)

    Lihoradova, Olga; Ikegami, Tetsuro

    2014-01-01

    Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae . RVFV encodes a major virulence factor, NSs , which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications.

  7. Developing Novel PepT1-Targeted Modulators for Inflammatory Bowel Disease (IBD) Therapy

    Science.gov (United States)

    2016-10-01

    physiological roles. PepT1 is found in the small intestine where it absorbs dietary degradation products and therapeutic agents such as antibiotics ...results provide a framework for developing more potent ligands in various cellular and animal IBD models, directly addressing Aims 2 and 3 of our... Products …………………………………….………….……………4 7. Participants & Other Collaborating Organizations…….…………….5 8. Special Reporting Requirements…………..………………………5 9

  8. The development of glioblastoma multiforme reactive monoclonal antibodies and their use in drug targeting

    International Nuclear Information System (INIS)

    Klaich, G.M.

    1989-01-01

    The objectives of this project were to develop monoclonal antibodies reactive with the tumor glioblastoma multiforme and to use them to study and develop new treatment modalities for this disease. A tumor antigen enriched immunogen, prepared by immunoaffinity chromatography, was compared to a whole tumor homogenate immunogen with the difference in the yield of tumor reactive, normal brain unreactive monoclonal antibodies proving to be significant. Monoclonal antibody A7, reactive with tumor tissue but unreactive with normal tissue, was isotyped to be an IgG2a immunoglobulin and could be purified to electrophoretic homogeneity by using serum-free culture conditions and protein A sepharose chromatography. Monoclonal antibody A7 is noncytotoxic as measured by the 3 H-nicotinamide release assay and binds to a 138 kd membrane antigen which is not internalized. Localization studies using 14 C-labeled monoclonal antibody A7 and the U-87 MG nude mouse xenograft model resulted in a tumor:serum ratio of 1.25:1.0 as compared to 0.29:1.0 for the negative control. A monoclonal antibody A7-doxorubicin immunoconjugate proved to be more cytotoxic than free doxorubicin in vitro while lethality studies using Swiss mice demonstrated the lack of toxicity of the immunoconjugate as compared to free doxorubicin. In vivo chemotherapy studies using the U-87 MG nude mouse xenograft failed to demonstrate any immunoconjugate anti-tumor activity which may be attributable to the route of administration

  9. Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

    Directory of Open Access Journals (Sweden)

    Nir Qvit

    2016-04-01

    Full Text Available Parasitic diseases cause ∼500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase and TRACK (Trypanosoma receptor for activated C-kinase. We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase, may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs. Keywords: Chagas disease, Leishmaniasis, Peptide, LACK, TRACK, Scaffold protein

  10. Development of 87Sr/86Sr maps as targeted strategy to support wine quality.

    Science.gov (United States)

    Durante, Caterina; Bertacchini, Lucia; Cocchi, Marina; Manzini, Daniela; Marchetti, Andrea; Rossi, Maria Cecilia; Sighinolfi, Simona; Tassi, Lorenzo

    2018-07-30

    This study summarizes the results obtained from a systematic and long-term project aimed at the development of tools to assess the provenance of food in the oenological sector. In particular, 87 Sr/ 86 Sr isotope ratios were measured on statistically representative set of soils, vine branches and wines sampled in the production district of Modena, worldwide known for the Lambrusco wines production. The obtained data were used to build strontium isotopic maps able to objectively support the Lambrusco PDO wines origin as well as other products of the Modena district. Finally, a strong relationship was found between the 87 Sr/ 86 Sr isotope ratios of soils and vine branches on a large scale, highlighting and confirming once more the idea that plants can also represent an optimal sampling device to support geographical traceability. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. From screen to target: insights and approaches into the development of anti-virulence compounds

    Directory of Open Access Journals (Sweden)

    Katherine SH Beckham

    2014-09-01

    Full Text Available The detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential antivirulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls.

  12. Targeted disruption of CD1d prevents NKT cell development in pigs.

    Science.gov (United States)

    Yang, Guan; Artiaga, Bianca L; Hackmann, Timothy J; Samuel, Melissa S; Walters, Eric M; Salek-Ardakani, Shahram; Driver, John P

    2015-06-01

    Studies in mice genetically lacking natural killer T (NKT) cells show that these lymphocytes make important contributions to both innate and adaptive immune responses. However, the usefulness of murine models to study human NKT cells is limited by the many differences between mice and humans, including that their NKT cell frequencies, subsets, and distribution are dissimilar. A more suitable model may be swine that share many metabolic, physiological, and growth characteristics with humans and are also similar for NKT cells. Thus, we analyzed genetically modified pigs made deficient for CD1d that is required for the development of Type I invariant NKT (iNKT) cells that express a semi-invariant T-cell receptor (TCR) and Type II NKT cells that use variable TCRs. Peripheral blood analyzed by flow cytometry and interferon-γ enzyme-linked immuno spot assays demonstrated that CD1d-knockout pigs completely lack iNKT cells, while other leukocyte populations remain intact. CD1d and NKT cells have been shown to be involved in shaping the composition of the commensal microbiota in mice. Therefore, we also compared the fecal microbiota profile between pigs expressing and lacking NKT cells. However, no differences were found between pigs lacking or expressing CD1d. Our results are the first to show that knocking-out CD1d prevents the development of NKT cells in a non-rodent species. CD1d-deficient pigs should offer a useful model to more accurately determine the contribution of NKT cells for human immune responses. They also have potential for understanding how NKT cells impact the health of commercial swine.

  13. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs.

    Science.gov (United States)

    Zhang, Han-Ting

    2009-01-01

    Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant-like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold-based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.

  14. Fungal Biofilms: Targets for the Development of Novel Strategies in Plant Disease Management.

    Science.gov (United States)

    Villa, Federica; Cappitelli, Francesca; Cortesi, Paolo; Kunova, Andrea

    2017-01-01

    The global food supply has been facing increasing challenges during the first decades of the 21 st century. Disease in plants is an important constraint to worldwide crop production, accounting for 20-40% of its annual harvest loss. Although the use of resistant varieties, good water management and agronomic practices are valid management tools in counteracting plant diseases, there are still many pathosystems where fungicides are widely used for disease management. However, restrictive regulations and increasing concern regarding the risk to human health and the environment, along with the incidence of fungicide resistance, have discouraged their use and have prompted for a search for new efficient, ecologically friendly and sustainable disease management strategies. The recent evidence of biofilm formation by fungal phytopathogens provides the scientific framework for designing and adapting methods and concepts developed by biofilm research that could be integrated in IPM practices. In this perspective paper, we provide evidence to support the view that the biofilm lifestyle plays a critical role in the pathogenesis of plant diseases. We describe the main factors limiting the durability of single-site fungicides, and we assemble the current knowledge on pesticide resistance in the specific context of the biofilm lifestyle. Finally, we illustrate the potential of antibiofilm compounds at sub-lethal concentrations for the development of an innovative, eco-sustainable strategy to counteract phytopathogenic fungi. Such fungicide-free solutions will be instrumental in reducing disease severity, and will permit more prudent use of fungicides decreasing thus the selection of resistant forms and safeguarding the environment.

  15. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation

    Directory of Open Access Journals (Sweden)

    Boehm Franziska

    2012-07-01

    Full Text Available Abstract Background Mice lacking Foxp3+ regulatory T (Treg cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation. Methods Foxp3-GFP-DTR (human diphtheria toxin receptor C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin. The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag−/− C57BL/6 mice and the acute DSS-colitis model. Results Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag−/− C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines. Conclusion Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.

  16. The development of an ivermectin-based attractive toxic sugar bait (ATSB) to target Anopheles arabiensis.

    Science.gov (United States)

    Tenywa, Frank Chelestino; Kambagha, Athumani; Saddler, Adam; Maia, Marta Ferreira

    2017-08-15

    An increasing number of countries in sub-Saharan Africa are moving towards malaria-elimination, mostly thanks to successful vector control campaigns. However, elimination has proven challenging, resulting in the persistence of malaria transmission. It is now accepted that in order to eliminate malaria, new complementary vector control approaches must be developed. This study describes the development of a sugar-baited resting place containing a toxic dose of ivermectin for the control of Anopheles arabiensis. Dose response experiments were performed in insectary conditions to determine the LD90 of ivermectin against An. arabiensis. Over 95% of An. arabiensis were knocked down 48 h post-sugar feeding on 10% sucrose solutions containing 0.01% ivermectin. When investigating different juices as attractants, it was observed that An. arabiensis preferred orange, watermelon and commercial guava juice over pawpaw, tomato, mango or banana, but were most likely to feed on simple 10% sugar solution. Using recycled materials, different bait prototypes were tested to determine the best design to maximize sugar feeding. Baits that offered a resting place for the mosquito rather than just a surface to sugar feed were more likely to attract An. arabiensis to sugar feed. The optimized prototype was then placed in different locations within a screen-house, colour-coded with different food dyes, containing competing vegetation (Ricinus communis) and experimental huts where humans slept under bed nets. Around half of all the released An. arabiensis sugar fed on the sugar baits, and approximately 50% of all sugar fed mosquitoes chose the baits close to outdoor vegetation before entering the huts. Ivermectin is an effective insecticide for use in sugar baits. The design of the sugar bait can influence feeding rates and, therefore, efficacy. Sugar baits that offer a resting surface are more efficient and sugar feeding on the baits is maximized when these are placed close to peri

  17. Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

    International Nuclear Information System (INIS)

    El Khoury, Diala; Courty, José; Hovanessian, Ara G; Prévost-Blondel, Armelle; Destouches, Damien; Lengagne, Renée; Krust, Bernard; Hamma-Kourbali, Yamina; Garcette, Marylène; Niro, Sandra; Kato, Masashi; Briand, Jean-Paul

    2010-01-01

    The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity. The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse. HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice. Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or

  18. Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases.

    Science.gov (United States)

    Das Gupta, Kaustav; Shakespear, Melanie R; Iyer, Abishek; Fairlie, David P; Sweet, Matthew J

    2016-01-01

    Macrophages have central roles in danger detection, inflammation and host defense, and consequently, these cells are intimately linked to most disease processes. Major advances in our understanding of the development and function of macrophages have recently come to light. For example, it is now clear that tissue-resident macrophages can be derived from either blood monocytes or through local proliferation of phagocytes that are originally seeded during embryonic development. Metabolic state has also emerged as a major control point for macrophage activation phenotypes. Herein, we review recent literature linking the histone deacetylase (HDAC) family of enzymes to macrophage development and activation, particularly in relation to these recent developments. There has been considerable interest in potential therapeutic applications for small molecule inhibitors of HDACs (HDACi), not only for cancer, but also for inflammatory and infectious diseases. However, the enormous range of molecular and cellular processes that are controlled by different HDAC enzymes presents a potential stumbling block to clinical development. We therefore present examples of how classical HDACs control macrophage functions, roles of specific HDACs in these processes and approaches for selective targeting of drugs, such as HDACi, to macrophages. Development of selective inhibitors of macrophage-expressed HDACs and/or selective delivery of pan HDACi to macrophages may provide avenues for enhancing efficacy of HDACi in therapeutic applications, while limiting unwanted side effects.

  19. Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines.

    Science.gov (United States)

    Mocellin, Simone; Nitti, Donato

    2008-05-01

    Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation. Copyright (c) 2007 Wiley-Periodicals, Inc.

  20. Development of positron emission tomography (PET) labeled polypeptide nanoparticles for tumor imaging and targeting

    Science.gov (United States)

    Mohd Janib, Siti Najila

    The two main problems currently stalling the efficient treatment of cancer has been detecting cancer early enough in the disease process for successful treatment, and treating cancer cells while avoiding excessive toxicity to normal tissues. Arguably the most important factor in the fight against cancer, besides prevention is early detection because the cancer will be easier to treat and less likely to have drug resistance. The work highlighted in this thesis attempts to address the issues related to the effective treatment and management of cancer. The objective of this work is to develop new materials and methods for co-assembly of drugs and imaging agents that permit quantitative imaging of drug delivery and disease progression. By using molecular imaging technique to non-invasively study and detect various molecular markers of diseases can allow for much earlier diagnosis, earlier treatment, and better prognosis that will eventually lead to personalized medicine. Exploration of particulates and polymeric carriers is gaining momentum in diagnostic imaging, initiated by successful therapies using long circulating liposomes. However, liposomes are challenging pharmaceuticals, which include many chemical components, require complex drug encapsulation strategies, and must be physically sheared to control their particle diameter and polydispersity. Polymeric nanocarriers have emerged as an alternative to liposomes as carriers of drugs and imaging agents. Co-inclusion of therapeutic and imaging agents, into these carriers might be advantageous because they increase solubility of hydrophobic agents, may enhance permeability across physiological barriers, alter drug biodistribution, increase local bioavailability and reduce of side effects.

  1. Empirical development of brief smoking prevention videotapes which target African-American adolescents.

    Science.gov (United States)

    Sussman, S; Parker, V C; Lopes, C; Crippens, D L; Elder, P; Scholl, D

    1995-07-01

    Two studies are described which provide evaluations for two brief videotapes developed as supplemental materials in the prevention of tobacco use among African-American adolescents. One videotape (the "soap opera") provides a more general audience-oriented presentation of prevention material and it was filmed primarily at a shopping mall, whereas the other videotape (the "rap") provides a "hip-hop generation" presentation, and it was filmed primarily at an outdoor hangout. The first study compared the two videotapes against each other. The second study compared the two videotapes combined in the same presentation, controlling for order of presentation, against a discussion group control. The results of the two studies indicated few differences in receptivity to the two videotapes among primarily African-American and Latino young adolescents. The rap videotape was rated as more accurate in its depiction of the African-American lifestyle, although both videotapes were equally liked. When shown together, the videotapes were not found to be superior in decreasing behavioral intention to smoke compared to a discussion group control. No change in trial of smoking was observed within or across conditions measured over a pre-post summer interval. These data suggest that "culturally sensitive" videotapes have no more of a short-term effect on youth than do other types of brief interventions which involve minority implementers.

  2. Use of a bacteriophage lysin to identify a novel target for antimicrobial development.

    Directory of Open Access Journals (Sweden)

    Raymond Schuch

    Full Text Available We identified an essential cell wall biosynthetic enzyme in Bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. Focusing on the B. anthracis-specific PlyG lysin, we first identified its unique cell wall receptor and cognate biosynthetic pathway. Within this pathway, one biosynthetic enzyme, 2-epimerase, was required for both PlyG receptor expression and bacterial growth. The 2-epimerase was used to design a small-molecule inhibitor, epimerox. Epimerox prevented growth of several Gram-positive pathogens and rescued mice challenged with lethal doses of B. anthracis. Importantly, resistance to epimerox was not detected (<10(-11 frequency in B. anthracis and S. aureus. These results describe the use of phage lysins to identify promising lead molecules with reduced resistance potential for antimicrobial development.

  3. Development and application of a multi-targeting reference plasmid as calibrator for analysis of five genetically modified soybean events.

    Science.gov (United States)

    Pi, Liqun; Li, Xiang; Cao, Yiwei; Wang, Canhua; Pan, Liangwen; Yang, Litao

    2015-04-01

    Reference materials are important in accurate analysis of genetically modified organism (GMO) contents in food/feeds, and development of novel reference plasmid is a new trend in the research of GMO reference materials. Herein, we constructed a novel multi-targeting plasmid, pSOY, which contained seven event-specific sequences of five GM soybeans (MON89788-5', A2704-12-3', A5547-127-3', DP356043-5', DP305423-3', A2704-12-5', and A5547-127-5') and sequence of soybean endogenous reference gene Lectin. We evaluated the specificity, limit of detection and quantification, and applicability of pSOY in both qualitative and quantitative PCR analyses. The limit of detection (LOD) was as low as 20 copies in qualitative PCR, and the limit of quantification (LOQ) in quantitative PCR was 10 copies. In quantitative real-time PCR analysis, the PCR efficiencies of all event-specific and Lectin assays were higher than 90%, and the squared regression coefficients (R(2)) were more than 0.999. The quantification bias varied from 0.21% to 19.29%, and the relative standard deviations were from 1.08% to 9.84% in simulated samples analysis. All the results demonstrated that the developed multi-targeting plasmid, pSOY, was a credible substitute of matrix reference materials, and could be used as a reliable reference calibrator in the identification and quantification of multiple GM soybean events.

  4. Remote sensing data exploiration for geologic characterization of difficult targets : Laboratory Directed Research and Development project 38703 final report.

    Energy Technology Data Exchange (ETDEWEB)

    Costin, Laurence S.; Walker, Charles A.; Lappin, Allen R.; Hayat, Majeed M. (University of New Mexico, Albuquerque, NM); Ford, Bridget K.; Paskaleva, Biliana (University of New Mexico, Albuquerque, NM); Moya, Mary M.; Mercier, Jeffrey Alan (University of Arizona, Tucson, AZ); Stormont, John C. (University of New Mexico, Albuquerque, NM); Smith, Jody Lynn

    2003-09-01

    Characterizing the geology, geotechnical aspects, and rock properties of deep underground facility sites can enhance targeting strategies for both nuclear and conventional weapons. This report describes the results of a study to investigate the utility of remote spectral sensing for augmenting the geological and geotechnical information provided by traditional methods. The project primarily considered novel exploitation methods for space-based sensors, which allow clandestine collection of data from denied sites. The investigation focused on developing and applying novel data analysis methods to estimate geologic and geotechnical characteristics in the vicinity of deep underground facilities. Two such methods, one for measuring thermal rock properties and one for classifying rock types, were explored in detail. Several other data exploitation techniques, developed under other projects, were also examined for their potential utility in geologic characterization.

  5. Development of the TeamOBS-PPH - targeting clinical performance in postpartum hemorrhage.

    Science.gov (United States)

    Brogaard, Lise; Hvidman, Lone; Hinshaw, Kim; Kierkegaard, Ole; Manser, Tanja; Musaeus, Peter; Arafeh, Julie; Daniels, Kay I; Judy, Amy E; Uldbjerg, Niels

    2018-06-01

    This study aimed to develop a valid and reliable TeamOBS-PPH tool for assessing clinical performance in the management of postpartum hemorrhage (PPH). The tool was evaluated using video-recordings of teams managing PPH in both real-life and simulated settings. A Delphi panel consisting of 12 obstetricians from the UK, Norway, Sweden, Iceland, and Denmark achieved consensus on (i) the elements to include in the assessment tool, (ii) the weighting of each element, and (iii) the final tool. The validity and reliability were evaluated according to Cook and Beckman. (Level 1) Four raters scored four video-recordings of in situ simulations of PPH. (Level 2) Two raters scored 85 video-recordings of real-life teams managing patients with PPH ≥1000 mL in two Danish hospitals. (Level 3) Two raters scored 15 video-recordings of in situ simulations of PPH from a US hospital. The tool was designed with scores from 0 to 100. (Level 1) Teams of novices had a median score of 54 (95% CI 48-60), whereas experienced teams had a median score of 75 (95% CI 71-79; p < 0.001). (Level 2) The intra-rater [intra-class correlation (ICC) = 0.96] and inter-rater (ICC = 0.83) agreements for real-life PPH were strong. The tool was applicable in all cases: atony, retained placenta, and lacerations. (Level 3) The tool was easily adapted to in situ simulation settings in the USA (ICC = 0.86). The TeamOBS-PPH tool appears to be valid and reliable for assessing clinical performance in real-life and simulated settings. The tool will be shared as the free TeamOBS App. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

  6. 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.

  7. 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…

  8. 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...

  9. Development of a personalized dosimetric tool for radiation protection in case of internal contamination and targeted radiotherapy in nuclear medicine

    International Nuclear Information System (INIS)

    Chiavassa, S.

    2005-12-01

    Current internal dosimetric estimations are based on the M.I.R.D. formalism and used standard mathematical models. These standard models are often far from a given patient morphology and do not allow to perform patient-specific dosimetry. The aim of this study was to develop a personalized dosimetric tool, which takes into account real patient morphology, composition and densities. This tool, called O.E.D.I.P.E., a French acronym of Tool for the Evaluation of Personalized Internal Dose, is a user-friendly graphical interface. O.E.D.I.P.E. allows to create voxel-based patient-specific geometries and associates them with the M.C.N.P.X. Monte Carlo code. Radionuclide distribution and absorbed dose calculation can be performed at the organ and voxel scale. O.E.D.I.P.E. can be used in nuclear medicine for targeted radiotherapy and in radiation protection in case of internal contamination. (author)

  10. Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis.

    Science.gov (United States)

    He, Hongliang; Yuan, Quan; Bie, Jinghua; Wallace, Ryan L; Yannie, Paul J; Wang, Jing; Lancina, Michael G; Zolotarskaya, Olga Yu; Korzun, William; Yang, Hu; Ghosh, Shobha

    2018-03-01

    Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR-/- mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque

  11. Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.

    Science.gov (United States)

    Voutila, Jon; Reebye, Vikash; Roberts, Thomas C; Protopapa, Pantelitsa; Andrikakou, Pinelopi; Blakey, David C; Habib, Robert; Huber, Hans; Saetrom, Pal; Rossi, John J; Habib, Nagy A

    2017-12-06

    Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. 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.

  13. Development and Characterization of a Camelid Single Domain Antibody-Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2.

    Science.gov (United States)

    Tian, Baomin; Wong, Wah Yau; Uger, Marni D; Wisniewski, Pawel; Chao, Heman

    2017-01-01

    Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs). In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21) and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody-urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MS E peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3) pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[( N -maleimidopropionamido)-diethyleneglycol] ester (SM(PEG) 2 ), which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis(maleimido)diethylene glycol

  14. Development and Characterization of a Camelid Single Domain Antibody–Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2

    Directory of Open Access Journals (Sweden)

    Baomin Tian

    2017-08-01

    Full Text Available Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs. In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21 and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody–urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3 pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido-diethyleneglycol] ester (SM(PEG2, which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis

  15. 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

  16. MicroRNA-128 targets myostatin at coding domain sequence to regulate myoblasts in skeletal muscle development.

    Science.gov (United States)

    Shi, Lei; Zhou, Bo; Li, Pinghua; Schinckel, Allan P; Liang, Tingting; Wang, Han; Li, Huizhi; Fu, Lingling; Chu, Qingpo; Huang, Ruihua

    2015-09-01

    MicroRNAs (miRNAs or miRs) play a critical role in skeletal muscle development. In a previous study we observed that miR-128 was highly expressed in skeletal muscle. However, its function in regulating skeletal muscle development is not clear. Our hypothesis was that miR-128 is involved in the regulation of the proliferation and differentiation of skeletal myoblasts. In this study, through bioinformatics analyses, we demonstrate that miR-128 specifically targeted mRNA of myostatin (MSTN), a critical inhibitor of skeletal myogenesis, at coding domain sequence (CDS) region, resulting in down-regulating of myostatin post-transcription. Overexpression of miR-128 inhibited proliferation of mouse C2C12 myoblast cells but promoted myotube formation; whereas knockdown of miR-128 had completely opposite effects. In addition, ectopic miR-128 regulated the expression of myogenic factor 5 (Myf5), myogenin (MyoG), paired box (Pax) 3 and 7. Furthermore, an inverse relationship was found between the expression of miR-128 and MSTN protein expression in vivo and in vitro. Taken together, these results reveal that there is a novel pathway in skeletal muscle development in which miR-128 regulates myostatin at CDS region to inhibit proliferation but promote differentiation of myoblast cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Obesity Prevention from Conception: A Workshop to Guide the Development of a Pan-Canadian Trial Targeting the Gestational Period

    Directory of Open Access Journals (Sweden)

    Kristi B. Adamo

    2014-01-01

    Full Text Available This report summarizes a meeting, Obesity Prevention from Conception , held in Ottawa in 2012. This planning workshop was funded by the Canadian Institutes of Health Research (CIHR to bring together researchers with expertise in the area of maternal obesity (OB and weight gain in pregnancy and pregnancy-related disease to attend a one-day workshop and symposium to discuss the development of a cross-Canada lifestyle intervention trial for targeting pregnant women. This future intervention will aim to reduce downstream OB in children through encouraging appropriate weight gain during the mother's pregnancy. The workshop served to (i inform the development of a lifestyle intervention for women with a high pre-pregnancy body mass index (BMI, (ii identify site investigators across Canada, and (iii guide the development of a grant proposal focusing on the health of mom and baby. A brief summary of the presentations as well as the focus groups is presented for use in planning future research.

  18. Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.

    Science.gov (United States)

    Toyama, Satoshi; Shimoyama, Naohito; Szeto, Hazel H; Schiller, Peter W; Shimoyama, Megumi

    2018-04-18

    Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

  19. 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)

  20. Development of fast scattering model of complex shape target for seminatural tests of onboard proximity radars in real time mode

    Directory of Open Access Journals (Sweden)

    Likhoedenko Andrei K.

    2016-01-01

    Full Text Available Problems of creation of models of real time of complex shape targets on the basis of use of their polygonal models are considered. Formulas for radar cross section of multipoint model of target and power of input signal of onboard radar are described. Technique of semi-natural tests of onboard radar detector on the base of multipoint model of target is proposed. Results of digital simulation of input signals of the onboard radar detector of the target from the aerodynamic target on the basis of their multipoint models are given.

  1. Development of a method for the estimation of the useful life of the target in one helical; Desarrollo de un metodo para la estimacion de la vida util del target en una unidad de tomoterapia helicoidal

    Energy Technology Data Exchange (ETDEWEB)

    Delgado Aparicio, J. M.; Garcia Repiso, S.; Martin Rincon, C.; Perez Alvarez, M. E.; Verde Velasco, J. M.; Ramos Pacho, J. A.; Saez Beltran, M.; Gomez Gonzalez, N.; Cons Perez, N.; Sena Espinel, E. de

    2013-07-01

    The objective of this study is to evaluate the effect of this degradation and develop a method for the estimation of the duration of the life of the target independently used internally by the technical service. This can serve to plan the date of intervention when it comes to replace this component. (Author)

  2. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development.

    Directory of Open Access Journals (Sweden)

    Sushma Grellscheid

    2011-12-01

    Full Text Available Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2β (Sfrs10 is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2β is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2β binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl; Nestin-Cre(tg/+. This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2β regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2β binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2β protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2β. Versions of Tra2β lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2β protein.

  3. 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.

  4. Developing a multi-pollutant conceptual framework for the selection and targeting of interventions in water industry catchment management schemes.

    Science.gov (United States)

    Bloodworth, J W; Holman, I P; Burgess, P J; Gillman, S; Frogbrook, Z; Brown, P

    2015-09-15

    In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Charu Sharma

    2015-01-01

    Full Text Available The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2 which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

  6. Inhibition of protein synthesis and malaria parasite development by drug targeting of methionyl-tRNA synthetases.

    Science.gov (United States)

    Hussain, Tahir; Yogavel, Manickam; Sharma, Amit

    2015-04-01

    Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS(cyt) and PfMRS(api). Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS(cyt)) or proteobacteria/primitive bacteria (PfMRS(api)). We show that PfMRS(cyt) localizes in parasite cytoplasm, while PfMRS(api) localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with (35)S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  7. An interactive, bilingual, culturally targeted website about living kidney donation and transplantation for hispanics: development and formative evaluation.

    Science.gov (United States)

    Gordon, Elisa J; Feinglass, Joe; Carney, Paula; Ramirez, Daney; Olivero, Maria; O'Connor, Kate; MacLean, Jessica; Brucker, James; Caicedo, Juan Carlos

    2015-04-20

    As the kidney shortage continues to grow, patients on the waitlist are increasingly turning to live kidney donors for transplantation. Despite having a disproportionately higher prevalence of end-stage kidney disease (ESKD), fewer waitlisted Hispanic patients received living donor kidney transplants (LDKTs) than non-Hispanic whites in 2014. Although lack of knowledge has been identified as a barrier to living kidney donation (LKD) among Hispanics, little is known about information needs, and few bilingual educational resources provide transplant-related information addressing Hispanics' specific concerns. This paper describes the process of developing a bilingual website targeted to the Hispanic community. The website was designed to increase knowledge about LKD among Hispanic patients with ESKD, their families, and the public, and was inspired by educational sessions targeted to Hispanic transplant patients provided by Northwestern University's Hispanic Kidney Transplant Program. Northwestern faculty partnered with the National Kidney Foundation of Illinois for expertise in ESKD and Hispanic community partners across the Chicago area. We established a Community Advisory Board (CAB) of 10 Chicago-area Hispanic community leaders to provide insight into cultural concerns and community and patients' needs. Website content development was informed by 9 focus groups with 76 adult Hispanic kidney transplant recipients, living kidney donors, dialysis patients, and the general Hispanic public. The website development effort was guided by community input on images, telenovela scripts, and messages. After initial development, formal usability testing was conducted with 18 adult Hispanic kidney transplant recipients, dialysis patients, and living kidney donors to identify ways to improve navigability, design, content, comprehension, and cultural sensitivity. Usability testing revealed consistently high ratings as "easy to navigate", "informative", and "culturally appropriate

  8. Development of an electrochemical 90Sr-90Y generator for separation of 90Y suitable for targeted therapy

    International Nuclear Information System (INIS)

    Chakravarty, Rubel; Pandey, Usha; Manolkar, Remani B.; Dash, Ashutosh; Venkatesh, Meera; Pillai, M.R. Ambikalmajan

    2008-01-01

    90 Y of high specific activity and very high radionuclidic purity (>99.998%) is essential for targeted therapy. Since the current methods used for the preparation of 90 Y from 90 Sr are not adaptable for use in a central/hospital radiopharmacy, a simple 90 Sr- 90 Y generator system based on electrochemical separation technique was developed. Methods: Two-cycle electrolysis procedure was developed for separation of 90 Y from 90 Sr in nitrate solution. The first electrolysis was performed for 90 min in 90 Sr(NO 3 ) 2 feed solution at pH 2-3 at a potential of -2.5V with 100-200 mA current using platinum electrodes. The second electrolysis was performed for 45 min in 3 mM HNO 3 at a potential of -2.5V with 100 mA current. In this step, the cathode from the first electrolysis containing 90 Y was used as anode along with a fresh circular platinum electrode as cathode. The 90 Y deposited on the circular cathode after the second electrolysis was dissolved in acetate buffer to obtain 90 Y acetate, suitable for radiolabeling. Results: >96% recovery of 90 Y could be achieved in each cycle, with an overall decay corrected yield of >90%. The recovered 90 Y had high radionuclidic purity with barely 30.2±15.2 kBq (817±411 nCi) of 90 Sr per 37 GBq (1 Ci) of 90 Y (0.817±0.411 ppm). Consistent and repeated separation could be demonstrated using up to 1.85 GBq (50 mCi) of 90 Sr. The generator was named 'Kamadhenu,' the eternally milk-yielding Indian mythological cow. Conclusions: A technique suitable for adaptation at central radiopharmacies for obtaining therapeutic quantities of pure 90 Y has been developed

  9. Development of high pressure deuterium gas targets for the generation of intense mono-energetic fast neutron beams

    International Nuclear Information System (INIS)

    Guzek, J.; Richardson, K.; Franklyn, C.B.; Waites, A.; McMurray, W.R.; Watterson, J.I.W.; Tapper, U.A.S.

    1999-01-01

    Two different technical solutions to the problem of generation of mono-energetic fast neutron beams on the gaseous targets are presented here. A simple and cost-effective design of a cooled windowed gas target system is described in the first part of this paper. It utilises a thin metallic foil window and circulating deuterium gas cooled down to 100 K. The ultimate beam handling capability of such target is determined by the properties of the window. Reliable performance of this gas target system was achieved at 1 bar of deuterium gas, when exposed to a 45 μA beam of 5 MeV deuterons, for periods in excess of 6 h. Cooling of the target gas resulted in increased fast neutron output and improved neutron to gamma-ray ratio. The second part of this paper discusses the design of a high pressure, windowless gas target for use with pulsed, low duty cycle accelerators. A rotating seal concept was applied to reduce the gas load in a differentially pumped system. This allows operation at 1.23 bar of deuterium gas pressure in the gas cell region. Such a gas target system is free from the limitations of the windowed target but special attention has to be paid to the heat dissipation capability of the beam dump, due to the use of a thin target. The rotating seal concept is particularly suitable for use with accelerators such as radio-frequency quadrupole (RFQ) linacs that operate with a very high peak current at low duty cycle. The performance of both target systems was comprehensively characterized using the time-of-flight (TOF) technique. This demonstrated that very good quality mono-energetic fast neutron beams were produced with the slow neutron and gamma-ray component below 10% of the total target output

  10. 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.

  11. 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)

  12. Solar Europe industry initiative: research technology development and demonstration in support of 2020 and long-term targets

    NARCIS (Netherlands)

    Sinke, W.C.; Fraile Montoro, D.; Despotou, E.; Nowak, S.; Perezagua, E.

    2010-01-01

    The European Union has set an ambitious target for the implementation of renewable energy technologies by 2020, i.e. a share of 20% of the total energy consumption. In support of these targets the Strategic Energy Technology (SET) Plan has been initiated by the European Commission. One of the key

  13. Design, development and characterization of multi-functionalized gold nanoparticles for biodetection and targeted boron delivery in BNCT applications.

    NARCIS (Netherlands)

    Mandal, S.; Bakeine, G.J.; Krol, S.; Ferrari, C.; Clerici, A.M.; Zonta, C.; Cansolino, L.; Ballarini, F.; Bortolussi, S.; Stella, S.; Protti, N.; Bruschi, P.; Altieri, S.

    2011-01-01

    The aim of this study is to optimize targeted boron delivery to cancer cells and its tracking down to the cellular level. To this end, we describe the design and synthesis of novel nanovectors that double as targeted boron delivery agents and fluorescent imaging probes. Gold nanoparticles were

  14. Factors specifying the development of synapse number in the rat dentate gyrus: effects of partial target loss

    International Nuclear Information System (INIS)

    Lewis, E.R.; Cotman, C.W.

    1980-01-01

    The development of the dentate gyrus has been studied under conditions of partial reduction of granule cell number. Neonatal rats were subjected to X-irradiation, a procedure which reduces the number of granule cells to 20% of control values. In X-irradiated rats, quantitative analyses were performed on cells in the entorhinal cortex which give rise to the perforant path projection to the dentate granule cells, and on the remaining, undamaged dentate granule cells. These residual cells were examined morphologically for possible hyperdevelopment in comparison to granule cells from control animals. Granule cells in X-irradiated animals were similar to granule cells in control animals with respect to dendritic structure and synaptic density. The number of neurons in both the medical and lateral entorhinal cortices in X-irradiated animals appeared normal until day 12, at which time a selective reduction in cell numbers became apparent. By day 30, 25-55% of the cells of origin of the perforant path were absent in X-irradiated animals. It is hypothesized that these cells are subject to retrograde transynaptic degeneration as a result of target removal. Further, it appears that granule cells play an important role in determining the density of their innervation. (Auth.)

  15. Feasibility and preliminary effects of an intervention targeting schema development for caregivers of newly admitted hospice patients.

    Science.gov (United States)

    Lindstrom, Kathryn B; Mazurek Melnyk, Bernadette

    2013-06-01

    The transition to hospice care is a stressful experience for caregivers, who report high anxiety, unpreparedness, and lack of confidence. These sequelae are likely explained by the lack of an accurate cognitive schema, not knowing what to expect or how to help their loved one. Few interventions exist for this population and most do not measure preparedness, confidence, and anxiety using a schema building a conceptual framework for a new experience. The purpose of this study was to test the feasibility and preliminary effects of an intervention program, Education and Skill building Intervention for Caregivers of Hospice patients (ESI-CH), using an innovative conceptual design that targets cognitive schema development and basic skill building for caregivers of loved ones newly admitted to hospice services. A pre-experimental one-group pre- and post-test study design was used. Eighteen caregivers caring for loved ones in their homes were recruited and twelve completed the pilot study. Depression, anxiety, activity restriction, preparedness, and beliefs/confidence were measured. Caregivers reported increased preparedness, more helpful beliefs, and more confidence about their ability to care for their loved one. Preliminary trends suggested decreased anxiety levels for the intervention group. Caregivers who completed the intervention program rated the program very good or excellent, thought the information was helpful and timely, and would recommend it to friends. Results show promise that the ESI-CH program may assist as an evidence-based program to support caregivers in their role as a caregiver to a newly admitted hospice patient.

  16. Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

    Science.gov (United States)

    Zhu, Yong-Chuan; Li, Dan; Wang, Lu; Lu, Bin; Zheng, Jing; Zhao, Shi-Lin; Zeng, Rong; Xiong, Zhi-Qi

    2013-01-01

    The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, down-regulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5–PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation-dependent CDKL5–PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders. PMID:23671101

  17. Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development.

    Science.gov (United States)

    Zhu, Yong-Chuan; Li, Dan; Wang, Lu; Lu, Bin; Zheng, Jing; Zhao, Shi-Lin; Zeng, Rong; Xiong, Zhi-Qi

    2013-05-28

    The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, down-regulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation-dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders.

  18. Development of EST Intron-Targeting SNP Markers for Panax ginseng and Their Application to Cultivar Authentication.

    Science.gov (United States)

    Wang, Hongtao; Li, Guisheng; Kwon, Woo-Saeng; Yang, Deok-Chun

    2016-06-04

    Panax ginseng is one of the most valuable medicinal plants in the Orient. The low level of genetic variation has limited the application of molecular markers for cultivar authentication and marker-assisted selection in cultivated ginseng. To exploit DNA polymorphism within ginseng cultivars, ginseng expressed sequence tags (ESTs) were searched against the potential intron polymorphism (PIP) database to predict the positions of introns. Intron-flanking primers were then designed in conserved exon regions and used to amplify across the more variable introns. Sequencing results showed that single nucleotide polymorphisms (SNPs), as well as indels, were detected in four EST-derived introns, and SNP markers specific to "Gopoong" and "K-1" were first reported in this study. Based on cultivar-specific SNP sites, allele-specific polymerase chain reaction (PCR) was conducted and proved to be effective for the authentication of ginseng cultivars. Additionally, the combination of a simple NaOH-Tris DNA isolation method and real-time allele-specific PCR assay enabled the high throughput selection of cultivars from ginseng fields. The established real-time allele-specific PCR assay should be applied to molecular authentication and marker assisted selection of P. ginseng cultivars, and the EST intron-targeting strategy will provide a potential approach for marker development in species without whole genomic DNA sequence information.

  19. Developments in the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes: epidemiology, etiology, genetics, and targeted therapies

    Directory of Open Access Journals (Sweden)

    Raza A

    2014-07-01

    Full Text Available Azra Raza, Nicholas Iverson, Abdullah M AliThe MDS Center, Columbia University, New York, NY, USAAbstract: Myelodysplastic syndromes are malignant hematopoietic stem cell disorders that present with variable cytopenias and predominantly affect the elderly. Treatment options are limited, with allogeneic transplant being the only potentially curative strategy. Recent mutational profiling studies have led to cataloguing of driver and passenger mutations most commonly affecting the epigenetic regulators and genes involved in RNA splicing. Despite improved understanding of the disease biology, these emerging molecular insights have not led to identification of novel therapeutic strategies. Although several drugs approved in the last decade improve the cytopenias, the relief is temporary, most likely due to the sequential activation of clones. Future advances depend upon identification of signaling pathways in dominant clones and targeting these with agents that might be known but need to be matched to suit the needs of individual patients in a longitudinal, dynamic fashion. Myelodysplastic syndromes are ideally suited for the development of such personalized medicine.Keywords: cancer, epigenetics, iron, MDS, myelodysplasia, splicing

  20. Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.

    Science.gov (United States)

    Tsume, Yasuhiro; Drelich, Adam J; Smith, David E; Amidon, Gordon L

    2017-08-10

    One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

  1. 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.

  2. 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.

  3. A Robust Profitability Assessment Tool for Targeting Agricultural Investments in Developing Countries: Modeling Spatial Heterogeneity and Uncertainty

    Science.gov (United States)

    Quinn, J. D.; Zeng, Z.; Shoemaker, C. A.; Woodard, J.

    2014-12-01

    In sub-Saharan Africa, where the majority of the population earns their living from agriculture, government expenditures in many countries are being re-directed to the sector to increase productivity and decrease poverty. However, many of these investments are seeing low returns because they are poorly targeted. A geographic tool that accounts for spatial heterogeneity and temporal variability in the factors of production would allow governments and donors to optimize their investments by directing them to farmers for whom they are most profitable. One application for which this is particularly relevant is fertilizer recommendations. It is well-known that soil fertility in much of sub-Saharan Africa is declining due to insufficient nutrient inputs to replenish those lost through harvest. Since fertilizer application rates in sub-Saharan Africa are several times smaller than in other developing countries, it is often assumed that African farmers are under-applying fertilizer. However, this assumption ignores the risk farmers face in choosing whether or how much fertilizer to apply. Simply calculating the benefit/cost ratio of applying a given level of fertilizer in a particular year over a large, aggregated region (as is often done) overlooks the variability in yield response seen at different sites within the region, and at the same site from year to year. Using Ethiopia as an example, we are developing a 1 km resolution fertilizer distribution tool that provides pre-season fertilizer recommendations throughout the agricultural regions of the country, conditional on seasonal climate forecasts. By accounting for spatial heterogeneity in soil, climate, market and travel conditions, as well as uncertainty in climate and output prices at the time a farmer must purchase fertilizer, this stochastic optimization tool gives better recommendations to governments, fertilizer companies, and aid organizations looking to optimize the welfare benefits achieved by their

  4. Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Teresa D. Elo

    2010-11-01

    Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

  5. Precision-cut kidney slices (PCKS to study development of renal fibrosis and efficacy of drug targeting ex vivo

    Directory of Open Access Journals (Sweden)

    Fariba Poosti

    2015-10-01

    Full Text Available Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti-fibrotic compounds. Precision-cut slices (200-300 μm thickness were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFβ1 (5 ng/ml for 48 h in the presence or absence of the anti-fibrotic cytokine IFNγ (1 µg/ml or an IFNγ conjugate targeted to PDGFRβ (PPB-PEG-IFNγ. Following culture, tissue viability (ATP-content and expression of α-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFβ1 and IFNγ on viability were observed. TGFβ1 markedly increased α-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNγ and PPB-PEG-IFNγ significantly reduced TGFβ1-induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic human kidney tissue.

  6. Monte-Carlo model development for evaluation of current clinical target volume definition for heterogeneous and hypoxic glioblastoma.

    Science.gov (United States)

    Moghaddasi, L; Bezak, E; Harriss-Phillips, W

    2016-05-07

    Clinical target volume (CTV) determination may be complex and subjective. In this work a microscopic-scale tumour model was developed to evaluate current CTV practices in glioblastoma multiforme (GBM) external radiotherapy. Previously, a Geant4 cell-based dosimetry model was developed to calculate the dose deposited in individual GBM cells. Microscopic extension probability (MEP) models were then developed using Matlab-2012a. The results of the cell-based dosimetry model and MEP models were combined to calculate survival fractions (SF) for CTV margins of 2.0 and 2.5 cm. In the current work, oxygenation and heterogeneous radiosensitivity profiles were incorporated into the GBM model. The genetic heterogeneity was modelled using a range of α/β values (linear-quadratic model parameters) associated with different GBM cell lines. These values were distributed among the cells randomly, taken from a Gaussian-weighted sample of α/β values. Cellular oxygen pressure was distributed randomly taken from a sample weighted to profiles obtained from literature. Three types of GBM models were analysed: homogeneous-normoxic, heterogeneous-normoxic, and heterogeneous-hypoxic. The SF in different regions of the tumour model and the effect of the CTV margin extension from 2.0-2.5 cm on SFs were investigated for three MEP models. The SF within the beam was increased by up to three and two orders of magnitude following incorporation of heterogeneous radiosensitivities and hypoxia, respectively, in the GBM model. However, the total SF was shown to be overdominated by the presence of tumour cells in the penumbra region and to a lesser extent by genetic heterogeneity and hypoxia. CTV extension by 0.5 cm reduced the SF by a maximum of 78.6  ±  3.3%, 78.5  ±  3.3%, and 77.7  ±  3.1% for homogeneous and heterogeneous-normoxic, and heterogeneous hypoxic GBMs, respectively. Monte-Carlo model was developed to quantitatively evaluate SF for genetically

  7. 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

  8. Developing a commercial production process for 500,000 targets per day: A key challenge for inertial fusion energy

    International Nuclear Information System (INIS)

    Goodin, D.T.; Alexander, N.B.; Besenbruch, G.E.; Bozek, A.S.; Brown, L.C.; Flint, G.W.; Kilkenny, J.D.; McQuillan, B.W.; Nikroo, A.; Paguio, R.R.; Petzoldt, R.W.; Schroen, D.G.; Sheliak, J.D.; Vermillion, B.A.; Carlson, L.C.; Goodman, P.; Maksaereekul, W.; Raffray, R.; Spalding, J.; Tillack, M.S.

    2006-01-01

    As is true for current-day commercial power plants, a reliable and economic fuel supply is essential for the viability of future Inertial Fusion Energy (IFE) [Energy From Inertial Fusion, edited by W. J. Hogan (International Atomic Energy Agency, Vienna, 1995)] power plants. While IFE power plants will utilize deuterium-tritium (DT) bred in-house as the fusion fuel, the 'target' is the vehicle by which the fuel is delivered to the reaction chamber. Thus the cost of the target becomes a critical issue in regard to fuel cost. Typically six targets per second, or about 500 000/day are required for a nominal 1000 MW(e) power plant. The electricity value within a typical target is about $3, allocating 10% for fuel cost gives only 30 cents per target as-delivered to the chamber center. Complicating this economic goal, the target supply has many significant technical challenge - fabricating the precision fuel-containing capsule, filling it with DT, cooling it to cryogenic temperatures, layering the DT into a uniform layer, characterizing the finished product, accelerating it to high velocity for injection into the chamber, and tracking the target to steer the driver beams to meet it with micron-precision at the chamber center

  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. 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.

  11. 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.

  12. Current status of the 124Xe target system development for the high purity 123I production in KCCH

    International Nuclear Information System (INIS)

    Chun, Kwon Soo

    2002-01-01

    This report describes the 124 Xe gaseous target system employed for 123 I production at the Korea Cancer Center Hospital. Currently the control system is manual and will be computerized after the system parameters have been established

  13. Development and application of a channelized Hotelling observer for DBT optimization on structured background test images with mass simulating targets

    Science.gov (United States)

    Petrov, Dimitar; Michielsen, Koen; Cockmartin, Lesley; Zhang, Gouzhi; Young, Kenneth; Marshall, Nicholas; Bosmans, Hilde

    2016-03-01

    Digital breast tomosynthesis (DBT) is a 3D mammography technique that promises better visualization of low contrast lesions than conventional 2D mammography. A wide range of parameters influence the diagnostic information in DBT images and a systematic means of DBT system optimization is needed. The gold standard for image quality assessment is to perform a human observer experiment with experienced readers. Using human observers for optimization is time consuming and not feasible for the large parameter space of DBT. Our goal was to develop a model observer (MO) that can predict human reading performance for standard detection tasks of target objects within a structured phantom and subsequently apply it in a first comparative study. The phantom consists of an acrylic semi-cylindrical container with acrylic spheres of different sizes and the remaining space filled with water. Three types of lesions were included: 3D printed spiculated and non-spiculated mass lesions along with calcification groups. The images of the two mass lesion types were reconstructed with 3 different reconstruction methods (FBP, FBP with SRSAR, MLTRpr) and read by human readers. A Channelized Hotelling model observer was created for the non-spiculated lesion detection task using five Laguerre-Gauss channels, tuned for better performance. For the non-spiculated mass lesions a linear relation between the MO and human observer results was found, with correlation coefficients of 0.956 for standard FBP, 0.998 for FBP with SRSAR and 0.940 for MLTRpr. Both the MO and human observer percentage correct results for the spiculated masses were close to 100%, and showed no difference from each other for every reconstruction algorithm.

  14. Development of effective tumor immunotherapy using a novel dendritic cell-targeting Toll-like receptor ligand.

    Directory of Open Access Journals (Sweden)

    Nadeeka H De Silva

    Full Text Available Although dendritic cell (DC-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers. In murine experiments, most and significant inhibition of tumor growth and extended survival was observed in the group treated with the combination of h11c-activated DCs in combination with interferon-gamma and a cyclooxygenase2 inhibitor. Both monocytic and granulocytic myeloid-derived suppressor cells were significantly reduced by the combined treatment. Following the successful results in mice, the combined treatment was examined against canine cancers, which spontaneously generated like as those in human. The combined treatment elicited significant clinical responses against a nonepithelial malignant tumor and a malignant fibrous histiocytoma. The treatment was also successful against a bone-metastasis of squamous cell carcinoma. In the successful cases, the marked increase of tumor-responding T cells and decrease of myeloid-derived suppressor cells and regulatory T cells was observed in their peripheral blood. Although the combined treatment permitted the growth of lung cancer of renal carcinoma-metastasis, the marked elevated and long-term maintaining of the tumor-responding T cells was observed in the patient dog. Overall, the combined treatment gave rise to emphatic amelioration in DC-based cancer therapy.

  15. Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization.

    Directory of Open Access Journals (Sweden)

    Mohun Ramratnam

    Full Text Available Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+ recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i, and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/- mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to β-adrenergic activation.

  16. Targeting apoptosis signalling kinase-1 (ASK-1 does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

    Directory of Open Access Journals (Sweden)

    Victoria L Newton

    Full Text Available Apoptosis signal-regulating kinase-1 (ASK1 is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.

  17. Development and validation of a simple model for cellular and cell cluster dosimetry with practical application in targeted radionuclide therapy

    International Nuclear Information System (INIS)

    Bardies, M.; Myers, M.J.

    1992-01-01

    The authors have developed an analytical technique for calculating the mean absorbed dose to the cell nucleus from a variety of spatial distributions of cells and activities and a wide range of emitted energies and radionuclides. The dose to the nucleus has been calculated using this method from activity distributed (1) on the cell surface (2) throughout the cytoplasm (3) throughout a cluster of cells (micrometastasis) and (4) on the surface of the cluster of cells. The derived absorption factors have been based on the latest point kernels of Berger and have been validated against published estimates. They show good agreement and the model has the advantage of being easily adapted for revisions and extensions of available low energy data. Data sets may be derived with the absorbed fractions or the absorbed dose per emission as a function of the radial extent of the activity, and either the individual energies of the emissions or the totality of the emissions from a particular radio-nuclide. The practical applications of the model have included: (a) calculation of the absorbed dose to radioimmuno-targeted micrometastasis in the peritoneum; (b) calculations of doses to cells labelled on the surface with some novel emitters such as 67 Cu, 177 Lu, 153 Sm, 111 Ag, 186 Re, 188 Re as well as 131 I, 125 I and 90 Y; (c) comparison of doses to the cell nucleus from MIBG labelled with 125 I and 131 I and distributed in the cytoplasm of the cell; and (d) estimates of the absorbed dose to the cell nucleus from alpha emitters distributed on the surface of the cell

  18. Development of fission Mo-99 production technology - A nuclear feasibility study on UN target for Mo-99 production in HANARO

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Myung Hyun; Kim, Woo Sik [Kyunghee University, Seoul (Korea)

    2000-03-01

    Nuclear target design satisfying all the constraints for fission moly production in HANARO was proposed in this project. The 'MCNP-ORIGEN' code system which was previously proposed for a design tool, was evaluated by the comparison with through the 'MCNP-Analytic Eq.' system. A characteristics of each chemical processing step were analysed and material balance was set up to evaluate the overall yield ratio of Mo-99 recovery. A parametric study was done for the optimum HEU target design. Tested parameters were target thickness, recoil-loss rate to the fuel thickness, target radius, cladding materials, thickness of irradiation guide tube, and barrier materials. Optimized HEU target design was proposed which satisfying the constraints and having high production yield. For a LEU target design using 19.7 w/o UN powder fuel, a parametric study was also done for the optimization of fuel thickness, powder packing density, mixture material volume ratio. 24 refs., 35 figs., 57 tabs. (Author)

  19. 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

  20. The Impact Of The Definition Of Target Market On The Design Process In New Product Development: The Case Of New Ford Cargo

    OpenAIRE

    Tokatlı, Akgün

    2004-01-01

    The economic success of manufacturing companies depends on their ability to identify the needs of the customers and to develop new products to meet those needs rapidly. Achieving this goal is not solely a marketing problem, nor it is solely a design or a manufacturing problem; it is in fact a product development problem involving all of these functions. The subject of this study is to analyse the concept of target market in the product development process and its interaction with product desi...

  1. 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...

  2. 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

  3. Towards prostate cancer gene therapy: Development of a chlorotoxin-targeted nanovector for toxic (melittin) gene delivery.

    Science.gov (United States)

    Tarokh, Zahra; Naderi-Manesh, Hossein; Nazari, Mahboobeh

    2017-03-01

    Prostate cancer is the second leading cause of death due to cancer in men. Owing to shortcomings in the current treatments, other therapies are being considered. Toxic gene delivery is one of the most effective methods for cancer therapy. Cationic polymers are able to form stable nanoparticles via interaction with nucleic acids electrostatically. Branched polyethylenimine that contains amine groups has notable buffering capacity and the ability to escape from endosome through the proton sponge effect. However, the cytotoxicity of this polymer is high, and modification is one of the applicable strategies to overcome this problem. In this study, PEI was targeted with chlorotoxin (CTX) via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) cross-linker. CTX can bind specifically to matrix metalloproteinase-2 that is overexpressed in certain cancers. Melittin as the major component of bee venom has been reported to have anti-cancer activity. This was thus selected to deliver to PC3 cell line. Flow cytometry analysis revealed that transfection efficiency of targeted nanoparticles is significantly higher compared to non-targeted nanoparticles. Targeted nanoparticles carrying the melittin gene also decreased cell viability of PC3 cells significantly while no toxic effects were observed on NIH3T3 cell line. Therefore, CTX-targeted nanoparticles carrying the melittin gene could serve as an appropriate gene delivery system for prostate and other MMP-2 positive cancer cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand.

    Science.gov (United States)

    Barkey, Natalie M; Tafreshi, Narges K; Josan, Jatinder S; De Silva, Channa R; Sill, Kevin N; Hruby, Victor J; Gillies, Robert J; Morse, David L; Vagner, Josef

    2011-12-08

    The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.

  5. Design, development and characterization of multi-functionalized gold nanoparticles for biodetection and targeted boron delivery in BNCT applications

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Subhra [Department of Tumor Immunology, Radboud University Nijmegen Medical Centre (Netherlands); Bakeine, Gerald J., E-mail: Jamesbakeine1@yahoo.com [Department of Internal Medicine and Therapeutics-Section of Clinical Toxicology, University of Pavia, Piazza Botta 10, 27100 Pavia (Italy); Krol, Silke [Institute of Neurology, Fondazione IRCCS Carlo Besta, Milan (Italy); Ferrari, Cinzia; Clerici, Anna M.; Zonta, Cecilia; Cansolino, Laura [Department of Surgery, Laboratory of Experimental Surgery, University of Pavia (Italy); Ballarini, Francesca [Department of Nuclear and Theoretical Physics, University of Pavia (Italy); Bortolussi, Silva [Department of Nuclear and Theoretical Physics, University of Pavia (Italy)] [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy); Stella, Subrina; Protti, Nicoletta [Department of Nuclear and Theoretical Physics, University of Pavia (Italy); Bruschi, Piero [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy); Altieri, Saverio [Department of Nuclear and Theoretical Physics, University of Pavia (Italy)] [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy)

    2011-12-15

    The aim of this study is to optimize targeted boron delivery to cancer cells and its tracking down to the cellular level. To this end, we describe the design and synthesis of novel nanovectors that double as targeted boron delivery agents and fluorescent imaging probes. Gold nanoparticles were coated with multilayers of polyelectrolytes functionalized with the fluorescent dye (FITC), boronophenylalanine and folic acid. In vitro confocal fluorescence microscopy demonstrated significant uptake of the nanoparticles in cancer cells that are known to overexpress folate receptors. - Highlights: Black-Right-Pointing-Pointer Synthesis of multi-labeled gold nanoparticles for selective boron delivery to tumor cells. Black-Right-Pointing-Pointer Tumor selectivity is achieved through folic acid receptor targeting. Black-Right-Pointing-Pointer Optical fluorescent microscopy allows tracking of cellular uptake of the gold nanoparticle. Black-Right-Pointing-Pointer In vitro tests demonstrate selective nanoparticle up in folate receptor positive tumor cells.

  6. Development of a new anti-cancer agent for targeted radionuclide therapy: β- radiolabeled RAFT-RGD

    International Nuclear Information System (INIS)

    Petitprin, A.

    2013-01-01

    β-emitters radiolabeled RAFT-RGD as new agents for internal targeted radiotherapy. The αvβ3 integrin is known to play an important role in tumor-induced angiogenesis, tumor proliferation, survival and metastasis. Because of its overexpression on neo-endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins, αvβ3 integrin is an attractive molecular target for diagnosis and therapy of the rapidly growing and metastatic tumors. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin αvβ3 in vitro and in vivo. RAFT-RGD has been used for tumor imaging and drug targeting. This study is the first to evaluate the therapeutic potential of the β-emitters radiolabeled tetrameric RGD peptide RAFT-RGD in a Nude mouse model of αvβ3 -expressing tumors. An injection of 37 MBq of 90 Y-RAFT-RGD or 177 Lu-RAFT-RGD in mice with αvβ3 -positive tumors caused a significant growth delay as compared with mice treated with 37 MBq of 90 Y-RAFT-RAD or 177 Lu-RAFT-RAD or untreated mice. In comparison, an injection of 30 MBq of 90 Y-RAFT-RGD had no efficacy for the treatment of αvβ3 -negative tumors. 90 Y-RAFT-RGD and 177 Lu-RAFT-RGD are potent αvβ3 -expressing tumor targeting agents for internal targeted radiotherapy. (author)

  7. Beyond CD19: Opportunities for future development of targeted immunotherapy in pediatric relapsed-refractory acute leukemia

    Directory of Open Access Journals (Sweden)

    Haneen eShalabi

    2015-10-01

    Full Text Available Chimeric antigen receptor (CAR T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell ALL, this mode of therapy has become a very attractive option for these patients with high risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia, and potential therapeutic targets for additional high risk populations, including T cell ALL, AML, and infant ALL.

  8. The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development.

    Directory of Open Access Journals (Sweden)

    R van der Geize

    2011-08-01

    Full Text Available Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551, ipdB (rv3552, fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD and 3aα-H-4α(3'-propionic acid-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP. Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections.

  9. CERN: Fixed target targets

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1993-03-15

    Full text: While the immediate priority of CERN's research programme is to exploit to the full the world's largest accelerator, the LEP electron-positron collider and its concomitant LEP200 energy upgrade (January, page 1), CERN is also mindful of its long tradition of diversified research. Away from LEP and preparations for the LHC proton-proton collider to be built above LEP in the same 27-kilometre tunnel, CERN is also preparing for a new generation of heavy ion experiments using a new source, providing heavier ions (April 1992, page 8), with first physics expected next year. CERN's smallest accelerator, the LEAR Low Energy Antiproton Ring continues to cover a wide range of research topics, and saw a record number of hours of operation in 1992. The new ISOLDE on-line isotope separator was inaugurated last year (July, page 5) and physics is already underway. The remaining effort concentrates around fixed target experiments at the SPS synchrotron, which formed the main thrust of CERN's research during the late 1970s. With the SPS and LEAR now approaching middle age, their research future was extensively studied last year. Broadly, a vigorous SPS programme looks assured until at least the end of 1995. Decisions for the longer term future of the West Experimental Area of the SPS will have to take into account the heavy demand for test beams from work towards experiments at big colliders, both at CERN and elsewhere. The North Experimental Area is the scene of larger experiments with longer lead times. Several more years of LEAR exploitation are already in the pipeline, but for the longer term, the ambitious Superlear project for a superconducting ring (January 1992, page 7) did not catch on. Neutrino physics has a long tradition at CERN, and this continues with the preparations for two major projects, the Chorus and Nomad experiments (November 1991, page 7), to start next year in the West Area. Delicate neutrino oscillation effects could become visible for the first

  10. An Analysis of How Building a Collaborative Community of Professional Social Studies Teachers through Targeted Ambient Professional Development Impacts Social Studies Classroom Practices

    Science.gov (United States)

    Thomas-Brown, Karen; Shaffer, LaShorage; Werner, Sharon

    2016-01-01

    This study examined the impact of a yearlong ambient professional development (PD) program-The Wayne Schools Global Geography Project (WSGG-project)-that focused on improving teacher quality through PD and classroom observations for in-service social studies teachers. The project targeted middle and high school social studies teachers and used…

  11. 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.)

  12. Development and validation of a 48-target analytical method for high-throughput monitoring of genetically modified organisms.

    Science.gov (United States)

    Li, Xiaofei; Wu, Yuhua; Li, Jun; Li, Yunjing; Long, Likun; Li, Feiwu; Wu, Gang

    2015-01-05

    The rapid increase in the number of genetically modified (GM) varieties has led to a demand for high-throughput methods to detect genetically modified organisms (GMOs). We describe a new dynamic array-based high throughput method to simultaneously detect 48 targets in 48 samples on a Fludigm system. The test targets included species-specific genes, common screening elements, most of the Chinese-approved GM events, and several unapproved events. The 48 TaqMan assays successfully amplified products from both single-event samples and complex samples with a GMO DNA amount of 0.05 ng, and displayed high specificity. To improve the sensitivity of detection, a preamplification step for 48 pooled targets was added to enrich the amount of template before performing dynamic chip assays. This dynamic chip-based method allowed the synchronous high-throughput detection of multiple targets in multiple samples. Thus, it represents an efficient, qualitative method for GMO multi-detection.

  13. Development of a New Positron Emission Tomography Tracer for Targeting Tumor Angiogenesis: Synthesis, Small Animal Imaging, and Radiation Dosimetry

    Directory of Open Access Journals (Sweden)

    David S. Lalush

    2013-05-01

    Full Text Available Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET. To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c. Lewis lung carcinoma (LLC mouse model and conducted tissue distribution, small animal PET/CT imagin